Supporting individuals as they disclose their HIV serostatus may lead to a variety of individual and public health benefits. However, many women living with HIV are hesitant to disclose their HIV status due to fear of negative outcomes such as violence, abandonment, relationship dissolution and stigma.We conducted a systematic review of studies evaluating interventions to facilitate safer disclosure of HIV status for women living with HIV who experience or fear violence. Articles, conference abstracts and programme reports were included if they reported post-intervention evaluation results and were published before 1 April 2015. Searching was conducted through electronic databases for peer-reviewed articles and conference abstracts, reviewing websites of relevant organizations for grey literature, hand searching reference lists of included studies and contacting experts. Systematic methods were used for screening and data abstraction, which was conducted in duplicate. Study quality (rigor) was assessed with the Cochrane risk of bias tool.Two interventions met the inclusion criteria: the Safe Homes and Respect for Everyone cluster-randomized trial of combination HIV and intimate partner violence (IPV) services in Rakai, Uganda, and the South Africa HIV/AIDS Antenatal Post-Test Support study individual randomized trial of an enhanced counselling intervention for pregnant women undergoing HIV testing and counselling. Both programmes integrated screening for IPV into HIV testing services and trained counsellors to facilitate discussions about disclosure based on a woman's risk of violence. However, both were implemented as part of multiple-component interventions, making it impossible to isolate the impact of the safer disclosure components.The existing evidence base for interventions to facilitate safe HIV serostatus disclosure for women who experience or fear violence is limited. Development and implementation of new approaches and rigorous evaluation of safe disclosure outcomes is needed to guide programme planners and policy makers. HIV serostatus disclosure has been associated with many potential benefits. People who disclose their HIV status may receive social support and experience reduced stigma , which mDespite these potential benefits, evidence from a number of studies and several reviews shows that a substantial number of women are hesitant to disclose their HIV status due to fear of negative outcomes such as violence, abandonment, relationship dissolution, stigma, loss of children or loss of their home ,7. VioleIn 2006, the WHO issued a meeting report on addressing violence against women in HIV testing and counselling services . This reWe conducted a systematic review of the literature following PRISMA guidelines .Published in a peer-reviewed journal, presented as an abstract at a scientific conference or presented as a grey literature report prior to the search date of 1 April 2015Comparative study (including either pre-/post- or multi-arm comparison groups) assessing one or more interventions to facilitate safe disclosure of HIV status for women living with HIV who fear violence or who disclose that they are currently experiencing violence compared with no intervention or standard of careMeasures one or more of the following outcomes: (1) disclosure, (2) violence , (3) fear of violence, (4) other adverse events  or (5) positive outcomes Inclusion criteria for the review were as follows:HIV serostatus disclosure as “the process of revealing a person's HIV status.” However, while Obermeyer et al.'s definition encompasses both HIV-positive and HIV-negative serostatus disclosure, we focused on disclosure outcomes among HIV-positive women where such data were available. We included studies among all populations of women living with HIV, including adolescents (10 to 19 years) and young people (20 to 24 years) [Following Obermeyer et al. , we defile 20 to  years [2Interventions to facilitate safer disclosure of HIV status were defined as any effort to reduce the risk of violence or other negative outcomes associated with HIV serostatus disclosure. Such efforts could include identifying people at risk of violence following disclosure, helping them find strategies to disclose in a way that reduced their risk of violence  or helping them decide when non-disclosure was the safest option. Studies examining all types of violence were included, including physical, sexual and emotional violence, and all types of violence perpetrators, including intimate partners, family members and others. Studies could assess violence using any measure . We defined current experience of violence as recent violence (in the past 12 months); however, we included articles that used any definition of current or recent experience of violence as long as it was intended to identify violence experienced after the intervention. We were particularly interested in outcome measures that captured violence related to HIV serostatus disclosure as opposed to background levels of violence, such as lifetime prevalence of violence.No restrictions were placed based on location of the intervention. No language restrictions were used on the search; if we had identified articles published in languages other than English that met the inclusion criteria, we intended to translate them into English.We searched the following electronic databases through the cutoff date of 1 April 2015: PubMed, CINAHL  and EMBASE. The following terms were entered into all computer databases: (disclos*) AND (violence OR abuse OR rape OR “forced sex” OR “coerced sex”) AND (HIV OR AIDS). We also conducted secondary reference searching on all studies included in the review as well as other review articles on interventions to facilitate HIV serostatus disclosure  and key We searched for conference abstracts by searching websites for the following conferences through 1 April 2015: International AIDS Conference; IAS Conference on HIV Pathogenesis, Treatment, and Prevention; the Conference on Retroviruses and Opportunistic Infections; the International Conference on AIDS and STIs in Africa; and the Sexual Violence Research Initiative (SVRI) conference. We attempted to include abstracts from the End Violence Against Women International Annual Conference and the World Association for Sexual Health Congress, but they were not available online.HIV and violence and reviewed websites of the following organizations known to be involved in initiatives related to violence and HIV: SVRI, the STRIVE research consortium, London School of Hygiene and Tropical Medicine – Gender Violence and Health Centre, Futures without Violence, the Futures Group, Columbia University ICAP programme, International Planned Parenthood Federation, FHI360, MenEngage, EngenderHealth and Population Council.To search for other grey literature, we searched the USAID Development Experience Clearinghouse (DEC) under the terms Citations identified through the search strategy underwent an initial screening by a single reviewer based on title and abstract. All citations that were considered possibly relevant were then screened by two reviewers separately to assess whether they met the inclusion criteria, with differences resolved through consensus. Full text articles were obtained of all selected abstracts and two independent reviewers made a final determination of study inclusion after full text review.Data were extracted independently by two reviewers using standardized forms. Differences in data extraction were resolved through consensus and discussion with all authors when necessary. The following information was gathered from each included study: citation information, study objectives, location, population characteristics, description of the intervention, study design, sample size, follow-up periods and loss to follow-up, analytic approach, violence measures, outcome measures, comparison groups, effect sizes, confidence intervals (CIs), significance levels, conclusions and limitations. For randomized controlled trials, risk of bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias .Meta-analysis was not conducted due to the small number of included studies. Instead, we present a descriptive summary of the findings across studies based on our coding categories and outcomes.Our initial database search yielded 1080 published citations . In addiIn the rural Rakai district, Uganda, the Safe Homes and Respect for Everyone (SHARE) project provided a combination of IPV prevention and HIV services from 2005 to 2009 . SHARE eIn Umlazi Township, Durban, South Africa, the South Africa HIV/AIDS Antenatal Post-Test Support (SAHAPS) study evaluated an enhanced counselling intervention for pregnant women undergoing HIV testing and counselling . The intIn the SHARE study, women in the intervention group reported higher rates of HIV serostatus disclosure than women in the control group at the second follow-up; the adjusted prevalence rate ratio (aPRR) was 1.15 (95% CI: 1.06 to 1.24). Women's reports of past-year physical IPV, sexual IPV and forced sex were lower in the intervention group compared to the control group at the second follow-up (35 months after baseline) . Reports of emotional IPV were not statistically significantly different at second follow-up, nor were any outcomes significant at the first follow-up (16 months after baseline).The SHARE study authors provided additional data for women living with HIV in the sample. These data reflect women with prevalent infection, rather than just those who were newly learning their HIV-positive status (the main target of the safer disclosure intervention), and they reflect all women from the sample in the intervention communities rather than just women who received the safer disclosure intervention. At baseline, there was no difference in disclosure among women living with HIV across study arms. At both follow-ups, a higher proportion of women living with HIV in the intervention group reported disclosing compared to the control group, but this difference was not significant .While the SAHAPS study has not yet published disclosure and violence outcomes, the study authors provided additional data showing that there were no significant differences across study arms in either disclosure or IPV at the 14 week postpartum assessment. While the effect of the safer disclosure component cannot be isolated from the effect of the rest of the intervention, the fact that the study saw no measurable effect on disclosure or violence overall may also suggest that the individual components had no measurable effect. The authors also looked at interactions between HIV status, disclosure and IPV among participants in both study arms at follow-up. Among women who disclosed, IPV at 14 weeks postpartum was not significantly different for HIV-positive and HIV-negative women. However, among women who had not disclosed, the odds of reporting IPV at 14 weeks was almost five times higher for HIV-positive women as compared to HIV-negative women.Despite significant attention to the intersections between HIV and violence as well as international policy consensus on the need to facilitate safer disclosure of HIV serostatus for women who experience or fear violence, we identified only two studies evaluating such interventions globally. Both studies were from sub-Saharan Africa and employed strong randomized designs. However, neither provided clear evidence for the effectiveness of a safer disclosure intervention as they were not designed to isolate the contribution of the safer disclosure components from the broader multiple-component interventions. The evidence base for interventions to facilitate safer disclosure is thus quite limited, and further studies are needed.For all women, the SHARE study in Uganda reported positive outcomes for disclosure and violence at the second follow-up. Unpublished data among HIV-positive women showed non-significant but positive trends in disclosure. However, these analyses could not distinguish women who had received the enhanced counselling intervention from those who had not or newly diagnosed women from those who had known their HIV-positive status for a long time, both of which would likely attenuate an effect toward the null. In the SAHAPS study in South Africa, unpublished data showed that women who were exposed to the enhanced counselling intervention were no more likely to disclose to their partner or report violence after HIV diagnosis than women who received standard of care HIV testing services. Additional analyses suggested that women who were already at higher risk of IPV – particularly HIV-positive women – chose not to disclose despite, or perhaps because of, the safer disclosure intervention, while women who disclosed were those who already knew it was safe to do so. This interpretation is supported by previous descriptive studies showing that women who have disclosed their status are less likely to have ever experienced violence  and a syBoth studies included in this review evaluated interventions that integrated screening for IPV into HIV testing services and trained counsellors to facilitate discussions about disclosure based on a woman's risk of violence. HIV testing services provide an opportunity for safer disclosure interventions, but this is not the only potential approach to facilitating safer disclosure for women who experience violence. The 2006 WHO consultation found that programmes jointly addressing the problems of HIV and violence used two broad types of strategies: those addressing violence against women in HIV testing programmes and those addressing HIV-related needs among women who experience violence . While bIn this review, we included all studies that attempted to directly address safer HIV serostatus disclosure for women who experience or fear violence. We did not include studies that may indirectly encourage safer disclosure. For example, many violence prevention programmes that seek to change community norms around violence give women legal rights and protections and give women greater control over financial resources may also have the effect of creating safer environments for women to disclose their serostatus. Similarly, interventions that attempt to reduce HIV-related stigma and discrimination may also reduce the risk of violence for women living with HIV who choose to disclose. Efforts to change community norms that justify or tolerate violence against women and that perpetrate HIV-related stigma are critical to creating enabling environments that reduce violence, which in turn can contribute to facilitating safer disclosure . HoweverOur findings must be seen in the context of the limitations of our review. While we did not include any language restrictions in our inclusion criteria and searched several online databases that include articles in languages other than English, our search for grey literature only included English-language websites as we were not familiar with any relevant websites in other languages. We may therefore have missed some unpublished evaluations of interventions in other languages.While HIV serostatus disclosure may lead to many positive outcomes, for many women living with HIV, fear of violence in response to HIV serostatus disclosure is a serious concern. In many settings, health workers are not trained to identify women at risk of violence, provide them with appropriate care and support them in enhancing their safety in relation to health behaviours . Moreover, in many settings there are few support services or referral options for women who experience violence generally, regardless of their HIV status. This situation poses a challenge for all health services, including HIV and reproductive health programmes, which are often resource-constrained at the human and financial levels and may not be able to provide comprehensive violence services. Further, as new approaches to HIV testing are expanded as part of efforts to reach the UNAIDS 90-90-90 targets, including community-based and provider-initiated testing, self-testing and testing conducted by lay healthcare providers , program


The objective of this study was to examine workplace determinants of obesity and participation in employer-sponsored wellness programs among low-wage workers.We conducted key informant interviews and focus groups with 2 partner organizations: a health care employer and a union representing retail workers. Interviews and focus groups discussed worksite factors that support or constrain healthy eating and physical activity and barriers that reduce participation in workplace wellness programs. Focus group discussions were transcribed and coded to identify main themes related to healthy eating, physical activity, and workplace factors that affect health.Although the union informants recognized the need for workplace wellness programs, very few programs were offered because informants did not know how to reach their widespread and diverse membership. Informants from the health care organization described various programs available to employees but noted several barriers to effective implementation. Workers discussed how their job characteristics contributed to their weight; irregular schedules, shift work, short breaks, physical job demands, and food options at work were among the most commonly discussed contributors to poor eating and exercise behaviors. Workers also described several general factors such as motivation, time, money, and conflicting responsibilities.The workplace offers unique opportunities for obesity interventions that go beyond traditional approaches. Our results suggest that modifying the physical and social work environment by using participatory or integrated health and safety approaches may improve eating and physical activity behaviors. However, more research is needed about the methods best suited to the needs of low-wage workers. Obesity, a major risk factor for diabetes, affects more than one-third of adults in the United States and is associated with several demographic and socioeconomic factors, including low income . SeveralFrom a sociological perspective, the environments in which people live and work are strong influences on obesity and diabetes ,5. The wPromoting health through worksite wellness programs is a national priority. The Affordable Care Act creates new incentives to promote employer wellness programs and encourage opportunities to support healthier workplaces . The NatThis study focused on a little-studied health disparity — workplace health promotion among low-wage workers. The objective of the study was to examine through interviews and focus groups 1) worksite culture, environment, and policies that influence healthy eating and physical activity; and 2) barriers that reduce worker participation in workplace health promotion programs. An understanding of how the workplace affects health behaviors is can inform design of effective interventions to reduce and prevent obesity.We partnered with a large health care system and a national labor union representing retail workers to recruit study participants. Qualitative data collection included interviews with key informants  and worker focus groups with both partner organizations. The workforce in the union was relatively homogenous with regard to income and included workers in jobs such as cashier and merchandise stocker. Within the health care system, we targeted hospital work departments and locations that employed a large proportion of low-wage workers, including housekeepers, patient care technicians, and food service workers. This study was approved by the Washington University institutional review board.We interviewed 10 individuals from the union partner: 4 local union leaders, 5 store representatives, and 1 health benefits administrator. Key informants were recruited in person or through email, and interviews were conducted in person or over the telephone. We asked about current and previous wellness initiatives offered to employees, employee participation in these initiatives, and potential barriers to participation. Informants were also asked about workplace factors that influenced health behaviors  and employee attitudes about health and wellness.We conducted a total of 9 focus groups involving 61 workers. Twenty hospital employees (4 men and 16 women) participated in 4 groups. Forty-one unionized retail workers including 12 men and 29 women participated in 5 focus groups. Focus group participants were recruited through their work department, store, or local union hall. The research team attended union meetings to recruit members in person and posted flyers in break rooms at selected stores and hospital departments. We used a semistructured script to guide focus group discussions. The scripts covered 11 broad domains with follow-up questions and prompts for each domain . All groThe informants indicated that very few wellness programs related to weight management were offered to retail workers. The union-sponsored health plan covered some costs for nutritional counseling, but that benefit was not well advertised. The employer-sponsored initiatives such as an onsite gym or weight loss programs were primarily available to employees in the corporate offices, not to workers in retail stores. Both the union and employer representatives recognized the need for workplace wellness programs but were unsure about how to proceed with developing and implementing a program to reach their diverse and widespread workforce.Informants described various programs available to employees but noted several barriers to effective program implementation, including lack of management commitment at some levels, limited budgets, and communication and advertising limitations. One informant described results of a focus group conducted among employees of 1 hospital department regarding awareness of existing wellness programs and preferred methods of communication; results indicated that most workers were unaware of the wellness program and did not regularly use company email, which was the primary method of communicating information about the wellness program. Workers preferred to get information via personal email, text message, or in person. Workplace wellness efforts within the health care organization varied by worksite; some sites were more successful in promoting and delivering their wellness initiatives than others. Informants thought the size of organization and motivation of appointed representatives for each location influenced program success. An informant from a smaller hospital mentioned several successful wellness initiatives at her location, including an onsite gym, exercise classes, and 2 weight-loss challenges each year, and an informant from a larger hospital discussed struggles to find effective communication methods to reach all worker groups.The final list of themes from the focus group analysis included 10 work-related themes and 10 general themes . WorkersWorkers also discussed schedules and breaks as having a significant impact on their healthy eating and physical activity. For many retail workers, their schedules varied week-to-week, making it difficult to maintain any routine. Workers from both organizations stated that short and interrupted breaks made it difficult to eat healthy. They discussed how food options —healthy or unhealthy and purchased or provided for free  — affected their eating behaviors at work. Workers from both organizations felt that their workplaces had a lack of quick, convenient, and low-cost healthy food options. Moreover, in all groups we heard that free food was almost always unhealthy. Nearly all workers commented that social support and accountability to coworkers would improve their ability to initiate and maintain healthy behaviors.General themes were those that may be related to the workplace but also extended into workers’ personal lives. For example, workers often discussed how intrapersonal factors  and home life  affected their health behaviors both in the workplace and at home. Workers often discussed how their jobs influenced their health in terms of not having the money, time, or energy to exercise or plan healthy meals. Some workers also discussed the roles that health issues and transportation played in initiating and sustaining healthy behaviors.This study highlights factors related to obesity as described by 2 low-wage work groups; our findings are consistent with results from a similar study among low-wage workers in various industries . The worPolicy changes have increasingly been recognized as essential components of worksite health promotion  and are Changes solely in the workplace environment may not be enough to encourage healthy behaviors . Health Workplace participatory approaches may foster social support and help to overcome organizational and employee barriers to program success. Most worksite weight-loss programs have relied on a top-down approach, rather than a participatory approach based on employee involvement in the design of interventions . In workWorkplace wellness programs should also use effective communication strategies to engage workers from diverse work groups and backgrounds. As demonstrated with the health care system in this study, many low-wage workers were not aware of the wellness programs that were available to them. The same programs, however, have good participation from other work groups in the health care organization, primarily because of the method of communication. Rapid changes in information technology have enabled new interventions that use mobile telephones and other mobile devices . These techniques show great promise for weight reduction in low-income populations , and sucAlthough we did not directly ask about incentives, several participants discussed monetary incentives as a possible motivator to eat healthy and exercise. The use of incentives is common in workplace wellness programs; employers could maximize the benefits of incentives by incorporating lessons from behavioral economics. For example, the increasingly popular approach of delivering incentives through health insurance premium adjustments is unlikely to be as effective as more frequent and immediate rewards for behavior. This is because people tend to discount the future, meaning that they respond more readily to immediate than delayed costs and benefits . The parFinally, employers may consider integrating traditional occupational safety and health programs  with health promotion and wellness programs . The Total Worker Health program was launched by the National Institute of Occupational Safety and Health (NIOSH) to support the development and adoption of research and best practices to integrate these approaches and address health and safety risks at multiple levels, including the work environment  and individual behaviors. This integrative approach may lead to greater adoption of interventions by management and workers and hence to improvements in the health of workers , but morThe results of this study can help inform future worksite interventions for low-wage workers; however, our study has several limitations. First, we collected data from key informants who could be contacted or agreed to be interviewed. Second, although the participants in the focus groups represented a range of positions and worker groups, they were limited to those available during the implementation of the focus group discussions. Although using a convenience sample may be a limitation, those who elected to participate in the interviews or focus groups were able to provide helpful insights on the topic. Future intervention planning would need to be preceded by additional input from a broader participant base. Third, the information we collected may not be generalizable to other health conditions or work settings. Despite these limitations, the key informants and focus group participants provided rich and potentially actionable information on addressing obesity at the worksites of these worker populations.Workplaces can provide an effective venue for engaging low-income populations at risk for obesity and related illnesses. Results of this study suggest that future worksite interventions for low-wage workers can improve reach, effectiveness, and sustainability if they embrace more innovative methods than those used in current workplace wellness programs. Future interventions should address workplace policies and environment and social norms that affect health behavior decisions. Communication strategies and financial incentives should be better aligned with the needs of low-wage workers. Workplace participatory programs are a promising approach to engage workers in health improvement.


Comparative research provides a unique window into our understanding of human vocal perception. We commend Kriengwatana, Escudero, and ten Cate (KEtC) for providing a much-needed review of this diverse literature. Their appraisal of three research areas highlights conceptual and empirical gaps, while also pointing to fruitful directions for future research.This commentary addresses the literature on asymmetries in vowel perception. In their review of this topic KEtC focus on vowel contrasts that have revealed directional asymmetries in infants and non-human animals. We offer some clarification with respect to these stimulus issues and highlight another aspect of this research landscape—the role of task demands—that must also guide future comparative investigations.The salience and stability of natural referent vowels is due to formant frequency convergence or focalization. …Focalization is graded and gives rise to salience differentials across the vowel space.” To clarify, in all of the infant and animal experiments on the /ε-æ/ contrast to date, focalization differences are clearly observed; i.e., F1 and F2 are spectrally closer in the more peripheral vowel /æ/ compared to the less peripheral /ε/. Accordingly, there is no basis for viewing research on /ε-ae/ as irrelevant to a discussion of comparative differences in vowel perception asymmetries.The authors present a detailed overview of studies that reveal directional asymmetries in vowel discrimination in infants and several non-human species. To date infant perceptual asymmetries can be accounted for within the NRV framework  over many test sessions to discriminate a very small set of stimuli (one token per vowel), and memory demands are minimized by presenting the vowel stimuli with short inter-stimulus intervals (250–700 ms). This close temporal proximity allows the listener to access and compare acoustic details of the stimuli without encoding and retrieving information in a more enduring memory store. In contrast, the infant studies were conducted to understand how meaningful phonetic units are processed in more cognitively demanding tasks. Typically, a group of infants is tested using category-based discrimination tasks that involve stimulus variability (multiple tokens per vowel) and much less training, usually a single test session which may or may not involve reinforcement. Additionally, the temporal gaps between stimuli are longer (1000–1500 ms), placing higher demands on memory.The animal research has focused on perception of just-noticeable differences while the infant research has focused on just-meaningful differences. This distinction is critical in the context of vowel perception asymmetries. In the NRV framework asymmetries reveal vowel perceptual biases that emerge when perceivers are accessing phonetic units, not simply detecting acoustic differences. Thus, phonetic biases are predicted to surface in tasks that mirror at least some of the demands of natural speech processing . The tasks implemented in the current animal literature clearly do not tap this level of processing. The psychophysical tasks implemented with animals would likely yield ceiling effects in humans which, interestingly, is the pattern found in macaques Sinnott, , a speciWith respect to future research, we wholeheartedly agree with KEtC that testing human infants and non-human animals on the same vowel contrasts using comparable methods is required for drawing solid conclusions. More importantly, systematic manipulation of task demands is necessary to understand similarities and differences in the sensory, perceptual, and cognitive mechanisms across humans and non-human species. As highlighted by Weiss and Newport  the percOverall, when task differences are acknowledged, the current literature provides no compelling evidence that non-human animals show the kind of vowel perception biases that have been documented in humans. Despite the challenges, researchers are developing novel methods to assess perception in non-human animals across a wider range of processing demands. For example, several researchers have successfully measured spontaneous listening preferences in non-human primates (e.g., Watanabe and Nemoto, 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.


Animals show consistent differences in behaviour and physiology. Understanding these differences is vital for predicting the effects of gradual environmental change, such as climate change and ocean acidification. Here we review how such trait repeatability is relevant for conservation of wild fish. Repeatability of behavioural and physiological traits is increasingly a focus for animal researchers, for which fish have become important models. Almost all of this work has been done in the context of evolutionary ecology, with few explicit attempts to apply repeatability and context dependency of trait variation toward understanding conservation-related issues. Here, we review work examining the degree to which repeatability of traits  is context dependent. We review methods for quantifying repeatability (distinguishing between within-context and across-context repeatability) and confounding factors that may be especially problematic when attempting to measure repeatability in wild fish. Environmental factors such temperature, food availability, oxygen availability, hypercapnia, flow regime and pollutants all appear to alter trait repeatability in fishes. This suggests that anthropogenic environmental change could alter evolutionary trajectories by changing which individuals achieve the greatest fitness in a given set of conditions. Gaining a greater understanding of these effects will be crucial for our ability to forecast the effects of gradual environmental change, such as climate change and ocean acidification, the study of which is currently limited by our ability to examine trait changes over relatively short time scales. Also discussed are situations in which recent advances in technologies associated with electronic tags (biotelemetry and biologging) and respirometry will help to facilitate increased quantification of repeatability for physiological and integrative traits, which so far lag behind measures of repeatability of behavioural traits. RepeataThe majority of work quantifying trait variance and repeatability has been performed with the goal of understanding evolutionary processes in ecology, with few explicit attempts to apply repeatability and context dependency toward understanding management and conservation-related issues . Most woHere, we review work that has been done on trait variation and repeatability in fishes, and how these factors are affected by the environment. The key question we consider is as follows: is the best fish the best in every context or does the fittest fish within a population vary depending on the environmental conditions? Throughout, we discuss how these issues are relevant for management and conservation issues. We focus on fish because they are often used as models for research in both laboratory and field settings and because of the fact that they have often been at the forefront of research on repeatability of both behavioural and physiological traits  yet alsoR . Thus, R will decrease with greater changes in mean values between separate measuring instances. More details on differences between these metrics and on underlying model assumptions can be found in the article by The choice of repeatability metric can, however, be constrained by distributional assumptions and logistic limitations on the collection of sufficiently high numbers of repeated measures and resulting issues associated with poor statistical power  and Radj (continuous line) for a hypothetical example.Many behavioural and physiological traits are labile within individuals and vary from day to day and among environmental contexts. Systematic changes in mean scores across measuring instances or contexts will erode t-up see a. Owing t values . Figure Often, however, plastic changes are not similar across individuals, and individuals differ in the slope of reaction norms across changing contexts. Boldness  and aeroAs a result of individual plasticity, two aspects of individual consistency become of interest when we study individual differences in changing environmental contexts. First, we might examine the stability of individual trait differences within each environmental condition (within-context consistency). Second, we might want to determine how well individual trait measures in one environmental condition predict those in another (across-context consistency).Rcontext), also referred to as conditional repeatability  and then calculate one measure of repeatability across all measures. In balanced designs with one measure in each context, product–moment correlations or ranked alternatives have often been used to estimate the consistency of traits across contexts . Others asticity . In thisces Fig. .Rcontext estimates. Across-context correlations estimate the extent to which rank orders of individual trait values are maintained when the context changes. They will equal one when slopes are equal among individuals .Indeed, researchers have used a wide variety of metrics to measure individual consistency and often do this under the same heading of ‘repeatability’. In what follows, we aim to specify, where possible, which metric has been used whenever discussing studies illustrating variation in individual consistency  can be included as fixed or random factors .In general, a specific type of measuring error can occur when not all fish are measured in the same environmental conditions. This can artificially inflate repeatability scores and result in so-called ‘pseudo-repeatability’  is repeatable when fish are held in the laboratory in high-flow conditions but not when held in more benign static-flow conditions  can be drastic  when juvenile Ambon damselfish (Pomacentrus amboinensis) were tested for a range of behavioural traits (e.g. activity and boldness) either in the laboratory or in the field (R) when the same individuals were tested in the laboratory and then again in the wild , individuals differ in average activity levels, although repeatability of activity is a complex function of temperature and time since isolation, leading to approximately 2-fold differences in repeatability (Rcontext) scores across time and thermal regime  were repeatable (Pearson's r) across a 6°C increase in temperature, whereas aerobic scope was not significantly repeatable with the same temperature increase. Salvelinus confluentus) in the wild and showed high rank-order consistency (Spearman's ρ) of mean movement distance across seasons and time of day. Micropterus salmoides), but only after correction for strong effects of ambient temperature  decreases metabolic rate during hypoxia but that repeatability is maintained , probably because variation in spontaneous swimming activity was affected by the tendency of some individuals to perform aquatic surface respiration in hypoxic conditions. Aquatic environments exhibit extreme variation in the partial pressure of dissolved oxygen through time and space. Evidence suggests that the frequency and severity of hypoxic events in aquatic ecosystems has been worsening because of anthropogenic activities and eutrophication along waterways . Decreasr) of risk-taking tendency appears to be maintained with a 1 week period of food deprivation in European sea bass  after periods of starvation and refeeding, whereas R) in sprint performance to decrease in European sea bass. It is possible that the direct effects of starvation and diet on aspects of muscle physiology, metabolism and energy stores may vary among individuals, leading to variable individual reaction norms. This effect may be exacerbated by the effects of compensatory growth trajectories during refeeding, which could further alter repeatability across feeding contexts , 2 concentration (650 ppm). There have been documented effects of reduced pH on a number of ecologically relevant behaviours in fishes, including predator detection and avoidance  has been observed to be higher in high-flow conditions than when individuals are held in static water  shows highest repeatability along non-turbulent river sections but drops near sections with heavy turbulence  as well as climate-induced changes in river flow volumes or oceanic currents. Increasing flow is known to affect the spatial positioning of individual fish within swimming schools, although individual spatial preference within groups does show a large degree of repeatability within flow speeds that allow aerobic steady-state swimming (r) of hypoxia tolerance in juvenile sea bass (Dicentrarchus labrax), but both decreased repeatability of sensitivity to thermal stress in standardized challenge tests.The available evidence suggests that individual fish may vary in their sensitivity to environmental pollutants. R; Gobiomorphus cotidianus; There are also biotic environmental influences that may affect estimates of trait variability and repeatability. Parasitic infection, for example, has been shown to alter traits such as boldness and activity level in fish, generating variation in these traits and thus affecting repeatability  show within-individual variability in latency to emerge following a stimulus, and the magnitude of this variation varies among individuals  as well as the ways in which such information is or could be relevant to resource managers and conservation practitioners (applied perspectives).The available evidence from fish suggests that repeatability of traits seems to be highly context dependent Table . To dateIdentifying the context dependency of traits requires long-term study, particularly for long-lived organisms (i.e. many vertebrates). Time itself and its association with ontogeny, maturation and senescence would be highly relevant but is rarely studied in the context of repeatability given that most studies are of short duration. Aspects of habitat use, including depth, are also essential for understanding variation within populations, potential shifts in behaviour induced by environmental change, and variability among individuals in the ability to cope with such changes. Field studies will be essential in this regard, and there are a growing number of examples where researchers are using electronic tagging or marking of animals , whereas in reality, wild populations will have decades or centuries to respond to such changes. An increased understanding of how trait variation and repeatability is affected by these factors will help us to gain a greater understanding of the capacity for adaption present in populations. Given the pervasiveness of human disturbance, evaluating the consistency of trait repeatability relative to other types of disturbance gradients would also be useful.Moving forward, there are a number of research priorities that we regard as important for applying research into trait repeatability toward the conservation of wild fish populations. First is the need to look at more contextual variables. Of late there has been much focus on temperature given the imminence of climate change. As discussed in this review, however, there are a number of additional factors that may play a key role in affecting trait repeatability. Flow seems to be a particularly overlooked factor in this regard, particularly given the manner in which humans have harnessed and altered rivers. The observation that turbulent flow degrades the repeatability of migration speed .There are a number of other conservation issues that would benefit from further knowledge of trait repeatability among and within contexts. Behavioural traits such as individual sociability appear to be related to dispersal potential within fish species and, for invasive species, may influence which individuals with which specific traits disperse furthest and end up along the invasion front , starting with one to three traits. There may also be situations where it will be feasible to measure multiple traits between populations where nature is already applying experimental treatments . It is worth noting that efforts may be useless to managers if sample sizes are too small to infer anything biologically relevant. Given the rapidly advancing statistical techniques for assessing trait repeatability in various situations and experimental designs, we suggest that researchers consult with statisticians whenever possible when designing studies to determine how best to overcome the logistical difficulties of working in the field with wild animals while still providing useful information.We expect that in the coming years we will find additional examples where we think we understand a phenomenon, but things change drastically in another context. This will have important consequences, because shifts in environmental conditions brought on by human activities may change not only population abundances and distributions, but also which individual fish will gain a selective advantage in response to the prevailing selective forces. The individuals that have the greatest fitness in one set of conditions may be the least fit in another environment, or vice versa. Human-associated environmental change is therefore likely to affect evolutionary trajectories. Over shorter time scales, variation in trait repeatability among contexts could also affect our ability to transfer knowledge of physiology and behaviour gained in one context (e.g. the laboratory) to another.Urgently needed is more work examining trait repeatability in the field and how repeatability of traits directly relevant for conservation will respond to various environmental stressors. We certainly want to emphasize the importance of studying wild fish in the wild (as opposed to in the laboratory), but mesocosm studies and laboratory-oriented experiments will continue to be important in the future because they enable researchers to manipulate the context systematically while imparting necessary controls. The most powerful approaches to understanding environmental effects on trait repeatability will be those that bridge the field and the laboratory and combine long-term observational studies with experimental manipulations.S.S.K. was supported by Natural Environment Research Council (NERC) Advanced Fellowship NE/J019100/1 and European Research Council Starting grant no. 640004. S.J.C. was supported by the Natural Sciences and Engineering Research Council (NSERC) and the Canada Research Chairs Program. B.A. was supported by a NERC standard grant NE/K00400X/1.Supplementary DataClick here for additional data file.


Drosophila TRP channel that was initially identified as a molecular sensor responsible for detecting noxious thermal and mechanical stimuli. Here, we review recent behavioral genetic studies demonstrating that Pain expressed in the brain plays a critical role in both innate and learned aspects of sexual behaviors. Several members of the TRP channel superfamily play evolutionarily conserved roles in sensory neurons as well as in other peripheral tissues. It is thus expected that brain TRP channels in vertebrates and invertebrates would have some common physiological functions. Studies of Pain in the Drosophila brain using a unique combination of genetics and physiological techniques should provide valuable insights into the fundamental principles concerning TRP channels expressed in the vertebrate and invertebrate brains.Transient receptor potential (TRP) channels have attracted considerable attention because of their vital roles in primary sensory neurons, mediating responses to a wide variety of external environmental stimuli. However, much less is known about how TRP channels in the brain respond to intrinsic signals and are involved in neurophysiological processes that control complex behaviors. Painless (Pain) is the  Drosophila melanogaster as the causative gene for a phototransduction mutant in which photoreceptor potentials abnormally displayed a transient, rather than sustained responses during prolonged light stimuli  channel superfamily is a diverse group of non-selective cation-permeable ion channels Montell, . The firDrosophila, and sensory functions modulated by the fly TRP channels have been found to be remarkably similar to those modulated by their mammalian counterparts  in antennal lobes  with the GAL4/UAS system show that the knockdown of pain expression in GABA- or acetylcholine-producing neurons, but not in dopamine- or serotonin-producing neurons, enhances female sexual receptivity as in pain mutant females. This result indicates that Pain TRP channels expressed in cholinergic or GABAergic neurons are involved in the regulation of female sexual receptivity , the male-male courtship phenotype of pain mutants is suggested to be caused by defects in their olfaction , produced by male flies suppresses male-male courtship , rather than in the sensory neurons , play a primary role in the suppression of male-male courtship.Wild-type Drosophila male courtship involves a plastic aspect and can be modified by previous sexual experience  and protons  in an isolated cultured Drosophila brain (Ueno et al., Drosophila learning and memory. Although it remains to be determined whether AL-MB synapses show LTD-like synaptic plasticity in Drosophila, the Ca2+ imaging of an isolated cultured brain will be useful for determining whether Pain TRP channels in AL and MB have an essential role in activity-dependent synaptic plasticity similarly to LTP and LTD in the mammalian brain.We also expect that o et al.  have repThe 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 Extended Parallel Process Model (EPPM) is an established threat- and efficacy-based behavioral framework for understanding health behaviors in the face of uncertain risk. A growing body of research has applied this model to understand these behaviors among the public health workforce. In this manuscript, we aim to explore the application of this framework to the public health workforce, with a novel focus on their confidence in vaccines and perceptions of vaccine injury compensation mechanisms. We characterize specific connections between EPPM’s threat and efficacy dimensions and relevant vaccine policy frameworks and highlight how these connections can usefully inform training interventions for public health workers to enhance their confidence in these vaccine policy measures. Health providers’ personal decisions not to receive influenza vaccination present a major ongoing public health challenge, with significant implications for morbidity and mortality, medical workforce capacity and healthcare system costs . Low ratA growing body of research has examined perceptual barriers impeding health providers’ self-adherence to influenza vaccination guidelines. To date, such identified barriers have included a lack of information about novel and seasonal influenza vaccines, the risk of influenza infection, the role of the healthcare worker in transmission and vaccine safety and efficacy ,4,5,6. MOf note, modifying factors for providers’ own influenza vaccination behavior appear to be similar for both seasonal and pandemic influenza contexts ,7,8. IndSenior public health organizational and regulatory bodies  are leading purveyors of influenza vaccination practice guidance for physicians. Accordingly, the effectiveness of these public health authorities in mitigating influenza disease burden hinges substantially on healthcare providers’ adherence to the vaccine guidelines that these agencies deliver—for themselves and their patients.Public health department-based providers represent a critical component of the frontlines of vaccine delivery and are at the heart of the public health emergency preparedness system ,12. DespSpecifically, we will explore these EPPM-based implications in the following contexts: (1) National Vaccine Injury Compensation Program; (2) Public Readiness and Emergency Preparedness Act (PREP Act) for Pandemic Influenza Medical Countermeasures Utilization Protocol & Decision Tools; and (3) mandatory vaccination policies.Each of these three contexts involves a unique legal infrastructure with specific components that may impact public health workers’ confidence in vaccines. In particular, we focus on the compensation mechanisms that the government has established for individuals and families that experience vaccine-related adverse events. Public health workers’ awareness and understanding of these systems may influence their perceptions of threat and efficacy and, thus, their willingness to receive a vaccination. Introduced by Witte in 1992, the EPPM has the potential to cast light on how the public health workforce can be encouraged to participate in influenza vaccination. The model posits that for a message to induce behavior change, it must simultaneously convey the constructs of threat and efficacy. The construct of threat has two components: severity or the idea that the threat is significant enough to warrant action; and susceptibility or the idea that the person initiating the behavior may be affected by the threat. The construct of efficacy also has two components: self-efficacy or the idea of confidence that the person is able to perform the behavior; and response efficacy or the idea that the behavior change will achieve the intended impact. If the message induces both perceived threat and perceived efficacy in the recipient, the message may be accepted . If the The EPPM has been both qualitatively and quantitatively applied to or suggested for a variety of preventive health behaviors, including low income mothers’ access to preventive dental care for their children, contraceptive use among women, colonoscopy screening, hearing loss prevention and smoking cessation intentions ,22,23,24The foundation for the use of this model to understand and promote preventive behaviors toward influenza has recently been developed. Notably, in a study utilizing EPPM-framed forewarning messages to promote preventive behaviors, such as vaccination for H5N1 influenza, perceived threat was associated with fear arousal, which was less positively related to behavioral intention than perceived efficacy . These fHere, we describe in greater detail the three aforementioned law and policy contexts germane to confidence in vaccines among public health providers: (1) National Vaccine Injury Compensation Program; (2) Public Readiness and Emergency Preparedness Act (PREP Act) for Pandemic Influenza Medical Countermeasures Utilization Protocol & Decision Tools; and (3) mandatory vaccination policies.Each year, millions of people in the United States are vaccinated to prevent the morbidity and mortality associated with various infectious diseases. Although the effectiveness and general safety of vaccines have been repeatedly demonstrated, they are not without risk. On rare occasions, some individuals experience side effects, including seizures and anaphylactic shock after receiving a vaccination . Known aIn the mid-1980s, Congress tackled this issue with the drafting and passage of legislation to establish the National Vaccine Injury Compensation Program (VICP) . The VICWhile the VICP’s protections are available to both children and adults, it was intended to cover vaccinations routinely offered to children. The VICP does not offer compensation for vaccine-related adverse events associated with emergency countermeasures, such as vaccines used to treat H1N1 pandemic influenza or smallpox. To address this gap, Congress established the Countermeasures Injury Compensation Program (CICP) with the passage of the Public Readiness and Emergency Preparedness (PREP) Act in 2006 . Like the VICP, the CICP is housed in the U.S. Department of Health and Human Services. It provides compensation to individuals who experienced an adverse event related to a countermeasure they received that was covered by the CICP . CompensOver a century ago, the U.S. Supreme Court established that states can require individuals to receive vaccinations to protect and promote the public’s health . All staMandatory seasonal influenza policies have faced legal challenges from healthcare workers who, in some cases, argue that they contravene collective bargaining agreements. Such lawsuits, which tend to be highly publicized, can undermine confidence in vaccines, as they may raise questions for the general public about the safety and effectiveness of vaccines .PREP, VICP and mandatory vaccination policies could potentially serve as effect modifiers toward public health workers’ confidence in vaccines, with attendant implications for vaccine uptake rates among this vital health provider cohort. In that vein, the law has long been recognized as a policy tool with a demonstrated ability to impact behavior. Laws can cause numerous changes—to environments, to product availability, to the legality of certain practices—that may influence individuals’ behaviors. While the implementation of a new law may be associated with behavior change, it may also occur due to the amendment, repeal or expiration of an existing law or to other factors entirely. Two brief examples, from tobacco control and motor vehicle safety, illustrate the law’s potential to influence behavior change.Tobacco control researchers have repeatedly found that the law is a powerful component of smoking cessation and prevention efforts. The implementation of legal measures, such as the presence of tobacco taxes, which raise the price of cigarettes, has been associated with individuals’ increased intention to quit smoking, as well as their decreased purchase of cigarettes. A systematic review of tobacco taxes and smoking behavior concluded that a robust evidence base demonstrates that increasing the price of cigarettes through tobacco taxes is associated with the reduction of smoking, particularly among young people . SeveralStudies have repeatedly confirmed the important role that laws have played in reducing the number of annual traffic fatalities in the United States, particularly due to their impact on seatbelt use behavior . For exaAgainst this backdrop of law and its relationship to behavior change, EPPM can serve as a useful lens to gauge the extent to which VICP, PREP and mandatory vaccination policies may serve as effect modifiers toward vaccine confidence. In addition, the application of EPPM to this area may assist in the design of relevant training approaches for public health workers’ awareness of and confidence in available protections. Here, the recent public health preparedness literature provides relevant insights. Specifically, EPPM has recently been applied to several cohorts involved in the public health workforce to understand and improve their willingness to respond to a variety of emergencies in the all-hazards disaster spectrum, including pandemic influenza. Notably, the self-efficacy confidence construct was consistently identified as the leading overall predictor of willingness to respond to a pandemic influenza emergency among all cohorts studied ,49,50,51EPPM-based research to date on emergency response willingness points to the applicability of a threat- and efficacy-based behavioral model for future applied research aimed at understanding the interplay between legal protections and confidence in vaccines. i.e., potential, though rare, adverse events) can motivate public health workers to seek additional information about the protections that the VICP affords and how to access these protections should an adverse event occur. Meanwhile, EPPM’s efficacy dimension in this context applies to public health workers’ confidence in operational implementation of VICP as needed: in the case of self-efficacy, these workers can gain confidence in their knowledge of the VICP protections available to them and they can simultaneously increase their confidence by understanding the requisite protocols to access VICP protections. Under PREP, the elements of EPPM would apply in a similar way to the CICP, with the only difference being that the CICP applies to a more circumscribed set of vaccine-related countermeasures. Finally, in the context of mandatory vaccination, the threat dimension of EPPM reflects public health workers’ potential concerns that they may serve as vectors of vaccine-preventable illness to their own families and to the vulnerable patient populations they serve. With regard to EPPM’s efficacy domain in the case of mandatory vaccination policies, self-efficacy refers to public health workers’ confidence in their comprehensive understanding of the mandatory policy, a thorough knowledge of where to go to receive vaccinations and a clear awareness of whom to contact if they encounter a vaccine-related adverse event. Further, in the context of mandatory vaccination policies, EPPM’s response efficacy dimension would reflect these workers’ confidence that mandatory vaccination actually works to mitigate the likelihood of disease transmission.A closer examination of how EPPM’s threat and efficacy components apply to the three vaccine contexts discussed above illustrates EPPM’s considerable potential as a conceptual framework for vaccine confidence-boosting initiatives against these policy backdrops. In the case of the VICP, for example, EPPM’s threat dimension applies to public health workers’ concerns about experiencing a vaccine-related adverse event. According to EPPM principles, instilling awareness of this threat dimension ; and (2) instilling a clear awareness that the protections afforded are meaningful and substantive and would be fully implemented . The importance of explicit awareness—and confidence in—workplace protective measures is bolstered by the research finding that perceived safety at work is a highly significant modifier of public health workers’ willingness to fulfill role expectations in a variety of disaster contexts [Importantly, EPPM-centered training is the common operational thread that binds these conceptual understandings with practical implementation strategies that can boost confidence in vaccination amidst the three vaccine-policy backdrops described above. EPPM-centered training efforts could enhance public health workers’ confidence in vaccines through threat- and efficacy-building elements. Specifically, the threat elements of such training should address the respective vaccine policy threat dimensions noted above, as the EPPM indicates that threat awareness can have a positive motivational effect toward adoption of desired behaviors . Meanwhile, such EPPM-centered training activities should include a particularly strong emphasis on efficacy-building training measures surrounding these vaccine policies, as efficacy has been found to outweigh threat as a modifier of public health workers’ response behaviors in the face of perceived risk . The effcontexts . The role of legal protections in boosting confidence in vaccines has become increasingly relevant in an environment where mandatory vaccination for public health workers is a contentious policy issue. Further, EPPM-centered research could assist policy-makers, emergency planners and others to better understand root determinants of the influence of legal protections on vaccine uptake decisions among public health providers. Additionally, as noted above, the EPPM can be used to inform training interventions to enhance public health workers’ awareness of relevant vaccination policies and confidence in them.Future EPPM-based research on policy and practice can thus provide a vital evidence base for enhanced understanding of how public health workers’ confidence in vaccines is modified by relevant protective laws, through the lens of an established threat- and efficacy-centered behavioral model. This type of research can focus not only on public health workers, but also on other health provider cohorts on the frontlines of community vaccination efforts.


Current goals in the acute treatment of heart failure are focused on pulmonary and systemic decongestion with loop diuretics as the cornerstone of therapy. Despite rapid relief of symptoms in patients with acute decompensated heart failure, after intravenous use of loop diuretics, the use of these agents has been consistently associated with adverse events, including hypokalemia, azotemia, hypotension, and increased mortality. Two recent randomized trials have shown that continuous infusions of loop diuretics did not offer benefit but were associated with adverse events, including hyponatremia, prolonged hospital stay, and increased rate of readmissions. This is probably due to the limitations of congestion evaluation as well as to the deleterious effects linked to drug administration, particularly at higher dosage. The impaired renal function often associated with this treatment is not extensively explored and could deserve more specific studies. Several questions remain to be answered about the best diuretic modality administration, global clinical impact during acute and post-discharge period, and the role of renal function deterioration during treatment. Thus, if loop diuretics are a necessary part of the treatment for acute heart failure, then there must be an approach that allows personalization of therapy for optimal benefit and avoidance of adverse events. In patients with acute heart failure (AHF), the risk of death or rehospitalization within 60 days from admission ranges from 30 to 60 %, depending on the population studied , 2. The It has been difficult to demonstrate a uniform benefit with respect to any individual therapeutic intervention in patients with AHF –6. This Beyond hemodynamic derangement, there are systemic mechanisms that substantially contribute to congestion status, including neurohormonal activation which works to maintain organ perfusion and systemic pressure while enhancing sodium and water retention. Combined, increased vascular stiffness and reduced vein capacitance enhance both preload and afterload with a consequent rise in cardiac filling pressure that reflects on the pulmonary circulation. Arterial vasoconstriction associated with increased venous pressure affects the kidney, causing hemodynamic and parenchymal alterations: renal blood flow redistribution, tubuloglomerular feedback, tubule obliteration, and efferent arteriolar constriction which leads to reduced salt and water excretion. Slow plasma refill from extravascular to intravascular bed and overhydrated interstitium is another component: the intravascular volume decreases only marginally by diuretic treatment; in contrast, the interstitial volume has substantial reduction.Given the combination of hemodynamic and neurohormonal factors, each patient has an individual risk of AKI or type 1 cardiorenal syndrome after the first few doses of intravenous loop diuretics . A stronThe physical exam and traditional laboratories are poor tools in assessing this complex and dynamic pathophysiology in each patient. Futuristic approaches involve the use of non-invasive abdominal compartment monitoring, bioimpedance, or real-time assessments of glomerular filtration to establish the correct loop diuretic dosing and management of other drugs.The rates of AKI or type 1 cardiorenal syndrome range from 20 to 70 %, depending on different definitions, creatinine cutpoint values, and the study population –15. LoopThe administration of intravenous loop diuretics to patients with heart failure (HF) and congestion results typically in a prompt diuretic effect. In most patients, the increased diuresis is accompanied by a decrease in LV ventricular filling pressures and improvement of symptoms by reducing pulmonary capillary wedge pressure and intra-alveolar edema . When usBaseline renal function and the dynamic change in serum creatinine are related to short- and longer-term outcomes. A recent observational study showed that creatinine change during hospitalization was independently associated with a higher risk of 1-year mortality. However, in patients with normal or mildly impaired renal function, creatinine changes (ΔCr) (admission to 48–72 hours) were not significantly associated with mortality. Interestingly, in this subgroup of patients, a decrease in ΔCr was associated with worse outcomes. Perhaps a transient deterioration of renal function is required to relieve congestion and improve global symptom assessment. Thus, the intricate cardio-renal axis relation is much more confused by the diuretic administration that could potentially amplify deleterious effects at the kidney level. Studies in this field revealed contrasting results: some authors did not observe a poor prognosis during treatment in patients who experienced worsening renal function . Others The only two studies evaluating congestion and renal function during different diuretic strategy administration are the DOSE trial and the Diur HF trial. In the DOSE registry, patients submitted to higher dose and continuous modality administration revealed an increase in creatinine, although they experienced improvement in their symptoms and significant decongestion signs compared with low-dose administration. However, this study did not clarify which treatment modality is better to improve outcomes and renal function and showed no significant difference in hard endpoints during the follow-up period. Therefore, the authors did not report interactions between patients’ baseline characteristics and the efficacy of either intervention. The average dose administered was approximately 100 mg every 12 hours, and the average infusion was around 10 mg/hour . In clinConversely, in the Diur HF Trial, mean diuretic regimen was higher with respect to the DOSE patients; therefore, continuous versus bolus administration was compared. An increased rate of adverse outcome in patients developing renal impairment during hospitalization was observed. This occurs despite a significant reduction of B-type natriuretic peptide (BNP) level and urine output increase found in the continuous arm . AlthougTreating and solving congestion are among the principal goals of AHF management. Persistence of congestion and poor response to diuretic treatment are associated with increased risk of mortality and threefold higher rate of re-hospitalization , 37. BecTo avoid these pitfalls, many strategies have been proposed. The so-called breaking phenomena of loop diuretic resistance could in theory be overcome by continuous infusion. Sequential nephron blockade includes the contemporary use of loop diuretics together with thiazides and aldosterone antagonists in order to obtain a stepwise impairment of sodium reabsorption at multiple points along the nephron. This strategy is prone to increased risks of hypoperfusion, hypokalemia, and hyponatremia . Lastly,In the setting of neurohormonal activation and adequate perfusion, nesiritide could play an adjunctive role but does not have a broadly applied benefit in AHF . It is pPulmonary and systemic congestion are inextricably linked to renal function. Use of loop diuretics is clearly playing a role in decongestion but at the same time is probably precipitating AKI and type 1 cardiorenal syndromes in patients at risk for worsened renal function and poor outcomes. Future research using advanced tools and personalized approaches for optimal outcomes is needed. Broad applications of high-dose or continuous infusion of loop diuretics or adjunctive use of inotropic and new vasoactive therapies have not been associated with improved outcomes. We propose an algorithm including a metric measurement of decongestion with concomitant evaluation of renin-angiotensin-aldosterone system activity and renal dysfunction mechanisms. This approach would allow a better AHF treatment by actualizing the integrated actors of the cardio-renal axis.


Implantable cardioverter defibrillators (ICDs) are effective for both primary and secondary prevention of sudden cardiac death. For patients with reduced left ventricular ejection fraction (LVEF) caused by ischaemic or non-ischaemic aetiology, ICDs have received a class I indication in the recent European and American guidelines (reviewed by Maass and Van Veldhuisen ). SelectWhich diagnostic tests can be used to govern ICD implantations? Risk prediction is even more important for non-ischaemic cardiomyopathy as the evidence for prophylactic ICD implantation is rather weak. Tests should be easy to perform and results should be unambiguous.Currently, LVEF is the gold standard to indicate a patient for ICD implantation. The test that should be used to quantify LVEF, however, is not mentioned in the guidelines and results from echocardiography, nuclear imaging or magnetic resonance imaging might be divergent.Simple clinical characteristics such as functional class and history of syncope are easy to record but not unambiguous. Functional class is very subjective and neurocardiogenic syncope is very common and occurs often without underlying cardiac pathology. In addition to functional class, renal insufficiency, chronic obstructive pulmonary disease, age and sex all influence risk of sudden death. The predictive value, however, is offset by an increase in all-cause mortality, and risk reduction by ICDs is low in high-risk populations. High-risk patients derive no benefit from non-resynchronisation ICD therapy . Even thRegistration of spontaneous non-sustained ventricular tachycardias (VTs) via Holter monitoring is also simple but sensitivity might also be low with a single 24-hour recording. Furthermore, the prognostic value of spontaneous VTs has only been demonstrated in depressed ejection due to ischaemic aetiology whereas results in patients with non-ischaemic cardiomyopathy are less clear. Inducibility of monomorphic VTs by programmed electrical stimulation might be of predictive value but results from studies are not consistent especially for non-ischaemic cardiomyopathy and this test is invasive and not particularly easy to perform outside of specialised centres.Genetics are currently used to confirm the diagnosis in familial heart diseases such as hypertrophic and dilated cardiomyopathy. In dilated cardiomyopathy, common mutations in Dutch patients have malignant phenotypes such as lamin A/C and phospholamban. In these patients, ICD implantation can be useful even if decline in LVEF has not yet reached 35%. Most likely, the near future will reveal common disease-modifying polymorphisms that render their carriers at increased risk of sudden death if they develop heart disease. We will have to wait for identification of such genetic modifiers but once they are known testing would fulfil the criterion of simplicity and possibly unambiguity.Several parameters of the electrocardiogram have been used to predict risk: resting heart rate, heart rate recovery, heart rate variability or turbulence, QT dispersion or microvolt T wave alternans (MTWA). In this issue of the journal, Kraaier et al. test whether exercise MTWA can be used to identify patients at high risk of death or appropriate ICD shocks . MWTA teWhere are we headed with prophylactic ICD implantations? Cardiology has recently seen a dramatic increase in the use of scores to govern diagnostics and treatment. Oral anticoagulation therapy is governed by the CHADS-VASc score, cardiothoracic surgery risk is evaluated with the EUROSCORE, and we use the GRACE score to evaluate risk in patients with acute coronary syndromes. Why are we not using a risk score to predict efficacy of ICDs? We urgently need more than LVEF to decide on which patients should receive an ICD. In the current situation, we might implant patients at low risk who might never receive adequate ICD therapies and are at risk to develop serious complications. On the other hand, patients with an LVEF presumed to be above 35% might be at risk of sudden cardiac death and not receive this life-saving therapy. The prognosis of patients with heart failure with preserved ejection fraction (HFPEF) is not much better than that of patients with depressed ejection fraction . Sudden


As the passage of time structurally alters one’s brain, cognition does not have to suffer the same faith, at least not to the same extent. Indeed, the existence of age-related compensatory mechanisms allow for some cognitive preservation. This paper attempts to coherently review the existing concepts of neurofunctional compensation when applied to two different cognitive domains, namely executive function and language processing. More precisely, we explore the Cognitive reserve (CR) model in healthy aging as well as its two underlying mechanisms: neural reserve and neural compensation. Furthermore, we review the Compensation-Related Utilization of Neural Circuits Hypothesis as well as the Growing Of Life Differences Explains Normal Aging model. Finally, we propose, based on some functional neuroimaging studies, the existence of another compensatory mechanism characterized by age-related delayed cerebral activation allowing for cognitive performance to be preserved at the expense of speed processing: the Temporal Hypothesis for Compensation. Furthermore, the present review will explore if these compensatory mechanisms are the same for executive functions (including working memory) and language processing, or if different cognitive domains rely on different mechanisms.Executive function can be summarized as the general cognitive processes that support strategic organization and control other processes that play an important role in complex, goal oriented tasks Buckner, ; Table 1Language abilities can be considered as involving multiple cognitive processes allowing for the processing of grammatical rule which interplays with phonology (the speech sound processing system) and semantics (the meaning processing system)  hypothesis is a ‘functional’ model of reserve conceptualized by Stern  that refStern and companions have extensively explored the neural compensation hypothesis in several of their studies. Zarahn et al. , part ofThere are two possible explanations for this finding. One is that this observation cannot represent a compensatory mechanism since as older individuals increasingly use the alternative network, worse is their performance. However, one could also argue that this alternative network is needed to maintain function as age-related neural changes diminish the efficacy of the first (primary) network. In other words, those individuals using the primary and alternative network would perform even worse if they relied only on their (impaired) primary pathway. If the latter explanation proves to be true, the second network would then be an example of neural compensation.The same group , which measures the hemodynamic correlates of neural activity, have also shown how increased right DLPFC activity is often associated with better performance during executive tasks in healthy older adults. For example, Albinet et al.  investigSeveral neuroimaging studies that looked at language processing have also reported increased bilateral activity in high performing older persons compared with younger individuals during verbal generation , an area known to play a role in working memory including maintaining and rehearsing stored verbal information  activity. The dorsolateral PFC has been reported in several studies implying problem-solving activities, regardless of the nature of the material  while younger individuals rely more on an executive strategy (which imply the involvement of the PFC). They also point out that semantic fluency tends to rely on temporal regions whereas orthographic fluency is more dependent on frontal regions  have the potential to significantly modify task-related BOLD responses   especially when it is correlated with impaired performance; or, on the contrary, improved function when it is associated with better performance.Neural reserve has been extensively studied in the context of working memory. Indeed, Zarahn et al.  scanned In 2009, the same group  are not limited to older individuals, but they also occur in younger people when task demands increase . However, even younger individuals can show similarly increased activation patterns during high-load cognitive processes.The previous compensatory mechanisms described so far presented anatomically based functional changes in brain activation patterns. However, there is still the possibility of another compensatory mechanism involving not so much WHICH regions of the brain show increased activation, but WHEN are these regions activated.Velanova et al.  have sugPaxton et al.  contrastJimura and Braver  comparedOur group ; a noun-verb substitution ; and a transitivity violation (a sentence containing a verb that cannot be expressed in a passive form because the verb is intransitive). These three violations are presented in an ascending order regarding cognitive demand. In early time windows, the participants showed significant left IFC recruitment in low-demanding judgments, and bilateral IFC recruitment in more-demanding judgments. In late time windows , the young participants did not show any activation during low-demanding conditions, but presented left IFC recruitment in the noun-verb substitutions and transitivity violations. Wingfield and Grossman . This hypothesis states the following: (1) there is an age-related delay in brain activity, particularly in the PFC, during cognitive processing ; 2) there is an age-related shift from proactive to reactive cognitive control strategies when cognitive processes imply both anticipation and resolution; and (3) these age-related temporally based functional changes in brain activation patterns allow for cognitive performance to be preserved at the expense of speed processing . This new theory builds on previous hypothesis that postulated a shift from proactive to reactive cognitive control strategies in the elderly, namely the DMC hypothesis.In the introduction, we asked if different cognitive domains including language and executive function rely on similar compensatory mechanisms. Based on this review the elderly appear to present evidence of neural compensation, neural reserve and/or delayed brain activation (THC) while performing working memory, executive and/or language processes tasks. Why? First, because cognitive tasks rarely explore solely one cognitive domain at the time. Working memory, for example, not only merges with executive processes, but affects language abilities as well. It is known to constrain sentence comprehension especially regarding sentences with complex syntactic structures  should try to explore the factors affecting these specific patterns of neurofuntional reorganization. Indeed, the nature of the task, the complexity of the task, the cognitive processes explored and the cognitive strategies used by participants appear to be determinant in the specific shape compensatory mechanisms will take. We also strongly believe that the THC model should be explored in greater depth given the little research there is on temporal neurofuntional reorganization compared to anatomical changes in activation patterns. Finally, there should be more functional connectivity studies whose role is to investigate age-related compensatory mechanisms since some studies suggest already that task-relevant functional connections between specific brain regions can be disrupted with age and that these disruptions have a negative impact on task performance (Madden et al., 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.


Continued and accelerating change in the thermal environment places an ever-greater priority on understanding how organisms are going to respond. The paradigm of ‘move, adapt or die', regarding ways in which organisms can respond to environmental stressors, stimulates intense efforts to predict the future of biodiversity. Assuming that extinction is an unpalatable outcome, researchers have focussed attention on how organisms can shift in their distribution to stay in the same thermal conditions or can stay in the same place by adapting to a changing thermal environment. How likely these respective outcomes might be depends on the answer to a fundamental evolutionary question, namely what genetic changes underpin adaptation to the thermal environment. The increasing access to and decreasing costs of next-generation sequencing (NGS) technologies, which can be applied to both model and non-model systems, provide a much-needed tool for understanding thermal adaptation. Here we consider broadly what is already known from non-NGS studies about thermal adaptation, then discuss the benefits and challenges of different NGS methodologies to add to this knowledge base. We then review published NGS genomics and transcriptomics studies of thermal adaptation to heat stress in metazoans and compare these results with previous non-NGS patterns. We conclude by summarising emerging patterns of genetic response and discussing future directions using these increasingly common techniques. A wide array of observed biological changes in organisms have been attributed to the influence of anthropogenic climate change, including in body size  methods may provide a tool to begin to examine genomic responses to temperature stress, potentially revealing new understanding of responses to environmental change. One clear advantage of NGS over traditional genetic methods for examining response to temperature stress is that it can be applied to both model  and non-model  organisms and it provides a whole-organism snapshot of responsive genes. Moreover, a ‘macro' level approach can be accomplished through comparisons within and among populations and species and across landscape scales  to understand adaptive responses to heat. We limit our review to metazoans because they have lower thermal tolerances compared with non-metazoans . Combining studies of both intra- and interpopulation variation in response to the thermal environment can be a powerful framework for determining what facilitates and limits adaptive evolution to temperature. This is particularly true in a widely distributed species where populations experience different environmental temperatures. In species with sufficiently low gene flow, divergent selection pressures between environments can result in local adaptation. Local adaptation refers to genetic differentiation among populations that results in increased mean fitness in the local environment . These associations were determined either by functional genetic analysis of response to heat, cold, starvation and dessication  genes, Fst (frost) and the Turandot family of immune function genes. Other genes in this list had additional interesting annotated functions including per (period), associated with circadian clocks; mth (methuselah) associated with aging; and rut (rutabaga) associated with learning and memory.Another way to analyse these gene lists is to use gene ontology (GO) analysis, which allows categorisation of the responding genes and determining whether there is enrichment of genes for particular biological processes, molecular functions and cellular components. Such analysis may be a useful approach to identify core biological mechanisms that may be critical in thermal adaptation. We used the CESAR list and performed a GO term analysis using DAVID , but forThe current literature leaves us with a large gap between what is known generally at the macro level about physiological traits related to thermal stress and the underlying genes and genetic architecture of these responses. Linking these two is where NGS studies could add tremendously to our understanding of thermal adaptation and limits to such responses. Below we discuss the uses and challenges of NGS in the study of thermal adaptation.NGS methods (here meaning high-throughput sequencing of DNA or RNA) provide information on genetic variation and/or on gene expression within and among populations. This information can be used to address all of the steps that sensu stricto fall into three categories: reference genome sequencing, quantitative trait locus (QTL) mapping or analysis of genetic variation within and among populations. Reference genome sequencing provides the raw material that then can be used in any downstream analysis with other NGS technologies. For QTL mapping, NGS provides genome-wide markers at unprecedented density even in non-model organisms, in which QTLs are determined via either laboratory crosses in which parentage is controlled, pedigree analyses or association analyses. For example, Applications of genomics Drosophila  provides a different type of insight. It is a major approach in stress physiology to gain insights into regulatory changes that accompany patterns of variation, whether plastic or adaptive . For orgChanges in the gene expression associated with thermal adaptation occur on a wide range of timescales, including long-lasting effects of early-life exposures, maternal effects and transgenerational effects. These changes may be regulated epigenetically, that is, by inherited modifications of the DNA or chromatin other than base sequence changes . Epigenetic modifications regulate genome expression and chromatin conformation and have a crucial role in response to heat exposure during early development in a number of vertebrate species that strongly impact on adult phenotype. Such modifications can influence population demography and dynamics, particularly in the context of climatic change, and DNA methylation can be detected by NGS methods  and applied to thermal adaptation  until 28 February 2014 using combinations of two key phrases. Each query pair was of the form ai, bj, where ai ɛ A={‘Next-generation sequencing', ‘RNA-seq', ‘RAD-seq', ‘DNA-seq', ‘Pool-seq', ‘Illumina', ‘Roche 454', ‘SOLiD'} and bj ɛ B={‘Climate', ‘Thermal adaptation', ‘Heat stress'}. Technology terms were used rather than, for example, ‘transcriptomics' to avoid studies that were not relevant . All possible ai AND bj combinations were used in our search and, after removing studies covering plant, bacterial or archaeal species, a set of 32 publications, centred exclusively on 27 different metazoan species, was used for subsequent analysis , (3) laboratory heat stress experiments in which a population is subjected to rapid, but short-term, temperature increase, (4) common garden experiments in which populations adapted to different thermal environments  are subjected to a common temperature and (5) studies focused on the generation of genetic references  and reference transcriptomes. Approach (3) can identify plastic responses to thermal stress, whereas the other techniques can identify signatures of thermal adaptation. Although the majority of these approaches can be used in the wild, most have only been performed in the laboratory.de novo transcriptome assemblies. The construction of a high-quality transcriptome is clearly critical for accurate downstream analyses. However, despite its popularity, the RNA-seq Illumina platform generates transcriptomes that are generally oversized  even when paired end sequences are used for the assembly . This comparison identified 47 genes that had outlier SNPs that responded in the predicted direction during experimental evolution Payne, occurs in both clines, varies in frequency latitudinally and is thought to be important in both genetic and phenotypic differentiation along the clines . We found that only five genes overlap between the clinal and experimental evolution studies and 98 between the clinal study and the CESAR list (In(3R)Payne, whereas one localises within the inversion itself , two as heat tolerant L1231) and one as both heat and starvation tolerant (CG6733).Here we combine results from the clinal  but, instead, focused on identifying outlier SNPs and describing their association with gene function categories. GO analysis depends on having high-quality genome annotations so one issue with combining information across disparate non-model organisms is a potential bias in the results. Therefore, to limit any bias, we only analysed studies on related organisms  and sequence evolution in 3′ UTRs are associated with the evolution of regulatory sequences. These hsp findings corroborate earlier individual studies of hsp gene regulation evolution; for example, in Drosophila, insertions of transposable elements in the proximal promoters of hsp genes are positively selected  hsp70 is now constitutively, rather than inducibly, expressed  were found to be differentiating in parallel across the North American and Australian clines using NGS than a previous study on the same populations using non-NGS methods . Disparity among studies, even from the same populations, occurs when considering the exact genes that are responding. With respect to gene evolution, we only collated GO terms  and found similar response across studies.D. melanogaster E&R (In(3R)Payne. Whether these are independent targets of selection remains to be determined. Additional NGS techniques and functional genetics can address this question.The genetic architecture of genes responding to thermal stress is critical in determining whether populations can keep up with the velocity of environmental change . Most NGD. melanogaster cannot test for such patterns given that only the ends of the clines were examined. Predictions from local adaptation are also sensitive to departures from additivity such as epistasis, or interactions among traits, due to linkage or pleiotropy; as multiple traits must commonly be involved in thermal adaptation, these complexities are important. For example, as shown in our analysis of the CESAR data set, some genes are pleiotropic. Setting studies of thermal adaptation in a genetic architecture framework would be valuable for more detailed understanding of capacity for thermal responses.Although remaining locally adapted can allow population persistence, whether such microevolution mitigates or aggravates future responses to climate change is debated (see, for example, ‘Omics data have the potential to elucidate the network of genetic, regulatory and metabolic responses to thermal environments from cellular to evolutionary analysis. Although there is much to be gained by integrating these technologies, no published study has yet combined, for example, RNA-seq with either proteomics or metabolomics. And, as stated earlier, genes identified as responding in expression or allele frequency, subsequently requires investigation of the functions of putative candidate genes, genetic variation for the relevant traits within and among populations, the intensity of selection and links between adaptive responses and population dynamics that underlie population persistence. It is no surprise that, given the infancy of NGS, this necessary integration has yet to occur.A wide variety of experimental designs can be employed to address thermal responses, distinguishing the effects of adaptation and plasticity . Here weAll the reviewed studies have been performed in the laboratory or on two to three populations (for the one exception, see There were no data to deposit.