Stresses, either abiotic or biotic, severely affect agricultural productivity and world agriculture is facing the challenge of increasing the productivity in order to pace up with the increasing food demand of the growing population. These stresses have been reported to negatively affect the biomass and yield of crops up to 70%  metabolism of metabolites also tend to play important roles in detoxification processes. Similar to this, Zhu et al. showed that MEB2, a vacuolar gene, was involved in storing and detoxifying excess iron in Brassica napus. Another work performed by Yang et al. showed that high temperature stress leads to an accumulation of NtMYC2a which activates the synthesis of nicotine and jasmonic acid. Similarly, Huang and Wang, Ksouri et al., Cao et al., and Wu et al. also showed that transcriptional factors influence plants resistance under stress conditions.Research articles included a number of aspects of plant responses to abiotic stresses, from molecular mechanisms of plant stress tolerance to other approaches used to mitigate these stresses in crop plants. Wang et al. studied the involvement of several transporters e.g., Li et al. observed improved photosynthetic activity, nitrogen metabolism and amino acid production by applying brassinosteroids to Camellia sinensis. Similarly, Gondor et al. showed an improvement in flavonoid biosynthesis after exogenous application of salicylic acid. Li et al. showed that synergistic priming of maize seeds with salicylic acid and H2O2 improves hormone metabolism and their transduction, stimulating energy supply and antioxidant systems, which in turn help maize seedlings to tolerate chilling stress. Studies by Agarwal et al., Sharma et al., Per et al., Cheng et al., Gruszka et al., and Patanun et al. also proved the involvement of brassinosteroids, salicylates, and jasmonates under a number of abiotic stresses. In general, the common mechanism of action suggested in these studies was up-regulation of genes associated with antioxidant protection, expression of specific transcription factors, and activation of specific responsive pathways, including hormone homeostasis.Hormones are not only involved in regulating growth and developmental processes, but their exogenous applications may also help to improve the plant yield. 2S and glycerol. H2S was found to regulate changes in polyamine and sugar metabolism and thus providing drought tolerance , while glycerol application provided tolerance against powdery mildew disease by inducing expression of pathogenesis-related genes . Other than these, research articles also explored the possible involvement of E-subgroup pentatricopeptide repeat protein family under abiotic stress . Furthermore, He et al. showed that phytochrome B regulates expression of DREB1 gene to enhance cold tolerance.Among different exogenous mitigants, not only the role of hormones was explored, but some research articles also studied the impact of other mitigants like HOverall, these articles give a clear picture of ongoing dynamic research on phytohormones and other compounds in preventing negative effects of abiotic stresses. The impact of several stresses on the transcriptome, phytohormone profile, and regulatory processes at the cellular level was also elucidated, with an emphasis on the interaction between stresses and hormonal cross-talk. We hope that these compiled articles will give a fresh, new insight into this topic, providing new ideas to pave the way for future research.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The mini-review by Uphill et al. highlights the prominence of psychological issues in sport through various media. The review also highlights gaps in the research in conceptions in mental health, interventions needed, and collaborative work that remains outstanding. The review used the Keyes  model asA coach ill-equipped to deal with their own psychological issues may see a change in their coaching behavior which may impact their performance in training and competitive situations. A potential consequence of this would be an increase in negative coaching behaviors  which may impact their athletes (Badami et al., While there is advocacy for mental health support services for athletes, evidence of similar services for coaches is scarce. Sebbens et al.  developeCoaches are typically hired to achieve an improvement on past team performance (Pierce et al., Creating a positive coaching climate and a positive organizational culture (Fletcher and Wagstaff, There is an opportunity to present a short intervention such as that alluded to in Sebbens et al.  in all cThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BO and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Understanding how and why recombination rate varies is a major challenge in biology. Most theoretical and empirical work has been devoted to understanding the role of recombination in the evolution of sex—comparing between sexual and asexual species or populations. How recombination rate evolves and what impact this has on evolutionary processes within sexually reproducing organisms has received much less attention. This Theme Issue focusses on how and why recombination rate varies in sexual species, and aims to coalesce knowledge of the molecular mechanisms governing recombination with our understanding of the evolutionary processes driving variation in recombination within and between species. By integrating these fields, we can identify important knowledge gaps and areas for future research, and pave the way for a more comprehensive understanding of how and why recombination rate varies.Recombination, the process by which DNA strands are broken and repaired, producing new combinations of alleles, occurs in nearly all multicellular organisms and has important implications for many evolutionary processes. The effects of recombination can be  Recombination is inations ,2, but a alleles , and desividuals . AlthougWhen considering this question: ‘Why does recombination rate vary?’, there is much focus on the evolutionary advantage of sex, but much less attention given to understanding why recombination varies between sexually reproducing organisms. For us, as a group of evolutionary biologists who have observed variation in recombination rate in sexually reproducing organisms—we considered this an important knowledge gap. Hence, we proposed this special issue ‘Evolutionary causes and consequences of recombination rate variation in sexual organisms' with the aim to bring this question to the fore and to encourage more researchers to investigate if and how recombination rate varies, whether it responds to natural or sexual selection, and how it influences fundamental evolutionary processes within sexually reproducing organisms, such as adaptation and speciation.To understand the evolution of recombination, like any trait, we need information on the heritability and plasticity of the trait, on how the trait influences fitness, and on the molecular mechanisms controlling the trait. In this respect, we know a lot about recombination—recombination is heritable, many populations harbour additive genetic variation for it, and it can respond to selection in the laboratory . RecombiAddressing the question ‘Why does recombination rate vary?’ necessitates understanding both direct and indirect effects of selection. However, most researchers often do not consider selection operating at these different scales simultaneously. For example, population geneticists often view recombination as a population parameter that is under indirect and long-term selection, whereas developmental biologists consider the direct, short-term effects that an altered rate of recombination has on individual traits like fertility. One goal of this Special Issue is to try to better integrate these different perspectives. Thus, we sought contributions from the ‘population genetics–evolutionary’ perspective –16 as weThe Special Issue opens with a general review of how and why recombination rate varies across eukaryotes. It includes an analysis of data from the largest collection of linkage maps to date and an overview of the processes that explain variation in recombination rate—from genome architecture to evolutionary explanations. The review introduces many of the concepts and evolutionary theories that are explored in greater depth in the proceeding articles. Although empirical data for recombination are growing rapidly, progress in explaining this variation has been slow. Dapper & Payseur  argue thet al. [et al. [Daphnia, a genus that contains both sexual and asexual parthenogenetic species. In cyclically parthenogenic species for which linkage maps have been made, we observe a very high recombination rate per megabase compared to other crustaceans [Variation in recombination may be explained by variation in the sexual system and the evolutionary consequences of different reproductive modes. For example, selfing and inbreeding species may benefit from high rates of recombination because it can increase genetic diversity and allelic shuffling, and there is some evidence to support this . Howeveret al.  build a  [et al.  acknowlestaceans . These aA notable pattern to emerge from empirical data is the observation that the distribution of recombination events is distinctly non-random across the genome. Variation is observed at many genomic scales: between chromosomes, between megabase regions within chromosomes and across regions spanning only a few kilobases. Between closely related species, there is often more variation in the distribution of recombination events compared to the total frequency of these events, suggesting that the rate at which recombination evolves is likely to depend on the genomic scale ,17. Variet al. [et al. [Estimates of recombination at the fine genomic scale can provide information about how recombination influences or is influenced by genetic elements and neighbouring DNA sequence. Recombination is often higher in sequence regions with high gene density and GC content and lower in sequence regions that are enriched for simple repeats and transposable elements (TE). Although these patterns are known from a wide range of eukaryotes, the proximate and ultimate mechanisms driving these correlations are poorly understood. To begin to address this problem, Kent et al.  provide et al. . Kent et [et al.  propose Another commonly observed pattern in sequence data is a positive correlation between recombination rate and nucleotide diversity. This relationship can be driven by the mutagenic effects of recombination , but it Caenorhabditis elegans [Drosophila [et al. [trans-acting factor has provided a great deal of insight into how and why hotspot activity varies between species [et al. [A pervasive pattern to emerge from accumulating fine-scale recombination data is that in many species, recombination is localized to small genomic regions referred to as hotspots. Hotspots are present in a wide range of species, but absent from some well-known model species such as  elegans  and Drososophila . Progres [et al.  provide  [et al. ,15. One  species . The rap species  and PRDM species . The selDrosophila melanogaster has been instrumental in the development of this field and Stevison et al. [D. pseudoobscura as a proof of concept and to provide new data in less characterized species [et al. [Variation in recombination is not solely due to genetic factors: a multitude of environmental factors both extrinsic and intrinsic have been found to alter recombination frequency and distribution. Experimental work in n et al.  review t species . Alves e [et al.  explore  [et al. .et al. [et al. [within a group of selected loci are determined by an unlinked locus, alleles at the locus conferring condition-dependent recombination can readily invade a population with a fixed recombination rate. These modelling results agree with theoretical studies that indicate that in diploids, direct effects—where the locus determining recombination influences recombination between itself and the group of selected loci—are unlikely to lead to plasticity in recombination rate. Interestingly, the simulations in the paper also demonstrate that plasticity in recombination rate requires that the population spends relatively equal time in different selective environments—if the majority of time is spent in a single environment, a single, fixed rate of recombination is favoured [While there are many environmental cues known to influence recombination, temperature and condition are perhaps the most well known. Morgan et al.  provide et al. . The secet al. . Previou [et al.  construcfavoured .good, the bad and the variable.In conclusion, in spite of exciting recent results, understanding how and why recombination rate varies across the genome and across taxa remains a major challenge in biology. For this reason, we present a series of contributions that critically evaluate theoretical and empirical developments on variation in recombination rate between taxa ,17,18 an


The production of biobutanol is hindered by the product's toxicity to the bacteria, which limits the productivity of the process. In situ product recovery of butanol can improve the productivity by removing the source of inhibition. This paper reviews in situ product recovery techniques applied to the acetone butanol ethanol fermentation in a stirred tank reactor. Methods of in situ recovery include gas stripping, vacuum fermentation, pervaporation, liquid–liquid extraction, perstraction, and adsorption, all of which have been investigated for the acetone, butanol, and ethanol fermentation. All techniques have shown an improvement in substrate utilization, yield, productivity or both. Different fermentation modes favored different techniques. For batch processing gas stripping and pervaporation were most favorable, but in fed‐batch fermentations gas stripping and adsorption were most promising. During continuous processing perstraction appeared to offer the best improvement. The use of hybrid techniques can increase the final product concentration beyond that of single‐stage techniques. Therefore, the selection of an in situ product recovery technique would require comparable information on the energy demand and economics of the process. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:563–579, 2017 Butanol is a commodity chemical used in a wide range of industries. It can be produced through biological or petrochemical routes. The original process route, started in 1913,Fermentation originally ceased being the main production route for butanol when it became economically uncompetitive with the petrochemical production of butanol. The main reasons for this were high substrate cost, low solvent yield (approximately 2 wt%), and high energy requirement for butanol recovery by distillation.in vitro production using immobilized enzymes,In situ product recovery (ISPR) should increase the concentration of ABE for downstream processing, thereby reducing the energy demand and operational expenditure of the plant.To overcome these problems, various strategies have been investigated, including: strain modifications to improve butanol tolerance,This paper provides a review of applied ISPR to ABE fermentations. The primary focus has been free cell (not immobilized or biofilm based) fermentations in a stirred tank reactor (STR), to allow for comparison of the various ISPR techniques. Other reactor configurations, such as immobilized bioreactors, have been considered if STR fermentations have not been performed. The techniques that have been experimentally combined with the ABE fermentation are gas stripping, vacuum fermentations, pervaporation, liquid–liquid extraction, perstraction, and adsorption.et al.The aim of ISPR techniques is to remove the product from the vicinity of the cell as soon as it is formed,et al.et al.et al.Since 2012, there has been a dramatic increase in the number of reviews focusing on the ISPR from the ABE fermentation. Abdehagh in situ recovery fermentation and the non‐integrated (control) fermentation. These parameters have been selected as they are generally considered as the main parameters of comparison in experimental based literature, particularly productivity and yield. Substrate utilization was selected to demonstrate the improvements in the fermentation, particularly fermentation longevity due to reduced toxicity. Measurement of substrate can be considered more reliable compared to product concentration, which can be highly inaccurate based on product separation methods. The concentrated product is not always directly measured, sometimes being inferred from model solution data or assuming the yield is the same as the control fermentation To compare the ISPR techniques, the amount of substrate utilized, productivity, and yield have been used. The substrate utilized is the total amount of substrate consumed during the fermentation. The productivity is defined here as the mass (g) of ABE produced per liter of reactor volume per hour. The yield is the mass (g) of ABE produced per mass (g) of substrate used.This review differs from the previous reviews by taking a quantitative approach to the comparing the experimental data of the ISPR techniques and their impact on the fermentation. This review also considers the final concentration from each ISPR technique that will enter the downstream distillation process, where possible.et al.et al.Gas stripping is a separation technique that involves the removal of solvents via dissolution into a gas passing through the fermentation broth. This technique was studied by a range of authors from the mid 1980s , or application of other anaerobic gases such as oxygen‐free nitrogen,et al.,A wide range of studies have been performed for gas stripping, with Ezeji's body of workC. beijerinckii BA101. In the continuous fermentations performed by Ezeji et al.,Interestingly, there is a decrease in productivity when moving to a continuous fermentation compared to the fed‐batch fermentation, but it should be noted that this comparison is based upon only one strain et al.,et al.et al.et al.et al.et al.There are some results in Table et al.et al. et al.Gas stripping has limitations due to the low ABE concentration in fermentation broth, large quantities of water removed and high gas flow rates required.et al.Since 2013 there has been a flurry of investigations into hybrid separations. A major focus of the hybrid separation processes has been improving the efficiency of gas stripping. This has included investigations into multi‐stage gas stripping processes, increasing the temperature at which gas stripping is performed and hybrid gas‐stripping pervaporation processes,et al.et al.et al.et al. et al.et al.To achieve this higher concentration, Xue et al.Gas stripping has also been combined with pervaporation, using a carbon nanotube filled polydimethylsiloxane (CNT‐PDMS) membrane.et al.,et al.et al.These hybrid techniques apply a second/enhanced separation stage to the fermentation. Other than de Vrije Clostridium sp. used are strict anaerobes.et al.Vacuum fermentations have a reduced pressure in the fermenter, causing the ABE to “boil off” at fermentation temperature. Vacuum fermentations were first used in the ethanol industry to selectively remove ethanol from fermentation broths. The use of a vacuum for an ABE fermentation should be more straightforward than for an ethanol fermentation, as the et alet al.et al.et al.Mariano Two vacuum modes have been investigated: constant and cyclic. Cyclic vacuum fermentations were found to be considerably more competitive in terms of energy demand than traditional distillation. The cyclic vacuum process allows the concentration of butanol to build up, then reduces the concentration rapidly by applying a vacuum for 2 h, repeating this process throughout the fermentation.et al.et al.,All of the literature focusing on vacuum fermentations for the ABE process is a product of the same researchers.et al.et al.Mariano Generally, the conclusions over application of vacuum to ABE fermentations are not definitive, as there is not enough data Table . The appPervaporation utilizes a membrane between the fermentation broth and the gaseous phase,Pervaporation has been shown to increase the substrate utilization, productivity, and yield of ABE fermentations (see Table b‐polydimethylsiloxane‐b‐polystyrene (SDS),For pervaporation, the major decision to be made is the choice of membrane, as the ideal membrane should selectively allow the transfer of ABE while retaining butyric acid, acetic acid, water, and nutrients. The membrane also needs to be minimally fouling, so that it is not blocked by cells adhering to the membrane surface. Table et al.The membrane choice affects the selectivity and diffusion rates of the ABE, which will determine the concentration of the ABE in the permeate. Unfortunately, the selectivity is in competition with the flux. Improvements in flux can be made to pervaporation through the use of higher temperatures, for example, but this would require an additional step of microorganism removal prior to heating the pervaporation feed stream to 65–78°C), and cooling of the retentate prior to re‐addition to the bioreactor.–78°C, anet al.et al.et al.,The use of a composite membrane has also been proposed as a method of achieving non‐competitive flux and selectivity. Polymers have high flux, are relatively cheap and easy to fabricate into a membrane, but are prone to aging over a long time. Inorganic materials are often highly selective for butanol and have good strength but are expensive. By combining both materials together, the membrane should be more selective with a sufficient flux while not having a prohibitive cost for scale‐up.As pervaporation is an evaporative ISPR technique, the product is captured through condensation. The inefficiencies of condensation of ABE have already been discussed in the sections concerning gas stripping and vacuum fermentation. In the papers regarding these techniques, the inefficiencies of complete product capture are acknowledged, but this has not been the case for pervaporation. In Table Liquid‐liquid extraction (LLE) is a common technique in the processing industries. It exploits the differences between relative solubility of a compound in two immiscible components. Typically, the solvent used is an organic liquid which is immiscible in water, therefore when applied to a fermentation broth, the product will preferentially transfer from the aqueous phase into the organic phase.et al.There are a variety of key parameters that need to be considered, described in Table et al.et al.et al.et al.Ishii et al.−1.The downside of this was the final product concentration only reached 25.32 g ABE/L. Dibutylphthalate was used as an extractant by Wayman and Parekhet al.et al.et al.Other solvents have been tested with fermentations, such as decanol, dibutylphthalate, 2‐butyl‐1‐octanol, and poly (propylene glycol) 1200.With LLE, the achieved yields are very low Table , especiaOne of the proposed advantages of ISPR techniques is the increased product titers, reducing the downstream separation energy demand. Unfortunately, the product concentration in the organic phase is rarely stated; rather the total product quantity/concentration based on the fermenter volume is specified. Without this concentration, it is difficult to assess the extraction efficiency in the same manner as evaporative techniques, where the final condensate concentration is stated.et al.et al.For an economically viable process, it is essential that the extractant is recyclable, meaning that the removal of ABE is straightforward. Unfortunately, removal of ABE from the extractant and regeneration of the extractant have not been discussed much in the literature. Roffler et al.,et al.,et al.To circumvent the re‐extraction step, Ishizaki Perstraction is a development from liquid‐liquid extraction experiments. It works on the same principles of mass transfer of ABE from the aqueous phase to an organic solvent, but the organic solvent and fermentation broth are separated by a membrane. The ABE transfers across the membrane into the organic phase. It is very similar to pervaporation, but has a liquid on the permeate side to provide the “driving force” rather than a gas or vacuum. If the key criteria for LLE, outlined in Table et al.et al.et al.The main technique has been extraction into oleyl alcohol across a silicone membrane, as this has favorable partition characteristics for butanol.et al.et al.,et al.et al.C. acetobutylicum was used for the fermentation, this could reduce the chances of the bacteria coming into contact with the solvent at the membrane interface. The only acknowledgement of using a toxic extractant was by Tanaka et al.,There have been two examples, Shukla et al.et al.et al.One of the problems of LLE was the trade‐off between having a high partition coefficient and being non‐toxic to the bacteria. It was thought that the use of a membrane to aid the extractive process would allow for the use of extractants with higher partition coefficients. As seen in Table et al.−7 m/s for silicone, 0.4 × 10−7 m/s for neoprene, and 0.3 × 10−7 m/s for latex; meaning that the membrane choice will have a significant impact on the mass transfer in the system. No comparisons of polypropylene hollow fiber membranes and silicone have been performed. Grobben et al.et al.et al.The majority of research has used silicone tubing as the membrane, Table Comparing the fermentations in Table et al.Adsorption is the binding of a compound onto the surface of a solid adsorbent or resin. It is the oldest technique investigated for the use of ISPR from ABE fermentations. In 1948, Weizmann et al.et al.A wide range of adsorbents have been used in conjunction with the butanol and the ABE fermentation, and this list is continually evolving as new, more complex adsorbents become available. Some of the adsorbents used are activated carbon,et al.et al.et al.C. acetobutylicum ATCC 824, the product concentration could be increased due to the adsorption of products, reducing toxicity. The final broth concentration reached 10 g butanol/L; this is the same as the fermentation with no ISPR, and the same yield was observed in both fermentations.et al.ex situ adsorption column, combined with a fed‐batch fermentation using C. beijerinckii NCIMB 8052, saw no detrimental effects to the fermentation. The integrated and non‐integrated fermentation both had the same yield of 0.31, but the integrated fermentation had an increased total product concentration of 26 g ABE/L compared to 18.5 g ABE/L. No productivity was supplied for these fermentations.et al.et al.The majority of the adsorbents have not been tested while coupled to an ABE fermentation, rather using a model ABE solution instead. Thus, there is a small amount of fermentation data to compare in Table et al.,et al.et al.et al.et al.Weizmann A downside of adsorption is that it is inherently a batch process, as the ABE has to bind to the adsorbent and then, once it has reached capacity, desorption has to occur. In many experiments, batch adsorption was performed,Once the adsorbent has reached its capacity the ABE needs to be removed and the adsorbent regenerated. The main methods of adsorption are through increasing the temperature,Currently, no review has compared all possible ISPR techniques for ABE fermentations. One challenge is that it is difficult to make accurate comparisons between work performed by different groups, as different methods and procedures have been followed. This includes the use of different strains, media, reactor configurations, and mode of operation. To make a valid comparison between the different ISPR techniques, they have principally been compared in terms of their fermentation performance in STRs  can have a positive effect on the fermentation. This is due to the removal of the butanol inhibition allowing for complete utilization of the substrate and the possibility of prolonged fermentations. This is seen by the significant increase in substrate utilization in Tables Where overcoming product inhibition has been successfully demonstrated for any technique, the next step is to perform a fed‐batch fermentation which increases substrate loading and fermentation time giving higher productivity. Increases of substrate between 100 and 900% compared to the control fermentation are common, Tables et al.et al.et al.In literature, there have been some discrepancies between what is considered a fed‐batch and continuous process. There have been several occurrences where a fed‐batch fermentation has been called continuous in literature.Continuous fermentations can be performed, but the continuous removal of fermentation broth leads to a lower increase in yield than for fed‐batch fermentations Table . In spitet al.In recent years, there has been a growing trend to immobilized fermentations. A good example of this is Xue et al.One of the factors driving the application of ISPR to the ABE fermentation is the potential energy reduction, due to increased ABE concentration going to downstream processing. The energy associated with separation is generally not considered alongside the experimental results. Xue The review has compared six ISPR techniques based on available experimental data focusing on free cell fermentations. To mitigate the effects of various experimental methods, the % increase of substrate utilized, productivity, and yield was considered. The experimental data has successfully demonstrated that ISPR has a positive impact on the fermentation. The generation of models to represent the fermentation with integrated ISPR could help speed up developments in ISPR. They can help focus developments to the techniques which would provide the greatest improvements to the process. Experimental work can then be completed to validate the model results and confirm there are no biocompatibility issues. This will reduce the time and expense of testing every ISPR possibility experimentally, and provide a comparable baseline. The comparison of different experimental studies can also be improved through standardization of published experimental results for ISPR processes. This can be done by ensuring that enough data is provided to enable a mass balance of the process to be calculated, hence enabling an easier comparison; see supplementary material for a suggestive list of data to be included.From the comparison of STR fermentations, it is possible to say that all techniques exhibit improvements in fermentation productivity and that for different operating modes different techniques appear to be superior. For batch fermentations, gas stripping, and pervaporation were favorable, for fed‐batch: adsorption and gas stripping, and continuous perstraction has the greatest improvement. The use of novel two‐stage or hybrid techniques also needs to be considered, particularly their compatibility with free cell STR fermentations. This means that the decision on which technique to apply will be based on additional data such as energy consumption and an economic analysis. These should be considered alongside the fermentation data, and this would help to categorically state which is the best ISPR technique. Future work should include process optimization as part of trying new feedstocks, improved strains, or separating agents .


I am working on the role of aberrant gene expression in the pathogenesis of nonfunctioning pituitary adenomas. I started my work with a search of the literature and deposited data from previous expression profiling experiments. Therefore, I have read the article “Identification of Differentially Expressed Genes in Pituitary Adenomas by Integrating Analysis of Microarray Data” published by Zhao et al. with great interest . The autThis kind of study is essential to investigate molecular pathogenesis of pituitary adenomas as only a few microarray-based expression profiling studies were performed on samples of gland affected by this disease. Most of these investigations included a small number of patients, usually involving very few or no control samples from normal human pituitary tissue. Zhao et al. combined existing repositories of microarray data from three studies to collect expression profiles of 12 normal pituitary samples. According to the published methodology, six of these control samples are from the study reported by Hussaini et al. [The aim of the research of Zhao et al.  was the The integrative analysis of gene expression profiles in pituitary adenomas, based on the methodology used by Zhao et al., is still needed, and further research is expected to shed light on the pathogenesis of pituitary adenoma. Due to the fact that previously published large-scale expression analyses of pituitary adenomas included only a very small number of samples from normal pituitary, more subtle differences between normal and tumor tissue in the pituitary at the molecular level remain elusive. However, accurate selection of data is crucial for reliable outcome and its interpretation. For this reason, I feel obliged to point out the mistake that occurred in the analysis by Zhao et al.  and to e


In future, the South African Department of Health aims to purchase services from accredited private service providers. Successful private audiology practices can assist to address issues of access, equity and quality of health services. It is not sufficient to be an excellent clinician, since audiology practices are businesses that must also be managed effectively.The objective was to determine the existing and required levels of practice management knowledge as perceived by South African audiologists.An electronic descriptive survey was used to investigate audiology practice management amongst South African audiologists. A total of 147 respondents completed the survey. Results were analysed by calculating descriptive statistics. The Z-proportional test was used to identify significant differences between existing and required levels of practice management knowledge.Significant differences were found between existing and required levels of knowledge regarding all eight practice management tasks, particularly legal and ethical issues and marketing and accounting. There were small differences in the knowledge required for practice management tasks amongst respondents working in public and private settings.Irrespective of their work context, respondents showed that they need significant expansion of practice management knowledge in order to be successful, to compete effectively and to make sense of a complex marketplace. Audioloet al., et al., The future of private audiology practices depends on how well audiologists are able to take their clinical training and practice management skills to the marketplace Metz, . This ban = 256) in the United States of America (USA) and Canada . The data was collected anonymously and treated with confidentiality. No identifying information of the respondents was reported and internet protocol addresses were not tracked. An informed consent letter formed part of the web-based survey and was the first page that respondents viewed once they clicked on the link. By completing the web-based survey respondents gave their consent to participate in the study on a voluntary basis.n = 326) and SASLHA (n = 1300) as their member databases are updated annually, and they were able to send the survey to all their members. Since there was no effective way to determine which of the SASLHA members practice only as speech-language therapists, a number of redundant emails were sent to speech-language therapists. Some audiologists are also registered with both the SAAA and SASLHA, meaning that some respondents might have received an invitation to participate twice. An email message providing the web address where the respondent could link directly to the survey was thus sent to a total of approximately 1626 prospective respondents. A total of 147 respondents completed the survey indicating a minimum response rate of 9%. A description of the respondents is given in The population of interest was registered audiologists and dually qualified speech-language therapists and audiologists working in public or private settings in South Africa – whether they are involved in practice management or not. A non-probability, convenience sampling strategy was employed. Because a large number of audiologists are still dually qualified, it was not possible to determine how many of the professionals are practicing only as audiologists. At the time of data collection there were 1749 audiologists and dually registered speech-language therapists and audiologists registered with the Health Professions Council of South Africa HPCSA, , but emaAccording to n = 11) as demographic information was obtained last in the web-based survey, and some respondents did not complete all the questions.There is also incongruity regarding the number of respondents employed in each province and the size of each province. Some provinces, such as the Northern Cape, were underrepresented in the survey. There were a few missing values  for statistical analysis. Results were quantitatively analysed by calculating descriptive statistics such as percentages, frequency distribution, measures of central tendency and standard deviation. This assisted in organising and summarising the data. The Z-proportional test  were also rated highly. Finance (91.8%), accounting (91.7%) and strategic management (91.7%) were considered by the respondents to be equally important. An ability to understand the financial drivers of a successful practice is a fundamental and long-lasting skill set that will benefit any professional regardless of his or her work setting Traynor, . RespondBy combining the two tables, differences in knowledge can be highlighted. The difference between the required and the existing levels of knowledge levels is indicated in et al. (p < 0.05). The results are in agreement with Henson et al. , organisational behaviour and human resources (p = 0.049) and operations and systems management (p = 0.000). Respondents working in a private setting had a higher existing knowledge regarding these three tasks. Respondents working in a private setting may gain more experience regarding marketing as they have to actively market their practices. It is possible that respondents working in the public sector might be overburdened by the demand for their services and therefore have limited knowledge regarding marketing. Respondents working in the private sector are solely responsible for organisational behaviour and human resources. In a public setting these responsibilities are handled collectively. The Z-proportional test revealed no significant differences between respondents working in a public and/or private context regarding their required levels of knowledge in all eight of the practice management tasks. The results indicated that there is a great need for knowledge regarding practice management irrespective of the working environment. Respondents work in a variety of employment contexts throughout their careers with various common traits; for example, they all have to conform to legal and ethical constraints. Therefore, the required level of knowledge regarding legal and ethical issues is high, regardless of the employment context.According to Respondents indicated in the text data section that their biggest strengths were patient satisfaction, successful marketing, and starting their own practices. Respondents indicated that a lack of training, knowledge, experience and sufficient finances were their biggest challenges in practice management in South Africa. In the open comments section of the survey, one respondent stated that ‘a lack of knowledge and education before starting your own private practice is the biggest challenge in practice management in South Africa’. The majority of respondents indicated that training is required to overcome these challenges.According to et al. , and departments of audiology at universities were rated highly. The latter indicated that respondents wanted to learn from lecturers with experience in the field, and that universities are held in high regard by the respondents. According to Fasokun, Katahoire and Akpovire , experieet al.  adult le et al., . The maj et al., , adult l et al., .Marketing was rated as the most important topic to be included in training (93.5%), which is in agreement with the required levels of knowledge as indicated by the respondents in et al., et al., et al. (et al. (et al. (et al., et al., This study found significant differences between respondents’ self-perceived existing and required knowledge in all eight practice management tasks. Legal and ethical issues, as well as marketing and accounting, revealed the biggest differences. Respondents recognised that they need significant expansion of their practice management knowledge, skills and attitudes in order to be successful irrespective of their work context. The success of private audiology practices is also important for the future engagement between private and public sectors when the National Health Insurance system is implemented. To address these needs audiology programmes should incorporate aspects of all eight practice management areas that compose what is considered the most important body of knowledge for practice management (Henson , et al. , there a, et al.  states t, et al. , audiolo, et al. . There a (et al.  giving u (et al.  recommen et al., . Taking et al., A limitation of the current study is the fact that the results reported on are derived from a small sample of audiologists and dually qualified speech-language therapists and audiologists in South Africa. The response rate was below the desirable rate described in the literature (Maxwell & Satake,


Quality of life (QoL) is an important outcome for people with dementia living in care homes but usually needs to be rated by a proxy. We do not know if relative or paid carer proxy reports differ. We conducted the first systematic review and meta-analysis of data investigating whether and how these proxy reports of QoL differ.dementia, QoL, proxy, and care home. Included studies either compared proxy QoL ratings or investigated the factors associated with them. We meta-analyzed data comparing staff and family proxy rated QoL.We searched four databases: Medline, Embase, PsychInfo, and CINAHL in October 2015 with the terms: n = 1,290; pooled effect size 0.06 (95% CI = −0.08 to 0.19)). Studies investigating factors associated with ratings  found family and staff ratings correlated with the resident's physical and mental health. Staff who were more distressed rated resident QoL lower. Relatives rated it lower when the resident had lived in the care home for longer, when they observed more restraint, or contributed more to fees.We included 17/105 papers identified. We found no difference between global proxy ratings of QoL (Relatives and staff proxy QoL ratings share a clear relationship to resident health and overall ratings were similar. Rater-specific factors were, however, also associated with scores. Understanding why different raters consider the QoL of the same person differently is an important consideration when evaluating the meaning of proxy rated QoL. Proxy raters’ backgrounds may affect their rating of QoL. We hand-searched the references of all included papers and contacted authors of included papers to ask about other related literature. Where information from papers was missing, we contacted the authors to ask for the information.The review was registered on the International Prospective Register of Systematic Reviews (PROSPERO) on the 18th February 2015. Searches were conducted in October 2015 in Medline, Embase, PsychInfo, and CINAHL databases; using the search terms: We included studies in any language reporting quantitative ratings of QoL of people with dementia living in care homes and either (1) comparing two different proxy perspectives for the same individual or (2) describing the factors associated with proxy rated QoL.et al., 1.Was the population defined by a clear inclusion and exclusion criteria?2.Were the data collection methods standardized?3.Were the measures used for QoL valid, and reliable, and used in an appropriate way?4.Was there sufficient power to conduct the analysis, judged by a sample size of greater than 30 where a power analysis had not been conducted?SR extracted data and SR, OH, and AS independently rated quality using operationalized checklists for quantitative papers previously developed by our group , with five studies using the Alzheimer's Disease Related Quality of Life (ADRQL); other measures used (each in one paper) were: QoL in Late-Stage Dementia (QUALID); Dementia Quality of Life (DQOL); QUALIDEM; and a single item questionnaire. Five studies measured staff and family carer perspectives; ten studies only asked staff; and one only asked family carers to proxy-rate life quality.We identified 105 unique publications in the electronic database search, of which 16 met eligibility criteria. One additional paper was included from the references list of included papers, resulting in 17 included papers that reported 16 studies: five took place in the UK, six in other European counties, three in the USA, and one in each of Taiwan, Japan, and Australia. The majority of papers collected information using the Quality of Life-Alzheimer's Disease (QOL-AD)  collected data from both staff and relative perspectives. Data are described in et al., n = 3), these are also described in et al., et al., Four studies .Factors associated with a staff and relative rated QoL are summarized in et al., et al., et al., et al., et al., et al., et al., Lower staff and relative rated QoL was associated with: lower resident weight  with staff ratings of QoL but not with relative ratings   but this did not reach statistical significance for relative rated QoL   but relative ratings were not    and β = −4.64 ) ) and observed restraint ) but the relationship with staff ratings was much smaller and did not reach significance ) , “marriage” , “friends” , “ability to do chores” , and “ability to do things for fun” . This paper also found that if the primary nurse rated the QoL, there was significantly more agreement with resident ratings (p < 0.05).Graske et al.  reportedet al.  over a three month period. In contrast, greater dependency  and more depressive symptoms  at baseline were associated with declining staff proxy-reported QoL.Beerens et al.  found thWhen comparing the overall means of groups we did not find a significant difference between global QoL scores between relative and staff proxy ratings for care home residents with dementia. In three of four studies examining this, there was a non-significant trend toward care staff rating QoL higher than family members, but we can conclude from existing data that any systematic difference in global ratings is small, and not of the magnitude of those reported between self and proxy reports of life quality in people with dementia. The majority of studies included used the QOL-AD and ratings from different proxy groups have not been compared for a number of other QoL measures used in people with dementia. This is an important consideration when evaluating validity of QoL measures for use in care homes. When papers compared ratings for individuals by looking at the correlation between staff and family carer rated QoL there was moderate agreement in two of three papers. These results suggests raters are considering similar things when rating QoL but that there are also some differences that are not reflected in the overall mean score of groups.et al., et al., et al., et al., Relatives and staff proxy QoL ratings share a clear relationship to resident physical and mental health, including: lower weight, use of antipsychotic medication, depression, higher physical disability, pain, poorer cognitive function, and lower capacity to carry out ADL. Rater-specific factors were also associated with the scores they give. Staff QoL ratings were associated with their own levels of stress and burnout. This fits with existing research in the community that shows that low proxy rated QoL is strongly influenced by the family carer's mood and experience of caring (Karlawish The fact that staff rated the QoL of residents who exhibited more agitation, challenging behavior and unmet needs lower, but relatives did not, could suggest that there are aspects of the resident's life that relatives are less aware of, or that staff's own feelings affect their ratings. Agitated and challenging behavior may be more likely to occur at times of personal care or may be more common when relatives are not there, thus, limiting a relatives exposure to these behaviors. Care home studies more commonly measure staff rated QoL, so associations with relative rated QoL have been less widely studied. The relevance of the context of the proxy rater was also demonstrated by the finding that lower relative proxy ratings of QoL were associated with a longer stay in the care home, as well as higher relative contribution to nursing home fees; possibly indicating burden for the relative.These results suggest it is important to collect data about the environment of the residents as it may explain some of the variation in ratings, particularly in samples with participants recruited from different care homes. Many care home residents with dementia do not have a family member who visits regularly; findings from studies of those that do in which proxy-ratings can be compared, can help us interpret and validate staff rated QoL measurements that are potentially available for all residents.Existing research suggests there is little difference between paid carer and family carer perspectives of QoL when comparing overall means scores of the QOL-AD and QUALID but that this different does not imply ratings are the same as they are not strongly correlated. This can be explained by the fact that different factors are associated with proxy reported QoL for staff and family members. Paid carer and family carer proxy rated QoL is lower with the presence of more stress in their own life and this may lead to differences in overall ratings in other more detailed QoL questionnaires or in differences between individuals and this should be explored in future research.et al., Proxy rated QoL is a vital outcome in a care home context and it is important to understand what is being measured. Future research should investigate the differences between different perspectives of QoL using different QoL measures that allow cost calculations. Cost effectiveness is an important outcome to ensure that interventions give value for money and the DEMQOL (Smith None.Sarah Robertson conducted the literature searches, data extraction, study quality appraisal, and prepared the first draft of the paper as part of her PhD project. Aisling Stringer and Olivia Hamilton independently conducted study quality appraisal and resolved any disagreements with Sarah Robertson. Gill Livingston, Claudia Cooper, and Juanita Hoe revised the paper critically and approved the final version for publication.


On the contrary, if a doctor doesn't clean the instruments before surgery, microorganisms will be there during the operation, and they may infect us, because the environment in the OR won't kill them.Rummel and Conley  argued ti.e., the bioload)” of a mission will determine “the probability of microbes surviving either natural or human-mediated transfer” .” This means that the best candidates to be Special Regions on Mars are hypothetical, nonconfirmed, and unreachable, bringing our initial question to the table again: What exactly are we protecting with planetary protection policies on Mars?In the end, Rummel and Conley  acknowleet al.,et al.,Rummel and Conley  respondeIn any case, if we assume the premise that it is not so costly or difficult, then the question immediately arises as to why we are not investigating Special Regions today. This is not a rhetorical question; if it is not budget constraints, what is the reason that we have not conducted true life-seeking missions on Mars since Viking? Rummel and Conley  claimed et al.,et al.,i.e., La Duc et al.,Rummel and Conley  added thet al.,if (a big if) martian life is genetically similar to Earth's. Rummel and Conley ignored our disclaimer and then elaborated on the possibility that martian and Earth life would be genetically different; we do not object to those comments.Rummel and Conley  questionBut later in their response, Rummel and Conley alerted about the possibility of lateral gene transfer between terrestrial and martian biospheres “if Earth life and martian life are related, or if martian life is unrelated but still uses DNA/RNA.” This is in blatant contradiction to their previous argument that “there is a very real possibility that extraterrestrial life does not possess either RNA or DNA, which would make any question of sequence comparison irrelevant.” Given that these authors used this argument before to discredit our points about identifying life on Mars, Rummel and Conley  should ni.e., Parro et al.,et al.,et al.,et al.,et al.,et al.,et al.,To address the core of this issue, it should be said that there are indeed plenty of other strategies proposed with which to search for extant life on Mars, and most of them do not involve DNA/RNA examination  under today's martian conditions? The answer is no. If such Earth organisms were introduced into an underground martian environment, they would be rendered lifeless in a time measured in minutes or less.Their discussion then shifts to “self-calcifying crack-closing microbes used as a concrete additive” on Earth. But could these or any other of the “certain organisms” mentioned by Rummel and Conley , citing et al. , which aet al.,Rummel and Conley  stated tet al.,If martian microbes exist, they have been arriving at Earth for billions of years via meteorites, given that the trip from Mars to Earth is easier than from Earth to Mars, and it has been estimated that this happens 10 times more frequently  than the prospect of finding life on Mars. The search for life on Mars is one of the most fascinating scientific endeavors of our time. And interest in the search for life goes beyond the Mars science community, which is clear by the amount of press and media coverage missions to Mars receive.i.e., Grossman, et al.,et al.,et al.,et al.,et al.,et al.,et al.,et al., current habitability and expression of biosignatures contain evidence of extant life” . ESA argues in the same way that a “basic question” to answer in Mars exploration is whether “was there ever, or is there still, life on Mars” and that spacecraft investigations “should include science packages to search for evidence of extinct or extant life” ; indeed the objectives of the agency's first Mars rover, ExoMars, are “to search for signs of past and present life on Mars” . And the NASA Astrobiology Institute includes, among its main objectives, the “search for evidence of ancient climates, extinct life and potential habitats for extant life on Mars” .At the same time, all Mars missions are put forward as relevant for life detection. For example, NASA's Science Goal 1 for Mars exploration states: “On Mars, we will therefore search for evidence of life in areas where liquid water was once stable, and below the surface where it still might exist To check the consensus and priorities of the Mars community, a good start would be that a forthcoming MEPAG meeting put this question on the table. If we are erroneous, and the Mars community were to agree with Rummel and Conley  that a m


Wu et al.  describe2+-sensitivity  by almost 0.1 pCa units, with little or no effect on the maximum MgATPase activity or the maximum sliding speed of thin filaments in motility assays (Sommese et al., 2+-responsiveness of the myofilaments almost certainly results directly in reduced mechanical function of the heart during systole, to the detriment of the DCM patient. Remodeling of the DCM heart, however, depends in part on changes in gene expression. Mechanisms of altered gene regulation in cardiomyopathies have typically focused on changes in Ca2+-signaling, mechanosensing, and/or energy metabolism (Frey et al., The mutation studied by Wu et al.  is a poi2+ signal that activates systolic cardiac contraction (Figure Wu et al.  found thn Figure . Althougn Figure , 2016. IWu et al.  performeWu et al.  demonstrLC and PC wrote and edited the commentary, JD edited the commentary.The authors declare that the commentary was written in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer BB and handling Editor declared their shared affiliation, and the handling Editor states that the process nevertheless met the standards of a fair and objective review.


Editorial on the Research TopicZika Virus ResearchThe considerable number of viral infectious disease threats that have emerged, since the beginning of the twenty-first century has shown the need to dispose global and coordinated responses to fight properly and efficiently against them. Severe acute respiratory syndrome 2003), avian influenza in humans (2005), AH1N1) pandemic influenza (2009), Middle East respiratory syndrome coronavirus (MERS-CoV) (2012 onward), and Ebola virus disease (2014–2015) are some of the most important examples  and Southeast Asia (where the two most important vectors are well distributed). Recently, some of these concerns have become reality, especially in Southeast Asia where several countries have reported autochthonous cases in the past months . Rather et al. also reviewed the results of preventive campaigns conducted in different parts of the world, which were based on different approaches like, for instance, avoiding unnecessary travel to infected areas and mosquito bites. They argue that these and other proactive measures could “be employed to effectively combat the epidemic transmission of the Zika virus.”Prevention and control strategies have also been deeply discussed in the topic. One of the most applied examples has been given by Rather et al. provided an interesting and deep review about the scientific evidence supporting a causal relationship between ZIKV infection during pregnancy and congenital abnormalities. Coming closer to specific congenital and neurological problems, Yuan et al. commented a very interesting point of view regarding the teratogenic effects of Zika virus and the role of the placenta as natural barrier against the infection . Their results revealed abundant intrinsically disordered protein regions (IDPRs) in Zika virus polyprotein, capsid protein, and several non-structural proteins, which could play a role in the pathogenesis of the disease. In an interesting study of the mutational preference direction of Zika virus, Khrustalev et al. contributed with promising and useful data that may have further implications for vaccine development and for the understanding of the evolution of new Zika virus strains.Different virological aspects have also been well analyzed in the topic. Craig et al. and Saiz et al. crossed interesting points of view regarding the review article by Saiz et al.Short discussions by way of articles commentaries could not be missed in the topic. Munjal et al. gives a great overview of different advances in the development of therapies against Zika virus, while Shukla et al. focus their review on rapid detection strategies of the virus in order to have quick response mechanisms to fight efficiently against the disease and to prevent reaching epidemic levels. Wider approach has been given by Shankar et al., encompassing additional aspects related to virus genome, clinical manifestations, diagnosis, and vaccine development. The four classical steps of epidemic management  are also well addressed by Sharma and Lal. Mini reviews about Zika virus emergence at American and worldwide level have been also interestingly written by Fajardo et al. and Rather et al., respectively. With all this information, Saiz et al. elaborated a very pertinent compilation of data and information to arrange all that has been learned at virological, entomological, clinical, and epidemiological level, since the start of Zika epidemic in late 2015.Finally, some of the most relevant sources of knowledge of the Zika Virus research topic reside in several excellent reviews. We want to thank all the authors and reviewers for their valuable contributions to this research topic, and we hope that this collection of reviews, commentaries, and original articles will be helpful for clinicians, researchers, and students seeking for information about Zika virus.Main text has been redacted by RB-M. All authors revised and approved the Editorial.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The current edition of the journal brings forth diagnostic and surgical techniques in glaucoma. Mingguang He et al review the clinical applications of ultrasound biomicroscopy for the anterior segment, while Sathyan et al provide insight into the applications of optical coherence tomography in glaucoma diagnosis, and Kaushik et al review the uses of ocular response analyzer in determining corneal hysteresis. Khanna and Ichhpujani detail on the use of low vision devices in glaucoma, while Khurana et al give a perspective on drug-induced glaucoma. The Ex-PRESS shunt, a new microshunt for glaucoma surgery, is presented by Angmo et al in the treatment of neovascular glaucoma. We hope that the reader will find the articles of interest and help them in improving the standard of care in glaucoma patients.Editors


Marko Curkovic in his letter  points oGoogle Scholar and Google Search are considered to be important sources of grey literature, governmental and institutional reports (Haddaway et al.


As a pertinent addition to the literature, the study highlights several concerns currently facing those in the transcranial electrical stimulation (tES) community.Tremblay et al.  investigtDCS has become increasingly popular as a result of research by Nitsche and Paulus , which dIn this context, the article by Tremblay et al. represents a milestone for tES research. Systematic studies of tDCS effects are currently in the minority and researchers are largely unaware of the influence subtle variations in stimulation parameters are likely to have on results. Those studies that do exist have utilized relatively complex designs and atypical stimulation parameters (weak current strengths, novel stimulation intervals and/or small electrodes e.g., Batsikadze et al., It cannot be ignored that the article reflects a series of non-significant results. None of the four assessed intensity/duration pairings altered corticospinal excitability in a manner that was statistically meaningful. Prominent inter-individual differences in response rates were likely to have contributed to these outcomes, with non-responders constituting up to 80% of the sample, but what does this variability mean for the future of tES?One may assess these findings in the context of recent meta-analyses, which demonstrate a lack of consistent effects on behavioral and neurobiological metrics, and decide to view them as a further blow to a field already marred by controversy (Horvath et al., Advocating the publication of non-significant results, like those of the article in question, will inevitably assist in the reformation of tES research—especially where they originate from methods-driven investigations (Hanley et al., A number of issues concerning the validity of tES research are brought to light by Tremblay et al. . As outlThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


We welcome Jesus et al.’s paper, which makes an important contribution to the under-researched area of the physical rehabilitation workforce. The authors present recommendations to “advance a policy and research agenda for ensuring that an adequate rehabilitation workforce can meet the current and future rehabilitation health needs” (p. 1). We argue that their perspective could however be strengthened by adopting a stronger global perspective, including consideration of the needs of low-resource settings. In particular, we highlight the integral role of more effective sector and inter-sectoral governance, the opportunity to support the development of community-based rehabilitation (CBR), the lessons that can be learnt from human resources for health (HRH) research and practice more generally, and the recent developments in the global provision of assistive technologies. Each of these issues has important implications and contributions to make to advance the policy and research agenda for the global rehabilitation workforce. We welcome Jesus et al.’s paper , which mJesus et al. propose a policy agenda, highlighting the need to “adapt policy options to different contexts , even within a country” (p. 1), and provide recommendations for both local and global policymakers. However, the six rehabilitation workforce challenges outlined by the paper do not sufficiently recognise the integral role of governance and leadership in addressing these, including strategies to increase the priority of rehabilitation on the health agenda. Dieleman and Hilhorst  specify With the rapidly growing ageing population, and the majority of persons with disabilities living in low- and middle-income countries (LMICs), there is a need to consider the global context when addressing rehabilitation workforce challenges , 10. JesWhile Jesus et al. focus on setting an agenda for physical rehabilitation, it is important to consider that often professionals working with people with physical disabilities may need to have a multi-faceted skillset . This caWhile the role of task-shifting in providing services was alluded to by Jesus et al., this approach deserves much more attention. The evidence for task-shifting in rehabilitation is slowly growing . HoweverOne of the most significant global initiatives in the field of physical rehabilitation is WHO’s GATE  programme, which seeks to produce a step-change in the provision and use of affordable quality assistive technology (AT) . FollowiJesus et al. draw attention to the important and under-researched area of physical rehabilitation health workforce challenges. It is important that while setting a global agenda, such an effort should encompass the challenges and potential solutions for high-, medium- and low-resource settings, as well as urban and rural settings. We have sought to complement Jesus et al.’s important article by highlighting some of the ways in which this can be done.


Herbal medicines play an important role globally in the health care sector and in industrialised countries they are often considered as an alternative to mono‐substance medicines. Current quality and authentication assessment methods rely mainly on morphology and analytical phytochemistry‐based methods detailed in pharmacopoeias. Herbal products however are often highly processed with numerous ingredients, and even if these analytical methods are accurate for quality control of specific lead or marker compounds, they are of limited suitability for the authentication of biological ingredients.To review the benefits and limitations of DNA barcoding and metabarcoding in complementing current herbal product authentication.Recent literature relating to DNA based authentication of medicinal plants, herbal medicines and products are summarised to provide a basic understanding of how DNA barcoding and metabarcoding can be applied to this field.Different methods of quality control and authentication have varying resolution and usefulness along the value chain of these products. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control.DNA barcoding and metabarcoding have potential in the context of quality control of both well and poorly regulated supply systems. Standardisation of protocols for DNA barcoding and DNA sequence‐based identification are necessary before DNA‐based biological methods can be implemented as routine analytical approaches and approved by the competent authorities for use in regulated procedures. © 2017 The Authors. Phytochemical Analysis Published by John Wiley & Sons Ltd. Herbal medicines play an important role globally in the health care sector and in industrialised countries they are often considered as an alternative to mono‐substance medicines. Different methods have varying resolution and usefulness along the value chain of these products. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control. The global market for herbal products is projected to reach US$115 billion by 2020, with Europe leading the market , herbal products fall into two main categories, herbal medicines and herbal food supplements , depending on their primary intended use. The EU directive 2004/24/EC, commonly referred to as the Traditional Herbal Medicinal Products Directive (THMPD) establishes a simplified procedure allowing the registration of herbal medicines as medicinal products , Echinacea sp. (coneflowers), Actaea racemosa L. (black cohosh), Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. (Siberian ginseng).As a result of these distinct legislative frameworks, the same herbal product may coexist under different categories. For instance, et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., One of the core interests of modern pharmacognosy refers to the identification and authentication of drug substances and to the quality of the resulting herbal medicines  for primary qualitative analysis, or alternatively using hyphenated methods  to enable also the quantification of the lead or marker compounds , with the focus on plant sampling, barcode regions, DNA extraction, purification and amplification, and the sequences reference database  Regel . Only 15% of investigated Veronica herbal products contained the target species Veronica officinalis L., whereas the main known adulterant, Veronica chamaedrys L., was detected in 62% of the products  and DNA barcoding, known as DNA metabarcoding, enables simultaneous high‐throughput multi‐taxa identification by using the extracellular and/or total DNA extracted from complex samples containing DNA of different origins (Taberlet , et al.  found th (et al.  found th et al., . Out of et al., et al., All these studies report varying degrees of authentication success. Therefore, obtaining a representative assessment of complex herbal mixtures is influenced by many factors, including the quality and type of raw material, as well as several elements of the analysis that can however be varied to optimise the results (Staats et al., et al., et al., et al., et al., et al., et al., et al., In the context of the quality control of herbal products, DNA barcoding and metabarcoding do not provide any quantitative nor qualitative information of the active metabolites in the raw plant material or the resulting preparation, and this narrows its applicability only to identification and authentication procedures. However, the use to identify and discern taxa at any developmental or processed stage from which DNA can be extracted is an essential advantage of DNA barcoding and metabarcoding (Hebert Both chemical and biological methods require comparison of detected compounds against reference standards. For chemical methods these can be lead or marker compounds, adulterants or more advanced computational scans of chemical databases. For biological DNA‐based methods there are similar advanced computational scans linked to well‐curated nucleotide sequence repositories. Chemical methods can be used in all stages for quality control and provide insights into the presence or absence of compounds defining a product. Biological methods based on DNA barcoding can be used for authentication of raw biological materials from cultivation or wild‐harvest at source or before manufacturing, but not accurately once the material is mixed with other biological material. Biological methods based on DNA metabarcoding can be used for authentication of finished products, post‐marketing control and pharmacovigilance, and provide insight into the total species diversity in a product.Each method has its benefits and limitations, and its specific strength when applied correctly in the herbal product value chain. Both DNA barcoding and metabarcoding have potential in the context of quality control of both well and poorly regulated supply systems. DNA barcoding can be used for authenticating products based on single herbal ingredients and DNA metabarcoding for assessment of species diversity in processed products, and both methods should be used in combination with appropriate hyphenated chemical methods for quality control. Standardisation of protocols for DNA barcoding and DNA sequence‐based identification are necessary before DNA‐based biological methods can be implemented as routine analytical approaches and approved by the competent authorities for use in regulated procedures.


Climate model simulations uniformly show drier and warmer summers in the Eurasian midcontinent during the mid‐Holocene, which is not consistent with paleoenvironmental observations. The simulated climate results from a reduction in the zonal temperature gradient, which weakens westerly flow and reduces moisture flux and precipitation in the midcontinent. As a result, sensible heating is favored over evaporation and latent heating, resulting in substantial surface‐driven atmospheric warming. Thus, the discrepancy with the paleoenvironmental evidence arises initially from a problem in the simulated circulation and is exacerbated by feedback from the land surface. This region is also drier and warmer than indicated by observations in the preindustrial control simulations, and this bias arises in the same way: zonal flow and hence moisture flux into the midcontinent are too weak, and feedback from the land surface results in surface‐driven warming. These analyses suggest the need to improve those aspects of climate models that affect the strength of westerly circulation. CMIP5/PMIP3 mid‐Holocene simulations in the Eurasian midcontinent are too dry and too warm relative to paleoclimatic observationsThis mismatch is attributed to simulation of weak westerlies and moisture fluxes, amplified by surface‐energy‐balance and surface‐water‐balance feedbackThe mismatch is similar to bias in climate model simulations for the present day The midHolocene experiment shows the response to changes in the seasonal and latitudinal distribution in insolation 6000 years ago, with greenhouse gas concentrations at preindustrial levels . We usen et al. . Long‐tepiControl simulation (circa 1850 Common Era (C.E.)). We therefore use National Centers for Environmental Prediction‐Department of Energy (NCEP‐DOE) Reanalysis 2 data .The mid‐Holocene (MH) has been a major focus for paleoenvironmental and paleoclimate synthesis. We use data from the Global Lake Status Database  over the Eurasian midcontinent in the CMIP5/PMIP3 midHolocene simulations compared to the piControl  and soil moisture (as measured by α). Drier (than piControl) conditions are most marked in the belt between 40° and 60°N. Summer temperature is significantly higher than in the piControl  [see Bartlein et al., midHolocene simulations therefore appear to be too dry and too warm relative to the paleoclimatic observations.There is substantial agreement in the spatial and seasonal expression of the sign of change in the simulated climate variables across individual models see the , which aAlthough generally dry, the region of interest has a distinct summer wet season, when soil moisture is replenished by higher precipitation provided by increased moisture flux from westerly sources see the , and thepiControl over the first half of the year. Precipitation is lower than piControl through May and little different afterward  confirms that summer warming is a surface‐driven phenomenon , the latitudinal temperature gradient in the Northern Hemisphere was less steep than today during the winter (November through April) but steeper than today during summer , and much lower than observed in summer . As in the midHolocene case, the dry bias is exacerbated by the energy balance feedback: soil moisture is generally lower than in the reanalysis throughout the year, latent heat is lower and sensible heating higher than in the reanalysis. The mechanisms that give rise to biases in surface climates in the midHolocene simulations are thus operating in the piControl, and the circulation‐related variables are indeed weaker than in the reanalysis. This discrepancy is particularly noteworthy because the piControl climate is globally colder than the twentieth/21st centuries and the latitudinal temperature gradient steeper, and so a priori [Rind, The latitudinal temperature gradient in the s Figure  is weakeri Rind, , the sim4Braconnot et al., Wohlfahrt et al., Otto‐Bliesner et al., Zhang et al., Braconnot et al., Harrison et al., Schmidt et al., Mauri et al., Perez‐Sanz et al., Izumi et al., Bonfils et al., Mauri et al., Randall et al., Flato et al., We have shown that the erroneous simulation of warmer and drier summers in Eurasia during the MH (relative to present) is ultimately caused by the weaker westerly circulation, which results in low precipitation in early summer and is a precondition for the operation of strong positive energy balance feedbacks in driving simulated temperature increases. Data‐model comparisons of regional paleoclimates have often focused on model benchmarking, i.e., diagnosis of the quantitative mismatch between simulated and observed climates [e.g., Kohfeld et al., Herold and Lohmann, Caley et al., Dietrich et al., In our analyses, we have compared reconstructions of surface climates to model outputs. We have not attempted to diagnose atmospheric circulation directly. Although there have been some attempts to reconstruct paleocirculation [e.g., midHolocene simulations. Such robustness in the simulated climate is often taken as a sign that the signal is correct, for example, in the interpretation of future regional climate changes [e.g., Ciscar et al., Flato et al., Harrison et al., The long‐term average differences in both circulation‐related and surface energy balance variables, both seasonally and in their spatial patterning, are remarkably similar across the suite of CMIP5/PMIP3 Jung et al., In conclusion, the simulation of circulation needs to be improved in order to simulate midcontinental Eurasian surface climates better, both in the mid‐Holocene and under modern conditions. It is generally assumed that increasing model resolution, through improving the representation of topography and land‐sea geography, will improve the simulation of circulation and atmospheric dynamics [Supporting Information S1Click here for additional data file.Data Set S1Click here for additional data file.


Parental investment theory Trivers,  stipulatper se (Allan et al., In contrast, Smith et al.  propose Research into sex-specific memory biases for mate-choice relevant stimulus is still in its infancy. Yet it is encouraging to see evidence for the impact of delineated selection pressures between men and women. The data from Fitzgerald et al.  is signiThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This is illustrated by McKenna and co-workers [ Furthermore, as neutrons  are a non-destructive probe, the resulting structures are free from radiation damage even at room temperature  atom and proton , a sulfonamide, which binds with high affinity to human carbonic anhydrase isoform II  for both of the drugs against hCA II is similar (~10 nM), they discuss the balance between enthalpic and entropic contributions towards drug binding, and using molecular dynamics simulations suggest that in the case of MZM, hydrophobic forces perhaps compensate for the loss of an extensive H-bonding network.In this issue of et al., 2013et al., 2016et al., 2015In recent years, a growing number of neutron structures have been deposited in the Protein Data Bank, including a number of other examples of enzyme-drug complexes, such as the recent structures of HIV-1 protease with the clinical inhibitors amprenavir (Weber


The rational use of medicines is a goal that should not be attributed only to the meeting between health professional and user, because it goes beyond the limits of mere interaction between prescription and use that takes place in the doctor-patient relationship.This alleged rationality in the use of medicines would require a difficult alignment between distinct rationalities of the various actors that interact in the field of pharmaceutical services: federal, state, and municipal governments; universities and technical courses; health professionals; public and private health services; pharmaceutical industry and providers of supplies; patients and media.In this sense, the proposition “I think, therefore I am,” which would indicate the prominence of the Empire of reason, might fail, because “we think where we do not exist, or exist where we do not think”However, this cannot move us away from the pursuit of a common vision that articulates the different actors of the field around a set of principles and agreements that can promote a quality use of medicines, namely: (1) strengthening the right to health care by universal health systems; (2) providing care with solutions in line with the needs of the population; (3) encouraging effective procedures; (4) promoting health and preventing diseases; and (5) setting in a transparent way the roles of the actors in the field.Thus, we seek to reverse the logic that the medicine is only one “input” in the health care network, so that it can be seen as element of an interconnected chain that produces quality “outcomes”To do so, we need: (1) easy access to essential medicines at costs that society can endure; (2) medicines that meet criteria of quality, safety, and efficacy; (3) quality use of medicines; (4) stimulus to industry segments that are viable and responsiblePesquisa Nacional sobre Acesso, Utilização e Promoção do Uso Racional de Medicamentos  to produce a comprehensive scenario of the situation of access and use of medicines in BrazilIn this context, governments and universities gathered around the Revista de Saúde Pública has published, in previous supplementThis Supplement deals with the evaluation of pharmaceutical services in the primary health care – indicating advances and challenges –; the methods used; the concepts of what is meant by pharmaceutical services; clinical pharmaceutical activities carried out; the way how pharmaceutical services are being institutionalized in the cities; and how access to medicines occurs. Still, this supplement explores how the organization of the workforce, of the selection, availability, and dispensation of essential drugs in primary health care, and of the funding and management of pharmaceutical services takes place. Also, it examines patient-related aspects – access, use, rational use, polypharmacy, satisfaction, and quality of life.Costa et al.Although there are initiatives in the management of the Brazilian Unified Health System (SUS) to create some degree of standardization of procedures, Costa et al.However, Araújo et al.Souza et al.And how are medicines selected for the health care network? Karnikowski et al.In addition, Leite et al.Regardless of the features in the selection and dispensation, Costa et al.Without adequate financial resources, there is no way to improve the selection and dispensing aspects and the quality of conservation and inventory of medicines. Faleiros et al.And how do health professionals act before this profile established so far? Carvalho et al.Patients, which are the main reason of health services, are treated in many ways.Bolsa Familia benefit. Only 9.8% had health insurance, with higher proportion in the South region and lower in the North and Midwest. Alcohol consumption and smoking were more present among men. Costa and SilveiraInterviews were carried out with 8,803 patients distributed in different parts of the CountryNascimento et al.From the patients’ perspective, Álvares et al.Soeiro et al.In addition to the use of medicines, Ascef et al.The article by Lima et al.


Numerous studies have investigated whether additional abilities of artificial agents improve the interaction with their users. Typically, a specific capability was added to a baseline system and participants interacted with both versions. Questionnaires  capabilities contribute differently to an interaction and do not necessarily increase an artificial agent's comprehensibility. Conrad et al.  tested tIn sum, Conrad et al.  estimateThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Several review articles have been published on the history, biotechnology, and implications of CRISPR system recently  is a term that has become synonymous with genome editing. CRISPR enables researchers to modify genomic DNA The foundational discoveries that led to CRISPR biotechnology can be traced back to 1993 (Mojica et al., Shipman et al.  have recHuman and Animal Locomotion series, that of a galloping horse (Figures In their recent article, Shipman et al.  scale up Figures B,C. The Clustered regularly interspaced short palindromic repeats genomic loci consist of repeat sequences, typically 20–50 bp in length, separated by variable spacer sequences of similar length (Bolotin et al., In the previous work, Shipman et al.  providedEscherichia coli type I–E CRISPR–Cas system.In their recent article, Shipman et al.  were ablShipman et al.  encoded However, the rigid strategy did not work very well because it ended up generating some sequences that were not very compatible with the CRISPR system. In addition, Shipman et al.  found thE. coli which, using Cas1/Cas2 activity, added them to the CRISPR arrays in their genomes. After retrieving all arrays, again from the bacterial population by high-throughput sequencing, they finally were able to reconstruct all frames of the galloping horse movie, and the order they appeared in with 90% accuracy (Figure To create the galloping horse movie, Shipman et al.  used a sE. coli. This sophisticated experimental approach could not only open entirely new possibilities of recording, archiving, and propagating data but it could also be engineered further into an effective memory device. The properties of Cas1 and Cas2 that were engineered into the molecular recording tool, together with the novel understanding of the sequence requirements for optimal spacers, enables a significantly scaled-up potential for recording in the genome memories/molecular experiences cellular structures are having during their growth and development, or exposure to stresses and pathogens in a chronological fashion.The interesting part of this research is not necessarily the image encoding but rather how Shipman et al.  utilizedThe author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Excessive menstrual bleeding—menorrhagia is a common gynecologic disorder affecting women of reproductive age. Subjectively, menorrhagia is defined as a complaint of heavy cyclical menstrual bleeding occurring over several consecutive cycles (Rönnerdag and Odlind, Underlying bleeding disorders only have been recognized during the last two decades as a significant etiopathogenetic factor for menorrhagia formation. The available data from the literature show the frequency of hemostasis disorders in women with menorrhagia in the range of 10–20% (El-Hemaidi et al., Previous research has shown that in the population of women who suffer from menorrhagia, the frequency of disorders of hemostasis is 17% (Djukic et al., Studies have shown that physicians are not likely to consider a bleeding disorder as a possible cause of menorrhagia. Only 3% of them would refer patients to a specialist and four percent of gynecologists surveyed would consider von Willebrand's disease as a possible diagnosis in women with menorrhagia (Dilley et al., Disorders of hemostasis, especially the ones seldom recognized (Lukes et al., Certain lack of awareness of the potential of hemostasis disorders to cause abnormal bleeding is clearly present in the clinical gynecology. Besides there is a substantial need to develop more reliable clinical tools for the objective assessment of excessive menstrual bleeding. These circumstances lead to the underdiagnosed cases and suboptimal treatment of women with bleeding disorders, including unnecessary hysterectomy (Ranson and John, SD made conception of the work, data collection and interpretation. DL made data collection and interpretation. NJ made data collection. MV made conception of the paper, critical revision of the article and final approval.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The manuscripts in this thematic issue on musculoskeletal oncology present different techniques and address difficult topics that have received limited attention in the current literature. Because of the wide variety of clinical situations encountered with bone and soft tissue tumors, it is essential for oncologic surgeons to be both facile and versatile. The following manuscripts contain valuable techniques for readers to augment their surgical armamentarium and clinical acumen.et al. discuss the unique technique of thorascopic-assisted resection of a chondrosarcoma in a pediatric patient. Chondroid lesions can be a diagnostic challenge. A systematic review of malignant degeneration of synovial chondromatosis is discussed by Ng et al. In the third article, Conrad et al. discuss their experience with treating unicameral bone cysts.In the first article, Bawa et al. Infection and wound healing can be a significant challenge. Gupta et al. explores using negative pressure wound therapy and also a novel antibiotic spacer to address these issues.The remainder of articles focuses on techniques and issues related to surgical resection and reconstruction. The accuracy and precision of surgical navigation is explored by Gundle We hope that orthopaedic oncologists and general practitioners alike find this special issue both useful and interesting.


We read with great interest the paper entitled “World's First Clinical Case of Gene-Activated Bone Substitute Application” in Case Reports in Dentistry . We woulFirstly, it is important to understand that there is currently only one approved gene plasmid-based therapy on the world market. Indeed several authors in the Deev et al. paper actively participated in the development  of the VThis is why we focused on a completely new approach for gene activation of a demineralized bone allograft. We created a dual cassette expression plasmid, encoding for both proangiogenic vascular endothelial growth factor 165 (VEGF165) and proosteogenic bone morphogenetic protein 2 (BMP2). We believe that expression of both these growth factors not only stimulated angiogenesis, but also enhanced osteogenesis at the site of the bone graft transplantation.Similar to Deev et al., we demonstrated the effectiveness of gene-activated bone transplants in stimulating osteogenesis which, in our study, resulted in callus formation at the site of ulnar pseudarthrosis. Besides the many in vitro and in vivo animal studies expertly reviewed by Deev et al. , to our


Brachiopods represent an animal phylum of benthic marine organisms that originated in the Cambrian. About 400 recent species are known from today's oceans  are expressed in the area that becomes the pedicle lobe and the posterior domain of the mantle lobe in T. transversa, and also in the posterior domain of the posterior lobe in N. anomala (Figure T. transversa showed a split into three subclusters similar to that observed in other spiralians, such as in the annelid Capitella teleata and the limpet mollusc Lottia gigantea (Schiemann et al., Scr and Antp in the shell-forming epithelia of N. anomala and T. transversa larva suggests a role of these genes during juvenile shell formation (Schiemann et al., Several studies have investigated the expression patterns of developmental genes in lecithotrophic brachiopod larvae (Altenburger et al., a Figure  (Altenbua Figure . Hox gena Figure . AnalysiT. transversa and N. anomala, it is possible to trace the body axes to the post-metamorphic body plan, and there are no signs of a folding event. Cohen et al. (N. anomala (Nielsen, N. anomala showed that larva settle with the posterior-most tip of the posterior larval lobe and that vental and dorsal valves are not secreted from the same tissues (Altenburger et al., The expression patterns of “anterior” and “posterior” genes in lecithotrophic brachiopod larvae are in an anterior-posterior sequence similar to the expression domains as detected in, for example, annelids and sea urchin embryos (Wei et al., n et al.  based thNielsen, . HoweverKutorgina chengjiangensis clearly has a straight gut (Zhang et al., Since there is no folding event during metamorphosis in craniiform or rhynchonelliform brachiopods (Altenburger and Wanninger, Even though the data currently available do not allow for a conclusive hypothesis on the evolution of the brachiopod body plan, it is clear from the newly available gene expression data that the brachiopod fold hypothesis should be discarded and an alternative hypothesis for the evolution of brachiopod body plan is needed. One alternative scenario would involve a stem-group brachiopod with a tubular sclerite arrangement (Skovsted et al., AA designed the paper. AA, PM, GB, and LH wrote the paper.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Evolutionary perspectives are vital to tackling a wide range of health challenges in today’s world, including emerging infectious diseases, the evolution of antimicrobial resistance, increasing prevalence of autoimmune diseases, the obesity epidemic, threats to food safety, neurodegenerative disease, cancer and more. To address this scope of diseases, evolutionary medicine is highly interdisciplinary, drawing on perspectives and approaches in ecology, evolution, biological anthropology, and global health (which itself is very interdisciplinary). Some evolutionary medicine research programs focus on understanding why humans are vulnerable to disease, whereas others aim to apply evolutionary approaches to more effectively prevent or treat disease.Because of these broad health foci and approaches, it is challenging to distill core principles for evolutionary medicine. What are the major concepts that one must understand to enter this field of research, practice, and general understanding? For those of us who teach evolutionary medicine to undergraduates, this is particularly challenging and important to consider. It is obvious from discussions with many colleagues that our courses are as heterogeneous as the topics and approaches in evolutionary medicine itself, with professors gravitating toward their areas of familiarity and leaving gaps in our curricula. This is especially important for undergraduate courses, as this may be the only exposure that our future doctors, nurses, veterinarians, dentists and public health officials have to evolutionary medicine at a broad level.Evolution, Medicine and Public Health by Daniel Grunspan et al. [Some crucial guidance is now available in a paper just published in n et al. . In thiset al. [Grunspan et al.  pursued et al. , along wet al.’s [et al.’s [Grunspan et al.’s  paper iset al.’s  contribuEvolution, Medicine and Public Health will be publishing Foundational Clinical Briefs about each of the core principles that emerged from Grunspan et al.’s [To advance these findings, et al.’s  paper. Tet al.’s , which aConflict of interest: None declared.


Oncotarget. The management of modifiable risk factors in traumatic brain injury victims has a main role in the patients outcome and a inappropriate treatment is followed by a worse prognosis. Knowledge about the mechanism of hyperglycemia, comorbidities, potential causes, effects and associated factors can improve the treatment process associated with adequate therapeutics could reduce the complications and modify outcome of these victims [We read with great interest the recent study by Shi et al  publishe victims , 2.A strong point of the paper is providing a meaningful view of mechanisms of hyperglycemia after traumatic brain injury and the pathway that lead to systemic dysfunctions and the role of comorbidities, including iatrogenic factors . HoweverLiu-DeRyke et al  describeThe review described by Shi et al  showed t