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Randomization | SVS | REFRACTIVE ERROR | Eligible participants enrolled in the study were assigned to receive single-vision spectacles (SVS) only or photobiomodulation (PBM) therapy with SVS at a 1:1 ratio using a randomization sequence produced by Excel. The mechanism used to implement the random allocation sequence was sequentially numbered containers by random envelopes. The enrolled subjects were randomly divided into two groups based on random numbers placed in envelopes. The random numbers were generated by Excel, and the aim was to achieve balanced treatment groups based on their baseline right-eye refractive error, mean age and gender. After all 50 participants were enrolled, the random envelopes were opened to indicate the group assignment. Researchers who were assessing outcomes and performers (for cycloplegic autorefraction and AL measurements) were still blinded to group allocation, but participants and care providers were not blinded after the random envelopes were opened. | PMC9969012 |
Adverse events | dizziness, vision loss, headache | ADVERSE EVENTS, ADVERSE EFFECTS, ADVERSE EVENT, BLINDNESS | Those who received at least one session of therapy were analysed for safety. At each follow-up visit, the participants were asked about the symptoms and signs, including ocular symptoms (such as glare, dazzling, afterimages and flash blindness) and systemic adverse effects (such as headache or dizziness). Other information included the best corrected vision acuity (BCVA), anterior segment with slit-lamps and fundus with OCT. Additionally, each participant was also asked to report the reversible time of vision loss due to glare, dazzling, afterimages or flash blindness. Adverse events were reported based on interviews at the 12-month follow-up visit and were scored according to the common terminology standard for adverse events (CTCAE) version 5.0. | PMC9969012 |
Statistical analysis | SFChT | ACD | The data were analysed by IBM SPSS statistical software 22.0 (IBM Co., Armonk, USA). Continuous variables were analysed with a two-sample independent t test after being evaluated for normality using the Kolmogorov‒Smirnov test. If the data conformed to a normal distribution, the mean ± standard deviation was reported. Fisher’s exact test or the χThe independent samples t test was used to analyse the changes in AL (as the primary endpoint), ACD, SFChT, and CCP at the 3-, 6-, 9-, and 12-month follow-ups as well as changes in cycloplegic refraction at the 12-month follow-up.
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Ethics approval and consent to participate | EYE | All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Bioethics Committee of Ningbo Eye Hospital (No: 2020xjx-012). | PMC9969012 |
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Conference presentation | This paper was presented at the conference of the 26th Congress of Chinese Ophthalmological Society (CCOS) 2022 and the World Ophthalmology Congress (WOC) 2022 online meeting. | PMC9969012 |
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Acknowledgements | EYE | The authors thank the corporation of LONGDA for providing the photobiomodulation therapy devices. In addition, the authors gratefully acknowledge the ophthalmic technicians who helped conduct this trial at Ningbo Eye Hospital. Additionally, the authors appreciate the support from the South East Eye Hospital in Fuzhou. Finally, the authors sincerely thank the families and children who participated in this study. | PMC9969012 |
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Author contributions | L.Z. and K.Q. conceived the research ideas. L.Z. and L.T. performed the experiments. K.Q. analyzed the data and wrote the main manuscript text. Y.L. and T.L. provided the related references and funding. W.B. ran a thorough check on the use of English for scientific writing. All authors contributed to manuscript revision, and each read and approved the revision and final manuscript. All study subjects provided informed consent. | PMC9969012 |
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Funding | Supported by a grant from the Science and Technology Program of Ningbo, China (grant no. 2020Y55) and a grant from Xuzhou Medical University affiliated with Xuzhou Municipal Hospital Development Grant no. XYFM2020028. | PMC9969012 |
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Data availability | Datasets of this study are available from the corresponding authors upon reasonable request. | PMC9969012 |
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Competing interests | The authors declare no competing interests. | PMC9969012 |
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References | PMC9969012 |
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Background
| Active school transport (AST) can increase children’s and adolescents’ physical activity. The proportion of children and adolescents who engage in AST has declined internationally in recent decades. This study examines the prevalence, correlates, and perceived barriers to AST in the city of Leipzig, Germany. | PMC10037850 |
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Methods | The study sample includes 1070 participants, 364 children and 706 adolescents, aged between 6 and 18 years, as well as their parents. The parents as well as adolescents age 10 and above completed questionnaires concerning sociodemographic variables, means of transport/AST and perceived barriers to AST. The distance between home and school was calculated as the network distance from the home to school address using the Dijkstra algorithm. Based on these data, logistic models were fitted in a two-step variable selection process, using AST as the dependent variable. | PMC10037850 |
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Results | Approximately half of the children (59%) and adolescents (51%) engaged in AST. The prevalence of AST exhibited a negative correlation with age (Odds Ratio (OR) = 0.94, 95% confidence interval (CI) = 0.9–0.99, | PMC10037850 |
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Conclusions | Future interventions promoting AST in an urban environment should be guided by the identified perceived barriers. | PMC10037850 |
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Trial registration | LIFE Child has been retrospectively registered with ClinicalTrials.gov (NCT02550236). | PMC10037850 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s12889-023-15464-7. | PMC10037850 |
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Keywords | Open Access funding enabled and organized by Projekt DEAL. | PMC10037850 |
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Introduction | SECONDARY | Physical activity is considered a key factor in the prevention of several chronic conditions [An emerging body of literature discusses factors influencing AST on an individual, cultural, social, physical, and political level. Social-ecological models highlight the role of the environment in behavioral choices [List of questions regarding the means of transport (in the adolescents’ self-report questionnaire)1 We would like to know how you get to school and back home from school on most days!Please describe your path between the door of your home and school in summer and in winterPlease give the most frequent variant, which can also consist of multiple means of transport(e.g. partly walking and partly taking a bus)!Therefore, our study aimed to examine the prevalence, correlates, and perceived barriers to AST in Leipzig, a city in Germany. We analyzed which environmental characteristics and which conditions are perceived as barriers by parents of primary and secondary school pupils and adolescents themselves (age 10 and above). In addition, we examined the potential effect modifiers of age, gender, socioeconomic status (SES), and distance. | PMC10037850 |
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Methods | PMC10037850 |
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Study design | DISEASES, DISEASES | The present study is part of the LIFE Child study conducted at the Research Center for Civilization Diseases in Leipzig (Germany). LIFE Child is a longitudinal cohort study investigating the development of children and adolescents from pregnancy until early adulthood with a particular interest in the origins of non-communicable diseases. The annual visits comprise a comprehensive physical examination, collection of bio-samples, and several questionnaires regarding sociodemographic, psychological, and lifestyle characteristics [The following analysis is based on cross-sectional data collected between September 2018 and February 2020. In cases of multiple visits per child, the most recent visit was chosen.LIFE Child is conducted in accordance with the Helsinki Declaration and was approved by the Ethics Committee of the Medical Faculty of the Leipzig University (Reg. No. 264–10-19,042,010). All parents gave written informed consent for them and their children to be included in the study. An additional written informed consent was obtained from adolescents age 12 and above. | PMC10037850 |
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Study population | The initial sample consisted of 1456 children and adolescents. 386 participants were excluded because of missing information on their means of transport (Fifty-three percent of the participants were boys. Most participants had a mid-level socioeconomic status (SES) (58%); low SES (2%) was under- and high SES overrepresented (34%). Information on SES was missing in 6% of cases. A more detailed description of participants’ socioeconomic status is provided in Additional Table Questions regarding perceived barriers with answer options (multiple choice)
For 298 out of 364 children, information regarding all barriers as well as sociodemographic variables were available. The multivariate analyses were carried out on this complete subsample. The adolescent subsamples comprised 527 (out of 706, parent-reported information on barriers) and 570 (self-reported information on barriers) participants. Compared to participants without missing information, the excluded individuals had a significantly higher number of perceived barriers (b = 1.01, | PMC10037850 |
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Measures | phrasing:“It, Wilson et al. | SECONDARY | SES was calculated as the Winkler Index, a composite score considering parental education, parental occupations, and equivalized household net equivalent income. Scores on the Winkler Index range from 3 to 21 [The distance between home and school was calculated as the network distance from the home to school address using the Dijkstra algorithm [Information about means of transport (car, public transportation, walking, and/or cycling/skateboard/scooter), travel duration (minutes on each means of transport), and perceived barriers to AST were assessed in a questionnaire completed by the parents and, beginning at age 9.5, additionally by the children and adolescents themselves. Answers regarding the means of transport for participants below age 13.5 were primarily parent reports and only complemented with self-reports when parent reports were missing. For adolescents older than 13.5 years of age, self-reports were preferred because greater independence was assumed (Additional Fig. Associations between active school transport, age, and type of school: In general, a higher proportion of primary school children engage in active school transport. For both primary and secondary school children, the proportion increases with increasing ageAdolescents were additionally asked in a single-choice question to state which of the four given options they would prefer for their school transportation if they had free choice.The primary means of transport was categorized as (1) cycling or (2) walking for children and adolescents who used cycling or walking as their only means of transport or who used a combination that included at least 15 min of cycling or walking. The third category public transport was assigned when participants took the bus, tramway, or train; the fourth category was being taken by car. Cycling and walking were considered active school transport (AST), whereas using public transport or being taken by car were considered motorized school transportation.The perceived barriers were also assessed through questionnaires using the following phrasing:“It is difficult for me / for my child to walk or to cycle to school independently (without the company of an adult) because…”. The participants could rate each potential barrier on a four-level Likert scale with the following options: “I disagree”, “I mildly disagree”, “I mildly agree”, and “I fully agree”. The first two answer options were aggregated into the category “non-significant barrier” and the last two answer options into the category “perceived as a potent barrier".A list of questions and answers regarding the perceived barriers can be found in Table The phrasing of the questions is based on a Canadian research paper by Wilson et al. [Furthermore, children and parents were asked to state whether or not bad weather conditions hinder them/their children from walking/cycling to school on a scale from 0–100 (with 0 = not at all and 100 = a lot). Ratings > 50 were interpreted as considering weather as a significant barrier to AST. For parents stating that they have no reservations about letting their children cycle or walk to school without an adult’s company, the perceived barriers were set to “no barrier”. The barrier “bullying” was removed from the analysis because of the low number of positive answers (n < 10). The number of perceived effective barriers was also considered as a covariate. | PMC10037850 |
Statistical analysis | REGRESSION, DELETION | All analyses were performed using the software R [In order to identify the final set of explanatory variables, all variables with a significant result in the univariate analyses were included in the multivariate modelling process. In a second step, following the statistical principle of parsimony, we used a forward and backward deletion algorithm based on the Akaike criterion and, thereby, removed stepwise all non-significant variables. Hence, the final models do not comprise all variables which were significant in the univariate analysis. The reported ORs are not adjusted except in the final models or when otherwise stated. We used Poisson regression models to compare the number of barriers perceived by parents of children, parents of adolescents, and adolescents themselves. The significance level was set to α = 0.05. | PMC10037850 |
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Results | PMC10037850 |
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Descriptive | On average, children lived 1930 m (SD: 2688) away from school and adolescents 3468 m (SD: 3210). The mean duration of the school trip was 13.28 min (SD: 8.84) for children and 19.50 min (SD: 13.30) for adolescents. AST was significantly more common in summer (morning: 53.64%, afternoon: 54.58%) than in winter (morning: 43.18%, afternoon: 44.49%, Sixty-three percent of the children ( | PMC10037850 |
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Age, gender and SES | SECONDARY | The share taking AST decreased with age (OR = 0.94 per year, CI = 0.9–0.99 Children in secondary school had significantly lower odds of AST than children in primary school (OR = 0.57, CI = 0.45–0.74, Walking was more frequently reported than cycling. However, the share of cyclers increased with age while the share of walkers decreased (Table Distribution of means of transportation on the way to school in summer by age (values are % and (n))25.51%(273)15.65%(41)24.66%(55)26.79%(60)28.66%(47)30.15%(41)47.54%(29)16.17%(173)25.95%(68)28.25%(63)8.48%(19)6.10%(10)5.88%(8)8.20%(5)30.19%(323)12.98%(34)15.70%(35)42.41%(95)46.34%(76)46.32%(63)32.79%(20)28.13%(301)45.42%(119)31.39%(70)22.32%(50)18.90%(31)17.65%(24)11.48%(7)The prevalence of AST did not significantly differ by gender (children: ORChildren and adolescents with a high SES had significantly higher odds of AST compared to those with a middle to low SES (OR = 1.69, CI 1.3–2.21, The correlation between socioeconomic status and active school transport differs by season and direction of travel: For both children and adolescents, the odds of AST decreased significantly as the distance between home and school increased (children: ORAssociation between active school transport and distance for children and adolescents: In both groups, the probability of active school transport decreased as the distance between home and school growsFor example, the estimated probability for AST was 85.97% for children living 250 m, 68.83% for children living 1500 m and 38.43% for children living 2500 m away from school. Likewise, for adolescents living 650 m away from school, the probability for AST was 76.86%, whilst it was 45.81% for adolescents living 3500 m away from school and 16.68% for adolescents living 6500 m away from school. For adolescents living close to their schools, there was a positive correlation between distance and AST (OR = 1.37, CI = 1.03–1.88, | PMC10037850 |
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Perceived barriers | The mean number of perceived barriers was 3.26 (SD: 2.83) for the parents of children, 2.49 (SD: 2.86) for the parents of adolescents, and 1.55 (SD: 2.43) for adolescents themselves. The parents of adolescents perceived significantly fewer barriers than the parents of children (The number of perceived barriers reported by parents and by adolescents showed significant inverse correlations with AST in the univariate models. In the univariate models for children ≤ 10 years, most barriers exhibited a negative correlation to AST. Only the way is too boring, too exhausting, and having no desire to walk/cycle were not associated with the outcome (Table Models for children (≤ 10 years) analyzing correlations between active school transport and sociodemographic variables, distance between home and school, and perceived barriers (based on parental answers). OR = exp(ß) High socioeconomic status(ref.: low to middle) Distance between home and school(in 100 m) for very short distances Distance between home and school(in 100 m) for longer distancesThe answering options the path is too dangerous (positive correlation), too much traffic, no other children, too heavy load to carryIn the adolescent sample, the route being too exhausting or too boring were the only barriers not showing any significantly negative correlation with AST in the univariate analyses using the parental answers. The multivariate analysis using the parental answers showed significantly negative correlations between AST and the following perceived barriers: too heavy load to carry, number of perceived barriers, and longer distance (only for adolescents not living in the immediate surroundings of their school). Examining the adolescents’ answers, crime was the only barrier that did not show a significantly negative association with AST in the univariate models (Table Models for adolescents (> 10 years) analyzing correlations between active school transport and sociodemographic variables, distance between home and school, and perceived barriers (separate models based on parental or adolescents' answers). OR = exp(ß) High socioeconomic status(ref.: low to middle) | PMC10037850 |
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Discussion | ’ | This study analyzed the prevalence of AST among children and adolescents and barriers perceived by parents and adolescents in a city of about 600 000 inhabitants in Germany. The prevalence of AST in our study sample (53.6%) ranges below the percentages published for Germany as a whole: 78.3% in a nationwide cohort of children and adolescents [Our data shows that more children and adolescents would engage in AST if they could choose than the number of children and adolescents who actually reported AST. This underlines the necessity of studying what external reasons deter children from AST. In our sample, the correlation between AST and age was negative but became positive when controlling for school type. The highest proportion was found at age 10, which is consistent with results of a Canadian study by Pabayo et al. [Regarding perceived barriers, significant associations were found in the domains of physical environment, safety, social and individual/family preferences. Taking too much time was a significant barrier for adolescents, but not their parents. Conversely, in a Canadian study, this was a barrier only perceived by parents [Counterintuitively, the route being too dangerous exhibited a positive correlation with AST in the model for children. However, again, this association might be attributable to worse infrastructure or a higher awareness of traffic-related dangers among parents of children who use AST out of necessity than among parents whose children use passive means of transport. Too much traffic exhibited a significant negative correlation in the self-reported model for adolescents and in the model for children, but not in the parent-reported model for adolescents. It can be assumed that the parents of adolescents are less familiar with the exact route and its characteristics due to adolescents’ higher degree of independence. Conversely, the number of barriers perceived by adolescents’ parents was a significant predictor of AST, suggesting that the number may be more decisive than any specific barrier. Previous studies have shown that traffic-calming measures can increase use of active transport to school and elsewhere [ | PMC10037850 |
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Strengths and weaknesses | weakness | The strengths of our study include the objective definition of AST, which takes into account combined transport modes. To our knowledge, this is the only study assessing perceived barriers to AST for schoolchildren across the whole age span from 1A weakness is that we could not control for possible cluster effects on the neighbourhood, school or family level, as the sample sizes per cluster did not permit this (e.g., the most frequented school in our sample accounted for less than 3% of participants). There was also a discrepancy in the phrasing of questions: The questions regarding barriers referred to independent active travel, whereas the transport mode question focused on the active/passive transportation mode, ignoring the aspect of independence.Since our data collection was based on electronic case report forms, we were methodologically unable to survey children younger than 10 years, an age when they were not yet confident reading and using a computer. We also assume lower independence at that age. Therefore, the statements of the parents seemed to be of primary importance. Finally, the generalizability of our results might be limited because of the underrepresentation of participants with a low SES and because majority of participating families lived in an urban environment. | PMC10037850 |
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Conclusions | Significant associations were found between AST and factors from the domains of physical environment, safety, social and individual/family preferences. Some of them were consistently negatively related to AST (e.g., a heavy load to carry | PMC10037850 |
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Acknowledgements | The authors would like to thank all participants, the LIFE Child study investigators, and the LIFE Child colleagues for their advice. | PMC10037850 |
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Authors’ contributions | CM | IW refined the research question, analyzed and interpreted the data, and wrote the article. MG and IW performed the literature research and developed the research question. MV planned the study and provided guidance in the statistical data analysis, interpretation of data and writing of the article. TL, UI and CS critically reviewed the manuscript. CM provided the technological infrastructure for the project. WK supervised the project and its conceptualization and critically reviewed the manuscript. All authors read and approved the final manuscript. | PMC10037850 |
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Funding | Open Access funding enabled and organized by Projekt DEAL. This study was supported by the German Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01-GL1906; by the Free State of Saxony as per the budget approved by the state parliament (GeoEtiology); by the Regional Development Fund (LIFE Forschungszentrum), and by the Free State of Saxony within the framework of the excellence initiative. This publication was further supported by the Leipzig University's Open Access Fund. | PMC10037850 |
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Availability of data and materials | The datasets on which the present study is based are not publicly accessible, since the publication of data was not covered in study participants’ informed consent. Potentially sensitive information is collected in the context of the LIFE Child study; therefore, the data protection concept requires that all researchers interested in accessing the data sign a project agreement. Researchers interested in gaining access to the data collected in the LIFE Child study may contact the committee on data use and access ([email protected], Ms. Yvonne Dietz). | PMC10037850 |
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Declarations | PMC10037850 |
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Ethics approval and consent to participate | All parents gave written informed consent for them and their children to be included in the study. An additional written informed consent was obtained by adolescents age 12 and above. The study was conducted in compliance with the Declaration of Helsinki. Ethics approval was granted by the Ethics Committee of the Medical Faculty of the University of Leipzig (Reg. No. 264–10-19,042,010). | PMC10037850 |
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Consent for publication | Not applicable. | PMC10037850 |
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Competing interests | The authors declare no competing interests. | PMC10037850 |
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References | PMC10037850 |
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Introduction | delirium, PTE, insomnia, CTEPH | CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION | Individuals receiving care in the intensive care unit (ICU) suffer from extremely poor sleepRamelteon is a synthetic, melatonin-receptor (types 1 and 2) agonist that is FDA-approved for the treatment of insomnia. In the outpatient setting, studies have shown that ramelteon increases total sleep time (magnitude of effect approximately 7 min) and sleep efficiency and decreases subjective sleep latency (magnitude of effect approximately 4 min)As part of a randomized clinical trial (RCT) testing ramelteon versus placebo effect on delirium in patients recovering in the ICU who underwent elective pulmonary thromboendarterectomy (PTE) surgery, a major cardiothoracic surgery used for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), we collected objective measures of sleepHere we explore the hypothesis that ramelteon would improve actigraphy-based sleep metrics in this cohort, which was a pre-specified outcome in the original study. We further examined basic activity and circadian rest-activity parameters between drug groups to evaluate for differences. Finally, we examined sleep, activity, and circadian rest-activity differences between individuals who developed delirium versus those who did not to address the hypothesis that individuals with delirium would have reduced circadian rest-activity rhythmicity (i.e., objectively measured loss of day-night activity pattern) compared to those who did not develop delirium. | PMC9879948 |
Methods | PMC9879948 |
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Ethics approval and consent to participate | This study conducted in accordance with the Declaration of Helsinki, was granted approval by the UCSD Human Research Protections Program (#151294). Written, informed consent was obtained from each participant on the night prior to their procedure after a detailed explanation of the risks and benefits of participating was conducted and all participant and family questions were answered. The study was registered at clinicaltrials.gov (NCT 02691013, date of registration: February 24, 2016). | PMC9879948 |
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Parent study | delirium, delirious, Confusion | Detailed methods of the randomized control trial are published elsewhere, and a flow diagram for the current study that also includes patient enrollment from the original study is shown in Fig. Participant flow diagram. 120 participants were randomized as part of the original clinical trial. There were 97 patients include in the actigraphy analysis presented here.After enrollment, participants were randomized in a 4-factor blocked fashion to receive either ramelteon 8 mg or matching placebo each evening at 9 p.m. starting the night prior to surgery (post-operative day-1, or POD-1) and for a maximum of six additional nights (POD 5), or until discharge from the ICU, whichever occurred first. In addition to obtaining daily clinical data, patients were assessed for delirium twice daily using the Confusion Assessment Method ICU (CAM-ICU) through POD 8. Those not scored as CAM-ICU positive (CAM+) on any assessment are termed “never delirious,” while those with at least one CAM + assessment are termed “delirious.” Investigators, subjects, and other clinical care providers remained blinded to drug assignment until trial completion and all data collection was complete. | PMC9879948 |
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Actigraphy | All participants wore an actigraph (Actiwatch Spectrum Plus, Respironics Inc.; Murrysville, PA) beginning after the completion of surgery, placed shortly after their arrival to the ICU. These devices were set to record activity counts in 15 s epochs. Actigraphy devices use accelerometry-based technology to determine activity counts per epoch based on wrist movement. For active patients (e.g., outside the ICU), contiguous periods of inactivity are thought to be rest and/or sleep, and periods of rest can usually be reliably scored by an experienced scorer. However, the activity levels of individuals recovering from surgery in the ICU are very low, and thus manual scoring of the actograms could potentially be unreliable. Thus, we standardized our analysis by defining 22:00 to 06:00 as the nighttime rest period for all individuals, and defined 06:00 to 22:00 as the daytime period. Based on our inpatient experience, the 10 p.m.–6 a.m. period is after nighttime medications are normally administered (9 p.m.), hall lights are dimmed, and is generally the time where rest/sleep is encouraged by bedside nurses. Choosing a “rest interval” was an effort to standardize the rest period and to compare between our randomly allocated groups regarding the amount of sleep captured by the device. We also excluded individuals who were intubated for the entire duration of the study (through POD 8). We did not examine actigraphy data beyond the day of ICU discharge as the participant had reached study completion. If a patient left the ICU before noon, this day was not included. All periods were categorized according to post-extubation day. For example, if a patient was extubated on POD 2, this was considered post-extubation day 0. Actiware software (Respironics Inc.) was utilized to extract data from the devices. | PMC9879948 |
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Actigraphy analysis: light analysis | delirious | The actigraph device simultaneously collects white light data (reported in lux) with the activity data. Daytime and nighttime light levels were averaged for each participant based on post-extubation day, and are presented according to group (ramelteon vs. placebo; delirious vs. never delirious). | PMC9879948 |
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Data analysis and statistics | delirium, SE | Data for the sleep, activity, and non-parametric circadian rest-activity metrics were extracted for each patient as defined and described above. For all metrics except for IS, we first examined the main effects of both the drug and delirium state independently via linear mixed effects models accounting for the repeated measures among participants and estimated marginal means ± standard errors (SE) were reported. Next, to test for associations over time from extubation, we used linear mixed effects models including either drug or delirium state as well as time (based on post-extubation day) and the interaction of either drug or delirium state with time as fixed effects, and a random effect of subject to account for repeated measures. All mixed effects models were conducted using the lmerTest package | PMC9879948 |
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Results | PMC9879948 |
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Participants and baseline characteristics | There were Baseline characteristics of patients receiving placebo vs. ramelteon. | PMC9879948 |
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Effect of ramelteon on circadian rest-activity rhythms | This analysis consisted of 79 individuals and 180 days of data. Table | PMC9879948 |
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Circadian rest-activity rhythms in delirious vs. never delirious patients | delirious | We found that delirious patients had a lower IS (Fig. | PMC9879948 |
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Discussion | delirious | We present several important findings in this study. First, ramelteon, as compared to placebo, did not have an impact on total sleep time, sleep fragmentation, or circadian parameters as measured by actigraphy in this ICU cohort. Those who received ramelteon had a lower activity level over the post-extubation ICU period compared to placebo, though other total activity measures seemed similar. Second, overall circadian fit was low for the whole cohort. Finally, we found that delirious patients had a lower stability in their rest-activity patterns compared to those who did not become delirious. Importantly, our study associated actigraphy data with clinical outcomes, and suggests that actigraphy and similar technologies could be useful in determining sleep, activity, and circadian differences between groups of individuals, even in the ICU. | PMC9879948 |
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Effect of ramelteon on sleep | delirium | While some (though not all) studies have shown ramelteon to reduce the incidence of deliriumGiven the number of studies suggesting that efforts aimed at improving sleep reduce delirium | PMC9879948 |
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Sleep and light in the ICU | We note that, consistent with other studies, sleep in the ICU was quite poor at night. Assuming actigraphy may overestimate sleep time in the ICU, especially for those moving little after major surgery, we note that sleep time decreased each day post-extubation. This decrease is probably due to increased activity/movement that helps better estimate sleep duration (i.e. less time thought to be sleep due to inactivity). Additionally, sleep fragmentation as assessed by sleep bout length remained high throughout. By the end of the ICU stay, total nighttime sleep duration was only about 350 min per patient. Regarding the light data, while we found no between-group differences, we did find that the light levels were very low (generally below 100 lx). Low light levels are desirable at nighttime to help with sleep (high light levels at nighttime can suppress melatonin production, which is important for the maintenance of sleep), but should be much higher during the daytime as it is a major circadian rhythm cue (zeitgeber). This suggests a potential area of improvement for in critical care medicine. | PMC9879948 |
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Sleep and delirium | delirium, cognitive decline | We and others have previously shown that sleep fragmentation is associated with delirium and cognitive decline, whereas total sleep duration is often similar in those with and without delirium | PMC9879948 |
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Actigraphy in the ICU | CRITICAL ILLNESS MYOPATHY | Actigraphy, which relies on movements for its measurements, is not a replacement for polysomnography, particularly in the ICU, where medication, acute illness, and critical illness myopathy can all contribute to decreased activity. However, actigraphy does have benefits over polysomnography in that it is less cumbersome, data can be collected passively for long periods of time and over 24-h periods, and data collection is not limited to information about sleep. Furthermore, more recent digital devices use technology based on actigraphy, and many of these digital devices may be key in improving our approach to personalized medicine in the acute care setting | PMC9879948 |
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Limitations | As above, we did not use PSG. We restricted our analysis to days off mechanical ventilation. However, in our cohort, the majority of patients were on a ventilator for less than 24 h, and for most subjects (72%) we therefore analyzed at least 2 days’ worth of data. We did not confirm that the circadian activity rhythm measured by actigraphy reflected other markers of the endogenous circadian rhythm such as core body temperature or serum or urine melatonin measurements. Nevertheless, we emphasize that the circadian differences we saw had biological plausibility (reflected expected changes with administration of a melatonin agonist) and/or reflected clinical differences between groups. Furthermore, this was an exploratory analysis of rest-activity rhythms in the ICU, and resulting analyses were underpowered to detect significant effects. Given the high variability of multiple variables (including activity, light patterns, days studied), these data should serve to inform larger, powered studies in this setting and generate future research hypotheses. Finally, the lack of significant findings in our analysis could have been limited by a shorter recording time (~ 2–3 days of recordings per individual) which may not be adequate to fully assess circadian rhythms as at least 72 h of recording are usually suggested. | PMC9879948 |
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Conclusion | delirium | Using objective measurements, we found that the use of ramelteon did not improve sleep duration or circadian rest-activity rhythms. Differences in interdaily stability were seen in those with and without delirium. Further studies are warranted to determine the best uses of actigraphy in the ICU setting. | PMC9879948 |
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Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-28095-0. | PMC9879948 |
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Author contributions | S.J.J. helped conducted the project, analyzed and interpreted data and wrote the manuscript. S.R.S.B. contributed to data analysis and statistical interpretation, and edited the manuscript. S.A.I. contributed to the interpretation of activity, sleep and circadian analysis and edited the manuscript. E.T.T. assisted in data curation and analysis and edited the manuscript. B.B.K. edited the manuscript. R.L.O. designed the study, conducted the project, interpreted data and wrote the manuscript. | PMC9879948 |
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Funding | Dr. Jaiswal received support in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award number UL1TR002550. Dr. Kamdar is supported by a National Institutes of Health/National Institute on Aging Paul B. Beeson Career Development Award number K76AG059936. | PMC9879948 |
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Data availability | Datasets generated from this study are available upon reasonable request to Dr. Owens ([email protected]). | PMC9879948 |
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Competing interests | SAI consults for Eisai, Merck, Idorsia, PureTech. Otherwise, the authors declare that they have no competing interests. | PMC9879948 |
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References | PMC9879948 |
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Subject terms | heart failure symptoms, LVOTO, LV outflow tract obstruction, cardiac disease | DISEASE, HYPERTROPHIC CARDIOMYOPATHY (HCM), CARDIAC DISEASE | Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac disease in humans and cats and lacks efficacious pharmacologic interventions in the preclinical phase of disease. LV outflow tract obstruction (LVOTO) is commonly observed in HCM-affected patients and is a primary driver of heart failure symptoms and reduced quality of life. Novel small-molecule cardiac myosin inhibitors target actin-myosin interactions to alleviate overactive protein interactions. A prospective, randomized, controlled cross-over study was performed to evaluate pharmacodynamic effects of two doses (0.3 and 1 mg/kg) of a next-in-class cardiac myosin inhibitor, | PMC9807554 |
Introduction | disease of cardiac sarcomeric, HCM | DISEASE, LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION | Small molecule inhibitors are an emerging class of novel therapeutic agents that inhibit the function of specific proteins with the potential for neutralizing deleterious downstream effectsHCM is a disease of cardiac sarcomeric proteins with identified mutations in cats affecting the One contributing factor to morbidity and mortality of HCM in human patients is the presence of left ventricular outflow tract obstruction (LVOTO)Evidence is currently lacking for therapies with proven efficacy in delaying progression of disease or conferring survival benefits in subclinical human and feline HCM patientsThe aim of this study was to characterize the pharmacodynamic effects of a single oral administration of two dose strengths (0.3 mg/kg and 1 mg/kg) of the next-in-class cardiac myosin inhibitor, | PMC9807554 |
Discussion | HCM, LVOTO, fibrosis, myocardial disarray, myosin, cardiac disease, heart failure, Hypertrophic cardiomyopathy | DISEASE, FIBROSIS, CARDIAC DISEASE, HEART FAILURE, HYPERTROPHIC CARDIOMYOPATHY | A research colony of mixed-breed Maine Coon cats with the A31P Hypertrophic cardiomyopathy is the most prevalent inherited cardiac disease in humans with an estimated incidence of up to 1:500 (0.2%) in the general populationThe identification and treatment of LVOTO is important in humans with oHCM as it likely contributes to symptoms and is an independent predictor of progression to severe symptoms of heart failure and deathThe development of novel cardiac myosin inhibitors is a unique and promising new frontier for targeted therapies in affected individuals and may improve clinical signs as well as prevent deleterious effects of abnormal actin and myosin interactions, leading to reduced histopathologic changes and delayed progression of disease. A study in mice with HCM demonstrated the ability of another small molecule inhibitor, mavacamten, to significantly reduce the hallmark histopathologic features of fibrosis and myocardial disarray when administered prior to the development of significant hypertrophySafety and tolerability of Our study also demonstrates the plasma concentrations of Several limitations to this study exist. There is the possibility of type II error given the small sample size of eight cats. The temperament of the colony cats and drug administration by oral gavage requires significant sedation which may impact functional parameters. To minimize these effects, a three-hour recovery period was allowed following sedation with alfaxalone for oral gavage and a standardized sedation protocol (butorphanol and acepromazine) that previously demonstrated minimal effects on echocardiographic variables was used for each echocardiographic evaluationThe development of novel small molecule inhibitors is an exciting frontier for the advancement of therapeutic options in the management of preclinical HCM; the current study further highlights the utility of this feline model in evaluation of novel therapies that may benefit the human population. Based on the current study, the optimal dose of | PMC9807554 |
Methods | PMC9807554 |
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Animals | All experimental protocols were approved by the University of California Davis Institutional Animal Care and Use Committee (IACUC). Research was conducted in accordance with all relevant guidelines and regulations of the University of California, Davis, IACUC (Protocol number 20565) and all methods are reported in accordance with ARRIVE guidelines. A sample size of at least 7 cats in each dose group was calculated to have an 80% power to identify a 15% reduction in key parameters of echocardiographically-assessed systolic function. This a-priori sample size was estimated based upon colony-specific, preliminary data in HCM-affected feline subjects | PMC9807554 |
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Experimental design | This was a randomized, controlled, cross-over study. Cats received single oral doses of vehicle or Cross-over study design. | PMC9807554 |
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Echocardiographic evaluations | hyperthyroidism | HYPERTHYROIDISM, SYSTEMIC HYPERTENSION | Baseline echocardiographic evaluations were performed 24 h prior to each treatment dosing. On the morning of the examination, cats were dosed with gabapentin (100 mg PO) approximately one hour prior to the study. The cats were sedated with butorphanol (0.3 mg/kg IM) and acepromazine (0.1–0.5 mg/kg IM) to facilitate echocardiographic evaluation.All echocardiograms were performed by a single board-certified cardiologist (MSO) using a 12–4 mHz sector array transducer with harmonics (Philips EPIC CVx, Philips Healthcare, Andover, MA, USA). Two-dimensional (2D), M-mode, color Doppler, and spectral Doppler echocardiographic images were obtained in standard imaging planes from right and left lateral recumbencyOn the day of echocardiographic evaluation with vehicle or Images were stored and all measurements were performed by a single blinded observer (MSO) using a commercially available offline workstation (Syngo Dynamic Workplace v10.0.01_HF04_Rev5 [Build 2884], Siemens Medical Solutions, Malvern, PA, USA). Two-dimensional right parasternal long axis or short axis imaging planes were measured to obtain the maximum 2D thickness of the interventricular septum (IVSd) and left ventricular posterior wall (LVPWd) in diastole using an inner-edge to inner-edge measuring technique. Segmental or diffuse IVS or LVPW thickness exceeding 6 mm in the absence of systemic hypertension or hyperthyroidism on at least two serial examinations > 1 month apart was considered consistent with HCMM-mode and two-dimensional right parasternal short axis imaging planes were used to measure the left ventricular internal dimensions at end-diastole (LVIDd) and end-systole (LVIDs). Fractional shortening was calculated using the equation (LVIDd-LVIDs)/LVIDd × 100.Left atrial (LA) size was measured in 2D on the right parasternal short axis basilar view to determine the LA/Ao as previously describedSpectral Doppler and pulsed wave tissue Doppler imaging (PW TDI) from the left apical 4-chamber view were used to evaluate diastolic functional parameters including transmitral inflow patterns, lateral E’ and A’, and LV isovolumic relaxation time (IVRT) | PMC9807554 |
Author contributions | P.C. | J.A.S., S.P.H., and D.T.H. conceived the experiment(s). J.A.S., M.S.O., A.N.S., J.L.K., P.C., and S.L.K. conducted the experiment(s). A.N.S., M.S.O., A.L.W., V.N.R., and J.A.S. analyzed the results. A.N.S., J.A.S., and V.N.R. wrote the original manuscript draft. All authors reviewed and revised the final manuscript. | PMC9807554 |
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Funding | This study was funded by Cytokinetics Inc. | PMC9807554 |
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Data availability | Restrictions apply to the availability of these data. Data are available from the corresponding author with the permission of Cytokinetics, Inc. | PMC9807554 |
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Competing interests | D.T.H., B.P.M., P.C., and F.I.M. are employees of Cytokinetics and were financially compensated for their work. | PMC9807554 |
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References | PMC9807554 |
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Subject terms | TNBC, tumor malignancy | TRIPLE NEGATIVE BREAST CANCER, TUMOR GROWTH | Mathematical models based on partial differential equations (PDEs) can be exploited to handle clinical data with space/time dimensions, e.g. tumor growth challenged by neoadjuvant therapy. A model based on simplified assessment of tumor malignancy and pharmacodynamics efficiency was exercised to discover new metrics of patient prognosis in the OLTRE trial. We tested in a 17-patients cohort affected by early-stage triple negative breast cancer (TNBC) treated with 3 weeks of olaparib, the capability of a PDEs-based reactive–diffusive model of tumor growth to efficiently predict the response to olaparib in terms of SUV | PMC10366144 |
Introduction | cancer, Breast cancer, tumors, death | CANCER, BREAST CANCER, TUMORS | Breast cancer (BC) is the most common cancer in women and the most frequent cause of death by cancer in this sexIn the last few years, mathematical modeling has been entering the arena of oncological research in an attempt to predict spatial and temporal evolution of tumors transferring We hereby retrospectively applied our reactive–diffusive PDEs-based model to a wider BC patient cohort prospectively enrolled in a window-of-opportunity trial at our Institution | PMC10366144 |
Methods | PMC10366144 |
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Study population | This analysis was retrospectively performed on the BC patients enrolled within the OLTRE “window of opportunity” trial (NCT02681562) with available data for the mathematical modeling. Within the OLTRE study, conducted at the ASST Cremona between 2016 and 2019, treatment-naïve patients with locally advanced non-metastatic HER2-negative BC, with or without a germline All patients underwent a | PMC10366144 |
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Study hypotheses and objectives | The main hypothesis behind this sub-analysis of the OLTRE trial was to test an | PMC10366144 |
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Study procedures: theoretical premises | cancer | CANCER | From the engineering point of view, BC is a single-phase (solid) biomaterial, featuring sharp boundaries delineating the cancer cells population ØIn the equation, Key methodological steps of the mathematical model. ( | PMC10366144 |
Study procedures: analysis | tumor | TUMOR | The system of equations applied to the available breast volume, Eqs. (Population characteristics were assessed through standard descriptive statistics and variations in mean for main pathological variables pre/post olaparib were assessed through Students’ t-test for paired samples. The correlation of the main clinicopathological features (i.e. Ki67%, tumor-infiltrating lymphocytes [TILs] %, age in years, tumor size in mm, PD-L1 TPS and IC %) with the difference between post- and pre-olaparib SUV | PMC10366144 |
Ethical approval | The OLTRE trial (NCT02681562) was conducted in accordance with the Declaration of Helsinki, the Good Clinical Practice principles and all local regulations. The study obtained the approval of the ethical committee of the ASST of Cremona Hospital (IRB Approval 09/09/2015 n.21741/2015) and all participants provided written informed consent for participation. | PMC10366144 |
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Discussion | TNBC, HER2-positive, tumor | PROLIFERATION, TUMOR GROWTH, TUMOR | We tested, in a cohort of 17 patients affected by early-stage TNBC treated with 3 weeks of olaparib in a “window of opportunity” trial, a mass transfer PDEs-based reactive–diffusive mathematical model of tumor growth which might be capable of efficiently predicting the response to olaparib in terms of SUVThe model showed, without any preliminary assumption, the effective pharmacodynamic efficiency of olaparib was strongly dependent on basal TILs level and SUVThe need for biomarkers to guide escalated/de-escalated and more personalized therapeutic approaches is a hot topic in current OncologyNoteworthy, the evaluation of Ki67 is an already established prognostic biomarker in BC, which expression is strongly associated to tumor proliferation and growthThe morphological evaluation of TILs in BC has gained attention in the last few years, when preliminary evidences started to show a potential prognostic and predictive role, especially in TNBC and HER2-positive BCThere are several limitations that will have to be overcome to promote the implementation of this mathematical framework in the clinical research and practice scenarios. First of all, we had the possibility to study our mathematical model in a cohort of 17 patients, which is more than what is usually done in this research field, where modelling frameworks based on single patients are the normAnother limitation, is that SUVTo conclude, we observed that a mathematical framework based on realistic multidimensional governing PDEs, could be directly applied to the tailored simulation of an early therapeutic response to the PARPi olaparib in early-stage TNBC by using Prospective evaluation in independent cohorts and correlation of these outcomes with more recognized efficacy endpoints is now warranted. | PMC10366144 |
Acknowledgements | The authors want to gratefully thank all patients and their respective families involved in the OLTRE trial. | PMC10366144 |
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Author contributions | G.R., M.V.D.B., F.S. and D.G. conceived the study. All authors, except for F.S., M.V.D.B. and G.R., participated in OLTRE study procedures, along with study nurses, clinical research coordinators and other study-center staff. FS performed the statistical analyses, G.R. and M.V.D.B. performed the mathematical modeling. G.R., M.V.D.B., F.S. and D.G. interpreted study results and wrote the first manuscript draft. All authors revised and approved the final submitted manuscript. | PMC10366144 |
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Funding | ONCOLOGY | FS received a European Society for Medical Oncology (ESMO) Fellowship – Translational and the 2021 BBVA Foundation/Hospital Clinic of Barcelona Joan Rodés—Jose Baselga Advanced Research Contract in Oncology. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author and do not necessarily reflect those of Funding Entities. The OLTRE trial was conducted with Astra-Zeneca contribution providing olaparib. The funder had no role in the design of the study nor of its collateral sub-analyses; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. This research was also supported by Mednote, spin-off—University of Trieste—Mozart Program. | PMC10366144 |
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Data availability | The datasets generated during and/or analyzed during the current study are available from the Corresponding Author upon reasonable request. | PMC10366144 |
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Competing interests | DG declared personal fees for educational activities from Novartis, Lilly, Pfizer, Roche and Astrazeneca, outside of the submitted work. FS declared personal fees for educational activities from Novartis, outside of the submitted work. IP has declared consulting fees from Roche, Novartis, Lilly, Pfizer, Astra-Zeneca, Pierre Fabre and Ipsen outside of the submitted work. GS has declared Grant/Research Support from MSD Italia S.r.l., consulting role for TESARO Bio Italy S.r.l. Johnson & Johnson and Clovis Oncology Italy S.r.l., outside of the submitted work. All other authors declared no conflict of interest. | PMC10366144 |
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References | PMC10366144 |
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Background | gastric cancer | GASTRIC NEOPLASMS, GASTRIC CANCER | This protocol is for a multi-centre randomised controlled trial to determine whether the computer-aided system ENDOANGEL-GC improves the detection rates of gastric neoplasms and early gastric cancer (EGC) in routine oesophagogastroduodenoscopy (EGD). | PMC10176798 |
Discussion | The results of this trial will help determine the effectiveness of the ENDOANGEL-GC in clinical settings. | PMC10176798 |
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Trial registration | ChiCTR (Chinese Clinical Trial Registry), ChiCTR2100054449, registered 17 December 2021. | PMC10176798 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07346-5. | PMC10176798 |
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Keywords | PMC10176798 |
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Introduction | Gastric cancer, Upper gastrointestinal endoscopy, gastric cancers, upper gastrointestinal neoplasms, deaths | GASTRIC CANCER, GASTRIC CANCERS, GASTRIC NEOPLASMS, BLIND, GASTRIC CANCER | Gastric cancer is the fourth leading cause of cancer-related deaths, with an estimated 1,080,000 new cases and 760,000 deaths in 2020 [Upper gastrointestinal endoscopy is widely used to detect and diagnose early gastric cancers [Despite its diagnostic ability, the quality of endoscopic examination plays an important role in the detection of EGC, which is a prerequisite for lesion detection [With the rapid progress in artificial intelligence (AI) technology, several researchers have developed intelligent systems aimed at diagnosing EGC or upper gastrointestinal neoplasms, and few studies have aimed to ensure the completeness of examinations [Development of a tool with the ability to simultaneously improve the diagnostic performance of WLE and ensure high completeness of examination is an ideal way to fulfil these needs. Therefore, we proposed the AI system ENDOANGEL-GC (gastric cancer), which simultaneously combines the functions of blind spot monitoring and lesion detection and runs in real time. We designed this randomised, controlled, patient-blinded, multi-centre trial with two parallel groups and a 1:1 allocation to evaluate the hypothesis that ENDOANGEL-GC would improve the detection rates of gastric neoplasms and EGC. | PMC10176798 |
Methods/design | PMC10176798 |
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Study design | This is a prospective, single-blind, parallel-group, multicentre, RCT. The recruited participants will be randomised into either the experimental or control groups at a ratio of 1:1. Participants in the experimental group will undergo endoscopic examinations with the assistance of ENDOANGEL-GC, while those in the control group will undergo routine examinations without ENDOANGEL-GC feedback. The study design is illustrated in Fig. Study design of this trialThe SPIRIT schedule of enrolment, interventions, and assessments | PMC10176798 |
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Study setting | This study is being conducted in large-scale, primary hospitals in China. | PMC10176798 |
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