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Abstract Background Meningococcal meningitis is a major cause of disease worldwide, with frequent epidemics particularly affecting an area of sub-Saharan Africa known as the “meningitis belt”. Neisseria meningitidis group A (MenA) is responsible for major epidemics in Africa. Recently W-135 has emerged as an important pathogen. Currently, the strategy for control of such outbreaks is emergency use of meningococcal (MC) polysaccharide vaccines, but these have a limited ability to induce herd immunity and elicit an adequate immune response in infant and young children. In recent times initiatives have been taken to introduce meningococcal conjugate vaccine in these African countries. Currently there are two different types of MC conjugate vaccines at late stages of development covering serogroup A and W-135: a multivalent MC conjugate vaccine against serogroup A,C,Y and W-135; and a monovalent conjugate vaccine against serogroup A. We aimed to perform a structured assessment of these emerging meningococcal vaccines as a means of reducing global meningococal disease burden among children under 5 years of age. Methods We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In the first stage we systematically reviewed the literature related to emerging MC vaccines relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. Results For MenA conjugate vaccine the experts showed very high level of optimism (~ 90% or more) for 7 out of the 12 criteria. The experts felt that the likelihood of efficacy on meningitis was very high (~ 90%). Deliverability, acceptability to health workers, end users and the effect on equity were all seen as highly likely (~ 90%). In terms of the maximum potential impact on meningitis disease burden, the median potential effectiveness of the vaccines in reduction of overall meningitis mortality was estimated to be 20%; (interquartile range 20-40% and min. 8%, max 50 %). For the multivalent meningococcal vaccines the experts had similar optimism for most of the 12 CHNRI criteria with slightly lower optimism in answerability and low development cost criteria. The main concern was expressed over the cost of product, its affordability and cost of implementation. Conclusions With increasing recognition of the burden of meningococcal meningitis, especially during epidemics in Africa, it is vitally important that strategies are taken to reduce the morbidity and mortality attributable to this disease. Improved MC vaccines are a promising investment that could substantially contribute to reduction of child meningitis mortality world-wide.

Abstract Background Staphylococcus aureus is a commensal of human skin and nares. It is also one of the leading nosocomial pathogens in both developed and developing countries and is responsible for a wide range of life threatening infections, especially in patients who are immunocompromised, post-surgery, undergoing haemodialysis and those who are treated with catheters and ventilators. Over the past two decades, the incidence of nosocomial staphylococcal infections has increased dramatically. Currently there are at least seven vaccine and immunotherapy candidates against S. aureus in the developmental phase targeting both active and passive immunization. Methods We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging vaccines against Staphylococcus aureus relevant to several criteria of interest: answerability; cost of development, production and implementation; efficacy and effectiveness; deliverability, affordability and sustainability; maximum potential impact on disease burden reduction; acceptability to the end users and health workers; and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies) to participate. The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to sensitive nature of their involvement in such exercises. They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. Results The panel of experts expressed low levels of optimism (score around or below 50%) on the criteria of answerability, efficacy, maximum disease burden reduction potential, low cost of production, low cost of implementation and affordability; moderate levels of optimism (scores around 60 to 80%) that these vaccines could be developed at a low cost, and thus on the deliverability, sustainability and impact on equity; and high levels of optimism (scores above 80%) regarding acceptable of such a product to both the end-users and health workers. While assessing the candidates for passive immunization against S.aureus, the experts were poorly optimistic regarding low production cost, low implementation cost, efficacy, deliverability, sustainability, affordability and equity; moderately optimistic regarding answerability and acceptability to health workers and end-users. They were of the opinion that these interventions would have only a modest impact (3 to 5%) on the burden of childhood pneumonia. . Conclusion In order to provide an effective vaccine against S. aureus, a number of unresolved issues in vaccine development relating to optimal antigenic target identification, criteria for acceptable efficacy, identification of target population, commercial development limitations, optimal timing of immunization strategy, storage, cold chain requirements and cost need to be addressed properly. There is still a great deal unknown about the complex interaction between S. aureus and the human host. However, given the nature of S. aureus and the lessons learned from the recent failure of two emerging vaccines, it is clear that a multi-component vaccine is essential. Combating only one virulence factor is not sufficient in the human host but finding the right combination of factors will be very challenging.

Abstract Background Measles was responsible for an estimated 100,000 deaths worldwide in 2008. Despite being a vaccine-preventable disease, measles remains a major cause of morbidity and mortality in young children. Although a safe and effective injectable measles vaccine has been available for over 50 years it has not been possible to achieve the uniformly high levels of coverage (required to achieve measles eradication) in most parts of the developing world. Aerosolised measles vaccines are now under development with the hope of challenging the delivery factors currently limiting the coverage of the existing vaccine. Methods We used a modified CHNRI methodology for setting priorities in health research investments to assess the strengths and weaknesses of this emerging intervention to decrease the burden of childhood pneumonia. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging aerosol vaccines against measles relevant to several criteria of interest. Although there are a number of different aerosol vaccine approaches under development, for the purpose of this exercise, all were considered as one intervention. The criteria of interest were: answerability; cost of development, production and implementation; efficacy and effectiveness; deliverability, affordability and sustainability; maximum potential impact on disease burden reduction; acceptability to the end users and health workers; and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to the sensitive nature of their involvement in such exercises. They answered questions from the CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. Results The panel of experts expressed mixed feelings about an aerosol measles vaccine. The group expressed low levels of optimism regarding the criteria of likelihood of efficacy and low cost of development (scores around 50%); moderate levels of optimism regarding answerability, low cost of production, low cost of implementation and affordability (score around 60%); and high levels of optimism regarding deliverability, impact on equity and acceptability to health workers and end-users (scores over 80%). Finally, the experts felt that this intervention will have a modest but nevertheless important impact on reduction of burden of disease due to childhood pneumonia (median: 5%, interquartile range 1-15%, minimum 0%, maximum 45%). Conclusion Aerosol measles vaccine is at an advanced stage of development, with evidence of good immunogenicity. This new intervention will be presented as a feasible candidate strategy in the campaign for global elimination of measles. It also presents an unique opportunity to decrease the overall burden of disease due to severe pneumonia in young children.

Abstract Background Zinc deficiency is commonly prevalent in children in developing countries and plays a role in decreased immunity and increased risk of infection. Preventive zinc supplementation in healthy children can reduce mortality due to common causes like diarrhea, pneumonia and malaria. The main objective was to determine all-cause mortality and cause-specific mortality and morbidity in children under five in developing countries for preventive zinc supplementation. Data sources/ review methods A literature search was carried out on PubMed, the Cochrane Library and the WHO regional databases to identify RCTs on zinc supplementation for greater than 3 months in children less than 5 years of age in developing countries and its effect on mortality was analyzed. Results The effect of preventive zinc supplementation on mortality was given in eight trials, while cause specific mortality data was given in five of these eight trials. Zinc supplementation alone was associated with a statistically insignificant 9% (RR = 0.91; 95% CI: 0.82, 1.01) reduction in all cause mortality in the intervention group as compared to controls using a random effect model. The impact on diarrhea-specific mortality of zinc alone was a non-significant 18% reduction (RR = 0.82; 95% CI: 0.64, 1.05) and 15% for pneumonia-specific mortality (RR = 0.85; 95% CI: 0.65, 1.11). The incidence of diarrhea showed a 13% reduction with preventive zinc supplementation (RR = 0.87; 95% CI: 0.81, 0.94) and a 19% reduction in pneumonia morbidity (RR = 0.81; 95% CI: 0.73, 0.90). Keeping in mind the direction of effect of zinc supplementation in reducing diarrhea and pneumonia related morbidity and mortality; we considered all the outcomes for selection of effectiveness estimate for inclusion in the LiST model. After application of the CHERG rules with consideration to quality of evidence and rule # 6, we used the most conservative estimates as a surrogate for mortality. We, therefore, conclude that zinc supplementation in children is associated with a reduction in diarrhea mortality of 13% and pneumonia mortality of 15% for inclusion in the LiST tool. Preventive zinc supplementation had no effect on malaria specific mortality (RR = 0.90; 95% CI: 0.77, 1.06) or incidence of malaria (RR=0.92; 95 % CI 0.82-1.04) Conclusion Zinc supplementation results in reductions in diarrhea and pneumonia mortality.

Abstract Background Respiratory Syncytial Virus (RSV) is the leading cause of acute lower respiratory infections (ALRI) in children. It is estimated to cause approximately 33.8 million new episodes of ALRI in children annually, 96% of these occurring in developing countries. It is also estimated to result in about 53,000 to 199,000 deaths annually in young children. Currently there are several vaccine and immunoprophylaxis candidates against RSV in the developmental phase targeting active and passive immunization. Methods We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging vaccines against RSV relevant to 12 criteria of interest. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to the sensitive nature of their involvement in such exercises. They answered questions from the CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. Results In the case of candidate vaccines for active immunization of infants against RSV, the experts expressed very low levels of optimism for low product cost, affordability and low cost of development; moderate levels of optimism regarding the criteria of answerability, likelihood of efficacy, deliverability, sustainability and acceptance to end users for the interventions; and high levels of optimism regarding impact on equity and acceptance to health workers. While considering the candidate vaccines targeting pregnant women, the panel expressed low levels of optimism for low product cost, affordability, answerability and low development cost; moderate levels of optimism for likelihood of efficacy, deliverability, sustainability and impact on equity; high levels of optimism regarding acceptance to end users and health workers. The group also evaluated immunoprophylaxis against RSV using monoclonal antibodies and expressed no optimism towards low product cost; very low levels of optimism regarding deliverability, affordability, sustainability, low implementation cost and impact on equity; moderate levels of optimism against the criteria of answerability, likelihood of efficacy, acceptance to end-users and health workers; and high levels of optimism regarding low development cost. They felt that either of these vaccines would have a high impact on reducing burden of childhood ALRI due to RSV and reduce the overall childhood ALRI burden by a maximum of about 10%. Conclusion Although monoclonal antibodies have proven to be effective in providing protection to high-risk infants, their introduction in resource poor settings might be limited by high cost associated with them. Candidate vaccines for active immunization of infants against RSV hold greatest promise. Introduction of a low cost vaccine against RSV would reduce the inequitable distribution of burden due to childhood ALRI and will most likely have a high impact on morbidity and mortality due to severe ALRI.

Abstract Background Oxygen therapy is recommended for all of the 1.5 – 2.7 million young children who consult health services with hypoxemic pneumonia each year, and the many more with other serious conditions. However, oxygen supplies are intermittent throughout the developing world. Although oxygen is well established as a treatment for hypoxemic pneumonia, quantitative evidence for its effect is lacking. This review aims to assess the utility of oxygen systems as a method for reducing childhood mortality from pneumonia. Methods Aiming to improve priority setting methods, The Child Health and Nutrition Research Initiative (CHNRI) has developed a common framework to score competing interventions into child health. That framework involves the assessment of 12 different criteria upon which interventions can be compared. This report follows the proposed framework, using a semi-systematic literature review and the results of a structured exercise gathering opinion from experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies), to assess and score each criterion as their “collective optimism” towards each, on a scale from 0 to 100%. Results A rough estimate from an analysis of the literature suggests that global strengthening of oxygen systems could save lives of up to 122,000 children from pneumonia annually. Following 12 CHNRI criteria, the experts expressed very high levels of optimism (over 80%) for answerability, low development cost and low product cost; high levels of optimism (60-80%) for low implementation cost, likelihood of efficacy, deliverability, acceptance to end users and health workers; and moderate levels of optimism (40-60%) for impact on equity, affordability and sustainability. The median estimate of potential effectiveness of oxygen systems to reduce the overall childhood pneumonia mortality was ~20% (interquartile range: 10-35%, min. 0%, max. 50%). However, problems with oxygen systems in terms of affordability, sustainability and impact on equity are noted in both expert opinion scores and on review. Conclusion Oxygen systems are likely to be an effective intervention in combating childhood mortality from pneumonia. However, a number of gaps in the evidence base exist that should be addressed to complete the investment case and research addressing these issues merit greater funding attention.

Abstract Background Pneumonia is the leading cause of child mortality worldwide. Streptococcus pneumoniae (SP) or pneumococcus is estimated to cause 821,000 child deaths each year. It has over 90 serotypes, of which 7 to 13 serotypes are included in current formulations of pneumococcal conjugate vaccines that are efficacious in young children. To further reduce the burden from SP pneumonia, a vaccine is required that could protect children from a greater diversity of serotypes. Two different types of vaccines against pneumococcal pneumonia are currently at varying stages of development: a multivalent pneumococcal conjugate vaccine covering additional SP serotypes; and a conserved common pneumococcal protein antigen (PPA) vaccine offering protection for all serotypes. Methods We used a modified CHNRI methodology for setting priorities in health research investments. This was done in two stages. In Stage I, we systematically reviewed the literature related to emerging SP vaccines relevant to several criteria of interest: answerability; efficacy and effectiveness; cost of development, production and implementation; deliverability, affordability and sustainability; maximum potential for disease burden reduction; acceptability to the end users and health workers; and effect on equity. In Stage II, we conducted an expert opinion exercise by inviting 20 experts (leading basic scientists, international public health researchers, international policy makers and representatives of pharmaceutical companies). The policy makers and industry representatives accepted our invitation on the condition of anonymity, due to sensitive nature of their involvement in such exercises. They answered questions from CHNRI framework and their “collective optimism” towards each criterion was documented on a scale from 0 to 100%. Results The experts expressed very high level of optimism (over 80%) that low-cost polysaccharide conjugate SP vaccines would satisfy each of the 9 relevant CHNRI criteria. The median potential effectiveness of conjugate SP vaccines in reduction of overall childhood pneumonia mortality was predicted to be about 25% (interquartile range 20-38%, min. 15%, max 45%). For low cost, cross-protective common protein vaccines for SP the experts expressed concerns over answerability (72%) and the level of development costs (50%), while the scores for all other criteria were over 80%. The median potential effectiveness of common protein vaccines in reduction of overall childhood pneumonia mortality was predicted to be about 30% (interquartile range 26-40%, min. 20%, max 45%). Conclusions Improved SP vaccines are a very promising investment that could substantially contribute to reduction of child mortality world-wide.

Abstract Background In Scotland colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer death. Epidemiological studies have reported conflicting associations between statins and CRC risk and there is one published report of the association between statins and CRC survival. Methods Analysis was carried out on 309 cases and 294 controls from the Scottish Study of Colorectal Cancer (SOCCS). Cox’s hazard and logistic regression models were applied to investigate the association between statin use and CRC risk and survival. Results In an adjusted logistic regression model, statins were found to show a statistically significant association for three of the four statin variables and were found to not show a statistically significant association with either all-cause or CRC-specific mortality (OR 0.49; 95%CI 0.49-1.36; p-value = 0.17 and OR 0.33; 95%CI 0.08-1.35; P-value = 0.12, respectively). Conclusion We did find a statistically significant association between statin intake and CRC risk but not statin intake and CRC-specific mortality. However, the study was insufficiently powered and larger scale studies may be advisable.

Abstract Background Serum creatinine (SCR) is the most important biomarker for a quick and non-invasive assessment of kidney function in population-based surveys. A substantial proportion of the inter-individual variability in SCR level is explicable by genetic factors. Methods We performed a meta-analysis of genome-wide association studies of SCR undertaken in five population isolates ('discovery cohorts'), all of which are part of the European Special Population Network (EUROSPAN) project. Genes showing the strongest evidence for an association with SCR (candidate loci) were replicated in two additional population-based samples ('replication cohorts'). Results After the discovery meta-analysis, 29 loci were selected for replication. Association between SCR level and polymorphisms in the collagen type XXII alpha 1 (COL22A1) gene, on chromosome 8, and in the synaptotagmin-1 (SYT1) gene, on chromosome 12, were successfully replicated in the replication cohorts (p value = 1.0 × 10-6 and 1.7 × 10-4, respectively). Evidence of association was also found for polymorphisms in a locus including the gamma-aminobutyric acid receptor rho-2 (GABRR2) gene and the ubiquitin-conjugating enzyme E2-J1 (UBE2J1) gene (replication p value = 3.6 × 10-3). Previously reported findings, associating glomerular filtration rate with SNPs in the uromodulin (UMOD) gene and in the schroom family member 3 (SCHROOM3) gene were also replicated. Conclusions While confirming earlier results, our study provides new insights in the understanding of the genetic basis of serum creatinine regulatory processes. In particular, the association with the genes SYT1 and GABRR2 corroborate previous findings that highlighted a possible role of the neurotransmitters GABAA receptors in the regulation of the glomerular basement membrane and a possible interaction between GABAAreceptors and synaptotagmin-I at the podocyte level.

Abstract Background Genome-wide homozygosity estimation from genomic data is becoming an increasingly interesting research topic. The aim of this study was to compare different methods for estimating individual homozygosity-by-descent based on the information from human genome-wide scans rather than genealogies. We considered the four most commonly used methods and investigated their applicability to single-nucleotide polymorphism (SNP) data in both a simulation study and by using the human genotyped data. A total of 986 inhabitants from the isolated Island of Vis, Croatia (where inbreeding is present, but no pedigree-based inbreeding was observed at the level of F > 0.0625) were included in this study. All individuals were genotyped with the Illumina HumanHap300 array with 317,503 SNP markers. Results Simulation data suggested that multi-point FEstim is the method most strongly correlated to true homozygosity-by-descent. Correlation coefficients between the homozygosity-by-descent estimates were high but only for inbred individuals, with nearly absolute correlation between single-point measures. Conclusions Deciding who is really inbred is a methodological challenge where multi-point approaches can be very helpful once the set of SNP markers is filtered to remove linkage disequilibrium. The use of several different methodological approaches and hence different homozygosity measures can help to distinguish between homozygosity-by-state and homozygosity-by-descent in studies investigating the effects of genomic autozygosity on human health.

Abstract Background Rhegmatogenous retinal detachment (RRD) is a potentially blinding condition and a common cause of ocular morbidity. Establishing an accurate estimate of disease incidence and distribution is an important first step in assessing the healthcare burden related to this condition and in subsequent planning and provision of treatment strategies. The aim of this study is to obtain a first estimate incidence of RRD in Scotland, to estimate the incidence of familial RRD and to describe the known associations of RRD within the study population. Methods/Design We have established a national prospective observational study seeking to identify and recruit all incident cases of RRD in the Scottish population over a 2 year period. After fully informed consent, all participants will have a blood sample taken and a full medical history and clinical examination performed including visual acuity, refraction, slit-lamp examination, intra-ocular pressure measurement and detailed fundal examination. We describe the study design and protocol. Conclusion This study will provide the first estimate of the annual incidence of RRD in Scotland. The findings of this study will be important in estimating the burden of disease and in the planning of future health care policy related to this condition. This study will also establish a genetic resource for a genome wide association study to investigate if certain genetic variants predispose to RRD.

Abstract Background Cognitive ageing is a major burden for society and a major influence in lowering people's independence and quality of life. It is the most feared aspect of ageing. There are large individual differences in age-related cognitive changes. Seeking the determinants of cognitive ageing is a research priority. A limitation of many studies is the lack of a sufficiently long period between cognitive assessments to examine determinants. Here, the aim is to examine influences on cognitive ageing between childhood and old age. Methods/Design The study is designed as a follow-up cohort study. The participants comprise surviving members of the Scottish Mental Survey of 1947 (SMS1947; N = 70,805) who reside in the Edinburgh area (Lothian) of Scotland. The SMS1947 applied a valid test of general intelligence to all children born in 1936 and attending Scottish schools in June 1947. A total of 1091 participants make up the Lothian Birth Cohort 1936. They undertook: a medical interview and examination; physical fitness testing; extensive cognitive testing (reasoning, memory, speed of information processing, and executive function); personality, quality of life and other psycho-social questionnaires; and a food frequency questionnaire. They have taken the same mental ability test (the Moray House Test No. 12) at age 11 and age 70. They provided blood samples for DNA extraction and testing and other biomarker analyses. Here we describe the background and aims of the study, the recruitment procedures and details of numbers tested, and the details of all examinations. Discussion The principal strength of this cohort is the rarely captured phenotype of lifetime cognitive change. There is additional rich information to examine the determinants of individual differences in this lifetime cognitive change. This protocol report is important in alerting other researchers to the data available in the cohort.

Abstract Background Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time. Results In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important. Conclusion We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.

Abstract Background Generation Scotland: the Scottish Family Health Study aims to identify genetic variants accounting for variation in levels of quantitative traits underlying the major common complex diseases (such as cardiovascular disease, cognitive decline, mental illness) in Scotland. Methods/Design Generation Scotland will recruit a family-based cohort of up to 50,000 individuals (comprising siblings and parent-offspring groups) across Scotland. It will be a six-year programme, beginning in Glasgow and Tayside in the first two years (Phase 1) before extending to other parts of Scotland in the remaining four years (Phase 2). In Phase 1, individuals aged between 35 and 55 years, living in the East and West of Scotland will be invited to participate, along with at least one (and preferably more) siblings and any other first degree relatives aged 18 or over. The total initial sample size will be 15,000 and it is planned that this will increase to 50,000 in Phase 2. All participants will be asked to contribute blood samples from which DNA will be extracted and stored for future investigation. The information from the DNA, along with answers to a life-style and medical history questionnaire, clinical and biochemical measurements taken at the time of donation, and subsequent health developments over the life course (traced through electronic health records) will be stored and used for research purposes. In addition, a detailed public consultation process will begin that will allow respondents' views to shape and develop the study. This is an important aspect to the research, and forms the continuation of a long-term parallel engagement process. Discussion As well as gene identification, the family-based study design will allow measurement of the heritability and familial aggregation of relevant quantitative traits, and the study of how genetic effects may vary by parent-of-origin. Long-term potential outcomes of this research include the targeting of disease prevention and treatment, and the development of screening tools based on the new genetic information. This study approach is complementary to other population-based genetic epidemiology studies, such as UK Biobank, which are established primarily to characterise genes and genetic risk in the population.

An ectotherm's performance and physiological function are strongly tied to environmental temperature, and many ectotherms thermoregulate behaviourally to reach optimum body temperatures. Tropical ectotherms are already living in environments matching their thermal tolerance range and may be expected to conform to environmental temperatures. We tracked the body temperatures ( T b ) of 163 estuarine crocodiles across 13 years and compared T b of 39 crocodiles to water temperature gathered using fish-borne sensors ( T w ) across 3 years (2015-2018). While T b largely conformed closely to T w , we found inter- and intra-individual differences in relative body temperature ( T b - T w ) that depended on sex and body size as well as the time of day and year. Deviations from T w , especially during the warm parts of the year, suggest that thermoregulatory behaviour was taking place: we found patterns of warming and cooling events that seemed to mediate this variation in T b . Thermoregulatory behaviour was observed most frequently in larger individuals, with warming events common during winter and cooling events common during summer. By observing free-ranging animals across multiple years, we found that estuarine crocodiles show yearly patterns of active cooling and warming behaviours that modify their body temperature, highlighting their resilience in the face of recent climate warming. Our work also provides the first evidence for thermal type in large-bodied reptiles.

How animals move and associate with conspecifics is rarely random, with a population's spatial structure forming the foundation on which the social behaviours of individuals form. Studies examining the spatial-social interface typically measure averaged behavioural differences between individuals; however, this neglects the inherent variation present within individuals and how it may impact the spatial-social interface. Here, we investigated differences in among-individual (co)variance in sociability, activity and site fidelity in a population of wild estuarine crocodiles, Crocodylus porosus, across a 10-year period. By monitoring 118 crocodiles using coded acoustic transmitters and an array of fixed underwater receivers, we discovered that not only did individual crocodiles repeatably differ (among-individual variation) in each behaviour measured but also in how consistently they expressed these behaviours through time (within-individual variation). As expected, crocodile activity and sociability formed a behavioural syndrome, with more active individuals being less sociable. Interestingly, we also found that individuals that were either more sociable or displayed greater site fidelity were also more specialized (lower within-individual variation) in these behaviours. Together, our results provide important empirical evidence for the interplay between spatial, temporal and social individual-level behavioural variation and how these contribute to forming behavioural niches. This article is part of the theme issue 'The spatial-social interface: a theoretical and empirical integration'.

Objective: Preoperative exercise training, or prehabilitation, aims to optimize cardiorespiratory fitness before surgery to reduce the risk of adverse perioperative events and delayed recovery. However, traditional exercise such as walking and cycling can be difficult for people with degenerative joint diseases of the lower limbs, such as osteoarthritis. The purpose of this study was to compare the effect of three low-impact interventions on cardiorespiratory fitness, physical function, and subjective health before total hip or knee arthroplasty., Methods: This was a randomized controlled trial involving 93 participants with severe knee or hip osteoarthritis awaiting joint replacement surgery. Participants underwent cardiopulmonary exercise testing (to measure peak oxygen consumption [ V ̇ $$ \dot{V} $$ O 2 ]), then were randomized to heat therapy (Heat; 20-30 min immersed in 40°C water followed by ~15 min light-resistance exercise), high-intensity interval training (HIIT; 6-8 × 60 s intervals on a cross-trainer or arm ergometer at ~90%-100% peak V ̇ $$ \dot{V} $$ O 2 ), or home-based exercise (Home; ~15 min light-resistance exercise); for up to 36 sessions (3 sessions per week for 12 weeks)., Results: Peak V ̇ $$ \dot{V} $$ O 2 increased by 16% across HIIT and to a greater extent than Heat (+2.5 mL × min -1 × kg -1 [95% CI: 0.5-4.4], P = 0.009) and Home (+3.2 mL × min -1 × kg -1 [1.2-5.2], P = 0.001). The anaerobic threshold increased across HIIT (+1.5 mL × min -1 × kg -1 [0.7-2.3], P < 0.001) and Heat (+1.2 mL × min -1 × kg -1 [0.4-1.9], P = 0.004), but not Home (-0.5 mL × min -1 × kg -1 [-1.3 to 0.3], P = 0.248). Subjective severity of osteoarthritis was unchanged with any intervention (P ≥ 0.250)., Conclusion: Heat therapy and HIIT improved indices of cardiorespiratory fitness preoperatively in patients who have difficulty performing lower-limb exercise., (© 2023 The Authors. Arthritis Care & Research published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

BACKGROUND: Androgen deprivation therapy (ADT) with radiotherapy can benefit patients with localized prostate cancer. However, ADT can negatively impact quality of life, and there remain no validated predictive models to guide its use. METHODS: We used digital pathology images from pretreatment prostate tissue and clinical data from 5727 patients enrolled in five phase 3 randomized trials, in which treatment was radiotherapy with or without ADT, as our data source to develop and validate an artificial intelligence (AI)–derived predictive patient-specific model that would determine which patients would develop the primary end point of distant metastasis. The model used baseline data to provide a binary output that a given patient will likely benefit from ADT or not. After the model was locked, validation was performed using data from NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 (n=1594), a trial that randomly assigned men to radiotherapy plus or minus 4 months of ADT. Fine–Gray regression and restricted mean survival times were used to assess the interaction between treatment and the predictive model and within predictive model–positive, i.e., benefited from ADT, and –negative subgroup treatment effects. RESULTS: Overall, in the NRG/RTOG 9408 validation cohort (14.9 years of median follow-up), ADT significantly improved time to distant metastasis. Of these enrolled patients, 543 (34%) were model positive, and ADT significantly reduced the risk of distant metastasis compared with radiotherapy alone. Of 1051 patients who were model negative, ADT did not provide benefit. CONCLUSIONS: Our AI-based predictive model was able to identify patients with a predominantly intermediate risk for prostate cancer likely to benefit from short-term ADT. (Supported by a grant [U10CA180822] from NRG Oncology Statistical and Data Management Center, a grant [UG1CA189867] from NCI Community Oncology Research Program, a grant [U10CA180868] from NRG Oncology Operations, and a grant [U24CA196067] from NRG Specimen Bank from the National Cancer Institute and by Artera, Inc. ClinicalTrials.gov numbers NCT00767286, NCT00002597, NCT00769548, NCT00005044, and NCT00033631.)

Background: The COVID-19 pandemic has been a catalyst for telehealth services for people who use opioids; however, the data show dramatic increases in opioid overdose deaths and ongoing lack of treatment options in North Carolina, particularly among rural residents., Methods: We conducted a listening session and qualitative interviews with 10 health care professionals, administrators, and community partners providing services for individuals who use opioids in Granville and Vance counties. Data were analyzed with an applied thematic approach., Results: Participants described several benefits of rapid expansion of telehealth services during the pandemic. Continued improvements in access to high-speed internet will be critical to maintain progress in rural areas. Participants advocated for integrated, co-located ser-vices and improved referral processes to minimize cost and burden of attending multiple appointments across sites. Integrated services could include medication for opioid use disorder (MOUD), mental/behavioral health support, primary medical care, and harm reduction services. Participants supported novel community-based strategies, such as mobile clinics, and described a need for after-hours and crisis services for opioid recovery in the region., Limitations: The study was exploratory in nature and elicited the perspectives of providers serving two rural counties in North Carolina, which may not be generalizable to broader populations. We did not include the perspectives of people who use opioids in this study but will do so in upcoming research., Conclusions: Participants were strong proponents of the benefits of telehealth and identified strategies for continuing recent progress in rural access to opioid treatment through novel integrated and community-based approaches., Competing Interests: Funding: This work was supported by funding from the Center for Nursing Research at the Duke University School of Nursing. We acknowledge additional support from the Duke School of Medicine Opioid Collaboratory and the Duke Center for AIDS Research, an NIH-funded program (5P30 AI064518). Disclosure of interests: The authors declare no conflicts of interest in relation to this work., (Copyright ©2023 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.)

Endurance exercise induces cardiovascular adaptations; the athletic phenotypes of the heart and arteries are well characterized, but few studies have investigated the effects of chronic exercise on the venous system. The aim of this study was to describe the anatomy and function of lower-limb deep and superficial veins in athletes compared with controls. Endurance-trained athletes and untrained controls (13 males, 7 females per group) were examined using ultrasound to measure vein diameter and flow, and air plethysmography to assess calf venous volume dynamics and muscle pump function at rest, during a single step, ambulation (10 steps) and after acute treadmill exercise (30 min ∼80% age-predicted heart rate maximum). Diameters of three of the seven deep veins assessed were larger in athletes ( P ≤ 0.0167) and more medial calf perforators were detectable (5 vs. 3, P = 0.0039). Calf venous volume was 22% larger in athletes ( P = 0.0057), and calf muscle pump ejection volume and ambulatory venous volume after 10 steps were both greater in athletes (20 and 46% respectively, P ≤ 0.0482). Following acute exercise, flow recovery profiles in deep and superficial veins draining the leg were not different between groups, despite athletes performing approximately four times more work. After exercise, venous volume and ejection volume were reduced by ∼20% in athletes with no change in controls (interaction, P ≤ 0.0372) and although ambulatory venous volume reduced, this remained greater in athletes. These findings highlight venous adaptations that compensate for the demands of regular endurance exercise, all of which are suited to enhance flow through the lower-limb venous system. NEW & NOTEWORTHY Although much literature exists describing adaptations to the heart and arteries in response to endurance exercise training, less is known about the effects on the venous system. Characteristics of "the athlete's vein" described here include deep and perforator vein remodeling, improved drainage, and greater calf venous volume at rest and on calf muscle pump activation. Following exercise, athletes demonstrated prompt flow recovery and appropriate volume reductions, and veins beneficially adapt to better tolerate the demands of regular physical activity.

Exercise is painful and difficult to perform for patients with severe lower-limb osteoarthritis; consequently, reduced physical activity contributes to increased cardiometabolic disease risk. The aim of this study was to characterize the acute and adaptive cardiovascular and metabolic effects of two low or no impact therapies in patients with severe lower-limb osteoarthritis: passive heat therapy (Heat) and high-intensity interval training (HIIT) utilizing primarily the unaffected limbs, compared to a control intervention of home-based exercise (Home). Participants completed up to 12 weeks of either Heat (20-30 min immersed in 40°C water followed by ~15-min light resistance exercise), HIIT (6-8 × 60-s intervals on a cross-trainer or arm ergometer at ~90-100% peak V ̇ $$ \dot{V} $$ O 2 ) or Home (~15-min light resistance exercise); all 3 sessions/week. Reductions in systolic (12 & 10 mm Hg), diastolic (7 & 4 mm Hg), and mean arterial (8 & 6 mm Hg) blood pressure (BP) were observed following one bout of Heat or HIIT exposure, lasting for the duration of the 20-min monitoring period. Across the interventions (i.e., 12 weeks), resting systolic BP and diastolic BP decreased with Heat (-9 & -4 mm Hg; p < 0.001) and HIIT (-7 & -3 mm Hg; p ≤ 0.011), but not Home (0 & 0 mm Hg; p ≥ 0.785). The systolic and diastolic BP responses to an acute exposure of Heat or HIIT in the first intervention session were moderately correlated with adaptive responses across the intervention (r ≥ 0.54, p ≤ 0.005). Neither intervention improved indices of glycemic control (p = 0.310). In summary, both Heat and HIIT induced potent immediate and adaptive hypotensive effects, and the acute response was moderately predictive of the long-term response., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Importance: Preoperative high-intensity interval training (HIIT) is associated with improved cardiorespiratory fitness (CRF) and may improve surgical outcomes., Objective: To summarize data from studies comparing the association of preoperative HIIT vs standard hospital care with preoperative CRF and postoperative outcomes., Data Sources: Data sources included Medline, Embase, Cochrane Central Register of Controlled Trials Library, and Scopus databases with no language constraints, including abstracts and articles published before May 2023., Study Selection: The databases were searched for randomized clinical trials and prospective cohort studies with HIIT protocols in adult patients undergoing major surgery. Thirty-four of 589 screened studies met initial selection criteria., Data Extraction and Synthesis: A meta-analysis was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Data were extracted by multiple independent observers and pooled in a random-effects model., Main Outcomes and Measures: The primary outcome was change in CRF, as measured by either peak oxygen consumption (V̇o2 peak) or 6-Minute Walk Test (6MWT) distance. Secondary outcomes included postoperative complications; hospital length of stay (LOS); and changes in quality of life, anaerobic threshold, and peak power output., Results: Twelve eligible studies including 832 patients were identified. Pooled results indicated several positive associations for HIIT when compared with standard care either on CRF (V̇o2 peak, 6MWT, anaerobic threshold, or peak power output) or postoperative outcomes (complications, LOS, quality of life), although there was significant heterogeneity in study results. In 8 studies including 627 patients, there was moderate-quality evidence of significant improvement in V̇o2 peak (cumulative mean difference, 2.59 mL/kg/min; 95% CI, 1.52-3.65 mL/kg/min; P < .001). In 8 studies including 770 patients, there was moderate-quality evidence of a significant reduction in complications (odds ratio, 0.44; 95% CI, 0.32-0.60; P < .001). There was no evidence that HIIT differed from standard care in hospital LOS (cumulative mean difference, -3.06 days; 95% CI, -6.41 to 0.29 days; P = .07). The analysis showed a high degree of heterogeneity in study outcomes and an overall low risk of bias., Conclusions and Relevance: The results of this meta-analysis suggest that preoperative HIIT may be beneficial for surgical populations through the improvement of exercise capacity and reduced postoperative complications. These findings support including HIIT in prehabilitation programs before major surgery. The high degree of heterogeneity in both exercise protocols and study results supports the need for further prospective, well-designed studies.

AbstractUnifying models have shown that the amount of space used by animals (e.g., activity space, home range) scales allometrically with body mass for terrestrial taxa; however, such relationships are far less clear for marine species. We compiled movement data from 1,596 individuals across 79 taxa collected using a continental passive acoustic telemetry network of acoustic receivers to assess allometric scaling of activity space. We found that ectothermic marine taxa do exhibit allometric scaling for activity space, with an overall scaling exponent of 0.64. However, body mass alone explained only 35% of the variation, with the remaining variation best explained by trophic position for teleosts and latitude for sharks, rays, and marine reptiles. Taxon-specific allometric relationships highlighted weaker scaling exponents among teleost fish species (0.07) than sharks (0.96), rays (0.55), and marine reptiles (0.57). The allometric scaling relationship and scaling exponents for the marine taxonomic groups examined were lower than those reported from studies that had collated both marine and terrestrial species data derived using various tracking methods. We propose that these disparities arise because previous work integrated summarized data across many studies that used differing methods for collecting and quantifying activity space, introducing considerable uncertainty into slope estimates. Our findings highlight the benefit of using large-scale, coordinated animal biotelemetry networks to address cross-taxa evolutionary and ecological questions.

The advancement and availability of innovative animal biotelemetry and genomic technologies are improving our understanding of how the movements of individuals influence gene flow within and between populations and ultimately drive evolutionary and ecological processes. There is a growing body of work that is integrating what were once disparate fields of biology, and here, we reviewed the published literature up until January 2023 (139 papers) to better understand the drivers of this research and how it is improving our knowledge of animal biology. The review showed that the predominant drivers for this research were as follows: (1) understanding how individual-based movements affect animal populations, (2) analyzing the relationship between genetic relatedness and social structuring, and (3) studying how the landscape affects the flow of genes, and how this is impacted by environmental change. However, there was a divergence between taxa as to the most prevalent research aim and the methodologies applied. We also found that after 2010 there was an increase in studies that integrated the two data types using innovative statistical techniques instead of analyzing the data independently using traditional statistics from the respective fields. This new approach greatly improved our understanding of the link between the individual, the population, and the environment and is being used to better conserve and manage species. We discuss the challenges and limitations, as well as the potential for growth and diversification of this research approach. The paper provides a guide for researchers who wish to consider applying these disparate disciplines and advance the field., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Epidemiological evidence has highlighted a strong relationship between cardiorespiratory fitness and surgical outcomes; specifically, fitter patients possess heightened resilience to withstand the surgical stress response. This narrative review draws on exercise and surgical physiology research to discuss and hypothesise the potential mechanisms by which higher fitness affords perioperative benefit. A higher fitness, as indicated by higher peak rate of oxygen consumption and ability to sustain metabolic homeostasis (i.e. higher anaerobic threshold) is beneficial postoperatively when metabolic demands are increased. However, the associated adaptations with higher fitness, and the related participation in regular exercise or physical activity, might also underpin the observed perioperative benefit through a process of hormesis, a protective adaptive response to the moderate and intermittent stress of exercise. Potential mediators discussed include greater antioxidant capacity, metabolic flexibility, glycaemic control, lean body mass, and improved mood., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Physical activity is the most common source of heat strain for humans. The thermal strain of physical activity causes overbreathing (hyperventilation) and this has adverse physiological repercussions. The mechanisms underlying heat-induced hyperventilation during exercise are unknown, but recent evidence supports a primary role of carotid body hyperexcitability (increased tonic activity and sensitivity) underpinning hyperventilation in passively heated humans. In a repeated-measures crossover design, 12 healthy participants (6 female) completed two low-intensity cycling exercise conditions (25% maximal aerobic power) in randomized order, one with core temperature (T C ) kept relatively stable near thermoneutrality, and the other with progressive heat strain to +2°C T C . To provide a complete examination of carotid body function under graded heat strain, carotid body tonic activity was assessed indirectly by transient hyperoxia, and its sensitivity estimated by responses to both isocapnic and poikilocapnic hypoxia. Carotid body tonic activity was increased by 220 ± 110% during cycling alone, and by 400 ± 290% with supplemental thermal strain to +1°C T C , and 600 ± 290% at +2°C T C (interaction, P = 0.0031). During exercise with heat stress at both +1°C and +2°C T C , carotid body suppression by hyperoxia decreased ventilation below the rates observed during exercise without heat stress ( P < 0.0147). Carotid body sensitivity was increased by up to 230 ± 190% with exercise alone, and by 290 ± 250% with supplemental heating to +1°C T C and 510 ± 470% at +2°C T C (interaction, P = 0.0012). These data indicate that the carotid body is further activated and sensitized by heat strain during exercise and this largely explains the added drive to breathe. NEW & NOTEWORTHY Physical activity is the most common way humans increase their core temperature, and excess breathing in the heat can limit heat tolerance and performance, and may increase the risk of heat-related injury. Dose-dependent increases in carotid body tonic activity and sensitivity with core heating provide compelling evidence that carotid body hyperexcitability is the primary cause of heat-induced hyperventilation during exercise.

North Carolina has some of the country's best health workforce supply data through cooperation with licensing boards, but the data don't encompass all health care workers. Workforce demand data are more difficult to track, and it's even harder to know how many health care workers are truly needed to improve the state's health., (© 2022 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.)

Humans hyperventilate under heat and cold strain. This hyperventilatory response has detrimental consequences including acid-base dysregulation, dyspnoea, decreased cerebral blood flow and accelerated brain heating. The ventilatory response to hypoxia is exaggerated under whole-body heating and cooling, indicating that altered carotid body function might contribute to thermally mediated hyperventilation. To address whether the carotid body might contribute to heat- and cold-induced hyperventilation, we indirectly measured carotid body tonic activity via hyperoxia, and carotid body sensitivity via hypoxia, under graded heat and cold strain in 13 healthy participants in a repeated-measures design. We hypothesised that carotid body tonic activity and sensitivity would be elevated in a dose-dependent manner under graded heat and cold strain, thereby supporting its role in driving thermally mediated hyperventilation. Carotid body tonic activity was increased in a dose-dependent manner with heating, reaching 175% above baseline (P < 0.0005), and carotid body suppression with hyperoxia removed all of the heat-induced increase in ventilation (P = 0.9297). Core cooling increased carotid body activity by up to 250% (P < 0.0001), but maximal values were reached with mild cooling and thereafter plateaued. Carotid body sensitivity to hypoxia was profoundly increased by up to 180% with heat stress (P = 0.0097), whereas cooling had no detectable effect on hypoxic sensitivity. In summary, cold stress increased carotid body tonic activity and this effect was saturated with mild cooling, whereas heating had clear dose-dependent effects on carotid body tonic activity and sensitivity. These dose-dependent effects with heat strain indicate that the carotid body probably plays a primary role in driving heat-induced hyperventilation. KEY POINTS: Humans over-breathe (hyperventilate) when under heat and cold stress, and though this has detrimental physiological repercussions, the mechanisms underlying this response are unknown. The carotid body, a small organ that is responsible for driving hyperventilation in hypoxia, was assessed under incremental heat and cold strain. The carotid body drive to breathe, as indirectly assessed by transient hyperoxia, increased in a dose-dependent manner with heating, reaching 175% above baseline; cold stress similarly increased the carotid body drive to breathe, but did not show dose-dependency. Carotid body sensitivity, as indirectly assessed by hypoxic ventilatory responses, was profoundly increased by 70-180% with mild and severe heat strain, whereas cooling had no detectable effect. Carotid body hyperactivity and hypersensitivity are two interrelated mechanisms that probably underlie the increased drive to breathe with heat strain, whereas carotid body hyperactivity during mild cooling may play a subsidiary role in cold-induced hyperventilation., (© 2022 The Authors. The Journal of Physiology © 2022 The Physiological Society.)

Teaching traditionally asserts that the arterial pressure pulse is dampened across the capillary bed to the extent that pulsatility is nonexistent in the venous circulation of the lower limbs. Herein, we present evidence of transmission of arterial pulsations across the capillary network into perforator veins in the lower limbs of healthy, heat-stressed humans. Perforator veins are connections from the superficial veins that drain into the deep veins. When assessed using ultrasound at rest, they infrequently demonstrate flow, and a pulsatile flow waveform is not described. We investigated perforator vein pulsatility in 10 young, healthy volunteers who underwent passive heating by +2°C core body temperature via a hot-water-perfused suit, and 5 who also underwent active heating by +2°C via low-intensity cycling while wearing the hot-water-perfused suit. At +0.5°C increments in temperature, blood velocity in an ankle perforator vein was measured using duplex ultrasound. In all perforators with heating, sustained flow was demonstrated, with a pulsatile waveform that was synchronous with the cardiac cycle. The maximum velocity was 30 ± 13 cm/s with passive heating and approximately half with active heating ( P = 0.04). The small veins of the skin at the ankle also demonstrated increased perfusion with pulsatility, seen with low-velocity microvascular imaging technology. We consider explanations for this pulsatility and conclude that it is propagated from the arterial inflow through the skin microcirculation as a result of increased dilatation and flow volume and that this is a normal response to increased skin blood flow.

New Findings: What is the central question of this study? What are the profiles of acute physiological and psychophysical strain during and in recovery from different modes of heating, and to what extent do these diminish after repeated exposure? What is the main finding and its importance? Mode of heating affects the strain profiles during heat stress and recovery. Exercise in the heat incurred the greatest cardiovascular strain during heating and recovery. Humid heat was poorly tolerated despite heat strain being no greater than in other heating modes, and tolerance did not improve with multiple exposures., Abstract: Heat stress is common and arises endogenously and exogenously. It can be acutely hazardous while also increasingly advocated to drive health and performance-related adaptations. Yet, the nature of strain (deviation in regulated variables) imposed by different heating modes is not well established, despite the potential for important differences. We, therefore, compared three modes of heat stress for thermal, cardiovascular and perceptual strain profiles during exposure and recovery when experienced as a novel stimulus and an accustomed stimulus. In a crossover design, 13 physically active participants (five females) underwent 5 days of 60-min exposures to hot water immersion (40°C), sauna (55°C, 54% relative humidity) and exercise in the heat (40°C, 52% relative humidity), and a thermoneutral water immersion control (36.5°C), each separated by ≥4 weeks. Physiological (thermal, cardiovascular, haemodynamic) and psychophysical strain responses were assessed on days 1 and 5. Sauna evoked the warmest skin (40°C; P < 0.001) but exercise in the heat caused the largest increase in core temperature, sweat rate, heart rate (post hoc comparisons all P < 0.001) and systolic blood pressure (P ≤ 0.002), and possibly decrease in diastolic blood pressures (P ≤ 0.130), regardless of day. Thermal sensation and feeling state were more favourable on day 5 than on day 1 (P ≤ 0.021), with all modes of heat being equivalently uncomfortable (P ≥ 0.215). Plasma volume expanded the largest extent during immersions (P < 0.001). The current data highlight that exercising in the heat generates a more complex strain profile, while passive heat stress in humid heat has lower tolerance and more cardiovascular strain than hot water immersion., (© 2022 The Authors. Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

New Findings: What is the central question to the study? Are primary indices of heat adaptation (e.g., expansion of plasma volume and reduction in resting core temperature) differentially affected by the three major modes of short-term heat acclimation, that is, exercise in the heat, hot water immersion and sauna? What it the main finding and its importance? The three modes elicited typical adaptations expected with short-term heat acclimation, but these were not significantly different between modes. This comparison has not previously been made and highlights that individuals can expect similar adaptation to heat regardless of the mode used., Abstract: Heat acclimation (HA) can improve heat tolerance and cardiovascular health. The mode of HA potentially impacts the magnitude and time course of adaptations, but almost no comparative data exist. We therefore investigated adaptive responses to three common modes of HA, particularly with respect to plasma volume. Within a crossover repeated-measures design, 13 physically active participants (five female) undertook four, 5-day HA regimes (60 min/day) in randomised order, separated by ≥4 weeks. Rectal temperature (T re ) was clamped at neutrality via 36.6°C (thermoneutral) water immersion (TWI; i.e., control condition), or raised by 1.5°C via heat stress in 40°C water, sauna (55°C, 52% relative humidity), or exercise in humid heat (40°C, 52% relative humidity; ExH). Adaptation magnitude was assessed as the pooled response across days 4-6, while kinetics was assessed via the 6-day time series. Plasma volume expansion was similar in all heated conditions but only higher than TWI in exercise in the heat (ExH) (by 4%, P = 0.036). Approximately two-thirds of the expansion was attained within the initial 24 h and was moderately related to that present on day 6, regardless of HA mode (r = 0.560-0.887). Expansion was mediated by conservation of both sodium and albumin content, with little evidence for these having differential roles between modes (P = 0.706 and 0.320, respectively). Resting T re decreased by 0.1-0.3°C in all heated conditions, and systolic blood pressure decreased by 4 mmHg, but not differentially between conditions (P ≥ 0.137). In conclusion, HA mode did not substantially affect the magnitude or rate of adaptation in key resting markers of short-term HA., (© 2021 The Authors. Experimental Physiology © 2021 The Physiological Society.)

Supporting the recovery of large carnivores is a popular yet challenging endeavour. Estuarine crocodiles in Australia are a large carnivore conservation success story, with the population having extensively recovered from past heavy exploitation. Here, we explored if dietary changes had accompanied this large population recovery by comparing the isotopes δ 13 C and δ 15 N in bones of crocodiles sampled 40 to 55 years ago (small population) with bones from contemporary individuals (large population). We found that δ 13 C and δ 15 N values were significantly lower in contemporary crocodiles than in the historical cohort, inferring a shift in prey preference away from marine and into terrestrial food webs. We propose that an increase in intraspecific competition within the recovering crocodile population, alongside an increased abundance of feral ungulates occupying the floodplains, may have resulted in the crocodile population shifting to feed predominantly upon terrestrial food sources. The number of feral pigs consumed to sustain and grow crocodile biomass may help suppress pig population growth and increase the flow of terrestrially derived nutrients into aquatic ecosystems. The study highlights the significance of prey availability in contributing to large carnivore population recovery.

There is a growing need for water managers to refine and optimise environmental flow strategies (e-flows) to balance water requirements for humans and nature. With increasing demands for freshwater and consequent declines in biodiversity, managers are faced with the problem of how to adaptively manage e-flows for multiple stakeholders and species whose flow requirements may overlap or vary. This study assessed the effectiveness of a regulated e-flow release strategy from a dam, aimed at providing movement opportunities and facilitating reproductive processes for multiple threatened species. Movements of 24 Mary River cod (Maccullochella mariensis), 20 Australian lungfish (Neoceratodus forsteri) and 13 Mary River turtle (Elusor macrurus) were quantified using acoustic telemetry over a three-year period. The influence of regulated e-flow releases, season, river depth, water temperature and rainfall on animal movements was assessed using Generalised linear mixed models (GLMMs). Models showed that hydraulic connectivity provided by both natural flows and regulated e-flow releases facilitated movement of all three species between pool habitats, throughout the year. Mary River turtles made extensive use of regulated e-flow releases when moving between habitats, whereas Mary River cod and Australian lungfish required additional natural rises in river height above the regulated e-flows to trigger movements. Significant movement activity was also recorded for cod and turtles during the dry season (winter and spring), broadly coinciding with breeding periods for these species. The effectiveness of, and potential improvements to, current e-flow strategies to sustain key life-history requirements of these species is discussed. Findings suggest a revised e-flow strategy with relatively minor increases in the magnitude of e-flow releases throughout winter and spring, would be effective in providing movement opportunities and supporting reproductive success for all three species. This study demonstrates that by quantifying movement behaviour in an e-flow context, ecological risk assessment frameworks can then be used to assess and provide for critical life-history requirements of multiple species within the context of a highly regulated system under increasing water use demands., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Key Points: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognition, orthostatic tolerance, work capacity and eventually, brain death. The brain's limitation in the heat is often ascribed to inadequate cerebral blood flow (CBF), but elevated intracranial pressure is commonly observed in mammalian models of heat stroke and can on its own cause functional impairment. The CBF response to incremental heat strain was dependent on the mode of heating, decreasing by 30% when exposed passively to hot, humid air (sauna), while remaining unchanged or increasing with passive hot-water immersion (spa) and exercising in a hot environment. Non-invasive intracranial pressure estimates (nICP) were increased universally by 18% at volitional thermal tolerance across all modes of heat stress, and therefore may play a contributing role in eliciting thermal tolerance. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under mild to severe heating due to lower blood flow but similarly increased nICP., Abstract: The human brain is particularly vulnerable to heat stress; this manifests as impaired cognitive function, orthostatic tolerance, work capacity, and eventually, brain death. This vulnerability is often ascribed to inadequate cerebral blood flow (CBF); however, elevated intracranial pressure (ICP) is also observed in mammalian models of heat stroke. We investigated the changes in CBF with incremental heat strain under three fundamentally different modes of heating, and assessed whether heating per se increased ICP. Fourteen fit participants (seven female) were heated to thermal tolerance or 40°C core temperature (T c ; oesophageal) via passive hot-water immersion (spa), passive hot, humid air exposure (sauna), cycling exercise, and cycling exercise with CO 2 inhalation to prevent heat-induced hypocapnia. CBF was measured with duplex ultrasound at each 0.5°C increment in T c and ICP was estimated non-invasively (nICP) from optic nerve sheath diameter at thermal tolerance. At thermal tolerance, CBF was decreased by 30% in the sauna (P < 0.001), but was unchanged in the spa or with exercise (P ≥ 0.140). CBF increased by 17% when end-tidal P C O 2 was clamped at eupnoeic pressure (P < 0.001). On the contrary, nICP increased universally by 18% with all modes of heating (P < 0.001). The maximum T c was achieved with passive heating, and preventing hypocapnia during exercise did not improve exercise or thermal tolerance (P ≥ 0.146). Therefore, the regulation of CBF is dramatically different depending on the mode and dose of heating, whereas nICP responses are not. The sauna, more so than the spa or exercise, poses a greater challenge to the brain under equivalent heat strain., (© 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society.)

The objective of this study was to compare acute effects of prolonged sitting, prolonged standing and sitting interrupted with regular activity breaks on vascular function and postprandial glucose metabolism. In a randomized cross-over trial, 18 adults completed: 1. Prolonged Sitting; 2. Prolonged Standing and 3. Sitting with 2-min walking (5 km/h, 10% incline) every 30 min (Regular Activity Breaks). Flow mediated dilation (FMD) was measured in the popliteal artery at baseline and 6 h. Popliteal artery hemodynamics, and postprandial plasma glucose and insulin were measured over 6 h. Neither raw nor allometrically-scaled FMD showed an intervention effect (p = 0.285 and 0.159 respectively). Compared to Prolonged Sitting, Regular Activity Breaks increased blood flow (overall effect of intervention p<0.001; difference = 80%; 95% CI 34 to 125%; p = 0.001) and net shear rate (overall effect of intervention p<0.001; difference = 72%; 95% CI 30 to 114%; p = 0.001) at 60 min. These differences were then maintained for the entire 6 h. Prolonged Standing increased blood flow at 60 min only (overall effect of intervention p<0.001; difference = 62%; 95% CI 28 to 97%; p = 0.001). Regular Activity Breaks decreased insulin incremental area under the curve (iAUC) when compared to both Prolonged Sitting (overall effect of intervention P = 0.001; difference = 28%; 95% CI 14 to 38%; p<0.01) and Prolonged Standing (difference = 19%; 95% CI 4 to 32%, p = 0.015). There was no intervention effect on glucose iAUC or total AUC (p = 0.254 and 0.450, respectively). In normal-weight participants, Regular Activity Breaks induce increases in blood flow, shear stress and improvements in postprandial metabolism that are associated with beneficial adaptations. Physical activity and sedentary behaviour messages should perhaps focus more on the importance of frequent movement rather than simply replacing sitting with standing., Competing Interests: The authors have declared that no competing interests exist.

Cardiopulmonary exercise testing is performed increasingly for cardiorespiratory fitness assessment and pre-operative risk stratification. Lower limb osteoarthritis is a common comorbidity in surgical patients, meaning traditional cycle ergometry-based cardiopulmonary exercise testing is difficult. The purpose of this study was to compare cardiopulmonary exercise testing variables and subjective responses in four different exercise modalities. In this crossover study, 15 patients with osteoarthritis scheduled for total hip or knee arthroplasty (mean (SD) age 68 (7) years; body mass index 31.4 (4.1) kg.m -2 ) completed cardiopulmonary exercise testing on a treadmill, elliptical cross-trainer, cycle and arm ergometer. Mean (SD) peak oxygen consumption was 20-30% greater on the lower limb modalities (treadmill 21.5 (4.6) (p < 0.001); elliptical cross-trainer (21.2 (4.1) (p < 0.001); and cycle ergometer (19.4 (4.2) ml.min -1 .kg -1 (p = 0.001), respectively) than on the arm ergometer (15.7 (3.7) ml.min -1 .kg -1 ). Anaerobic threshold was 25-50% greater on the lower limb modalities (treadmill 13.5 (3.1) (p < 0.001); elliptical cross-trainer 14.6 (3.0) (p < 0.001); and cycle ergometer 10.7 (2.9) (p = 0.003)) compared with the arm ergometer (8.4 (1.7) ml.min -1 .kg -1 ). The median (95%CI) difference between pre-exercise and peak-exercise pain scores was greater for tests on the treadmill (2.0 (0.0-5.0) (p = 0.001); elliptical cross-trainer (3.0 (2.0-4.0) (p = 0.001); and cycle ergometer (3.0 (1.0-5.0) (p = 0.001)), compared with the arm ergometer (0.0 (0.0-1.0) (p = 0.406)). Despite greater peak exercise pain, cardiopulmonary exercise testing modalities utilising the lower limbs affected by osteoarthritis elicited higher peak oxygen consumption and anaerobic threshold values compared with arm ergometry., (© 2020 Association of Anaesthetists.)

Anthropogenic derived environmental change is challenging earth's biodiversity. To implement effective management, it is imperative to understand how organisms are responding over broad spatiotemporal scales. Collection of these data is generally beyond the budget of individual researchers and the integration and sharing of ecological data and associated infrastructure is becoming more common. However, user groups differ in their expectations, standards of performance, and desired outputs from research investment, and accommodating the motivations and fears of potential users from the outset may lead to higher levels of participation. Here we report upon a study of the Australian ornithology community, which was instigated to better understand perceptions around participation in nationally coordinated research infrastructure for detecting and tracking the movement of birds. The community was surveyed through a questionnaire and individuals were asked to score their motivations and fears around participation. Principal Components Analysis was used to reduce the dimensionality of the data and identify groups of questions where respondents behaved similarly. Linear regressions and model selection were then applied to the principal components to determine how career stage, employment role, and years of biotelemetry experience affected the respondent's motivations and fears for participation. The analysis showed that across all sectors (academic, government, NGO) there was strong motivation to participate and belief that national shared biotelemetry infrastructure would facilitate bird management and conservation. However, results did show that a cross-sector cohort of the Australian ornithology community were keen and ready to progress collaborative infrastructure for tracking birds, and measures including data-sharing agreements could increase participation. It also informed that securing initial funding would be a significant challenge, and a better option to proceed may be for independent groups to coordinate through existing database infrastructure to form the foundation from which a national network could grow., Competing Interests: The authors have declared that no competing interests exist.

The optimal design of reserve networks and fisheries closures depends on species occurrence information and knowledge of how anthropogenic impacts interact with the species concerned. However, challenges in surveying mobile and cryptic species over adequate spatial and temporal scales can mask the importance of particular habitats, leading to uncertainty about which areas to protect to optimize conservation efforts. We investigated how telemetry-derived locations can help guide the scale and timing of fisheries closures with the aim of reducing threatened species bycatch. Forty juvenile speartooth sharks (Glyphis glyphis) were monitored over 22 months with implanted acoustic transmitters and an array of hydrophone receivers. Using the decision-support tool Marxan, we formulated a permanent fisheries closure that prioritized areas used more frequently by tagged sharks and considered areas perceived as having high value to fisheries. To explore how the size of the permanent closure compared with an alternative set of time-area closures (i.e., where different areas were closed to fishing at different times of year), we used a cluster analysis to group months that had similar arrangements of selected planning units (informed by shark movements during that month) into 2 time-area closures. Sharks were consistent in their timing and direction of migratory movements, but the number of tagged sharks made a big difference in the placement of the permanent closure; 30 individuals were needed to capture behavioral heterogeneity. The dry-season (May-January) and wet-season (February-April) time-area closures opened 20% and 25% more planning units to fishing, respectively, compared with the permanent closure with boundaries fixed in space and time. Our results show that telemetry has the potential to inform and improve spatial management of mobile species and that the temporal component of tracking data can be incorporated into prioritizations to reduce possible impacts of spatial closures on established fisheries., (© 2019 Society for Conservation Biology.)

Body size and age are crucial factors influencing reproductive capacity and success. As females grow, their reproductive investment and success often increase due to improved overall physiological condition and experience gained through successive reproductive events. While much of this work has been conducted on birds and mammals, surprisingly little is known on how body size affects nesting decisions in other long-lived vertebrates. We monitored the movements and nesting behaviour of 57 wild female estuarine crocodiles Crocodylus porosus over a 10-year period (and across consecutive nesting seasons) using externally mounted satellite tags, implanted acoustic transmitters and a network of submerged acoustic receivers. Applying Hidden Markov models to the telemetry-derived location data revealed that female nesting behaviours could be split into three distinct states: (i) ranging movements within home ranges and at nesting sites; (ii) migrations to and from nesting sites; (iii) and nesting/nest guarding. We found that during migration events, larger females migrated further and remained away from dry season territories for longer periods than smaller individuals. Furthermore, not only were migratory movements stimulated by increases in rainfall, larger females migrated to nest sites at lower rainfall thresholds than smaller females. We provide some of the first evidence of body size influencing nesting decisions in an ectothermic vertebrate, with shifts likely resulting from an increased willingness to invest in nest protection among larger and more experienced females.

A request for raw data from the corresponding authors of 771 animal biotelemetry-focused manuscripts, published between 1995 and 2015, highlighted a difference in data sharing practices across researcher career levels. Responses were positive in only 11% of requests made to corresponding authors (CAs) that were senior researchers, while 72% of responses were positive when CAs were early career researchers (ECRs), demonstrating that the majority of senior researchers perceived little benefit from the public data archiving of their published research, while they often remain the data custodian., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Acoustic telemetry is a principle tool for observing aquatic animals, but coverage over large spatial scales remains a challenge. To resolve this, Australia has implemented the Integrated Marine Observing System's Animal Tracking Facility which comprises a continental-scale hydrophone array and coordinated data repository. This national acoustic network connects localized projects, enabling simultaneous monitoring of multiple species over scales ranging from 100 s of meters to 1000 s of kilometers. There is a need to evaluate the utility of this national network in monitoring animal movement ecology, and to identify the spatial scales that the network effectively operates over. Cluster analyses assessed movements and residency of 2181 individuals from 92 species, and identified four functional movement classes apparent only through aggregating data across the entire national network. These functional movement classes described movement metrics of individuals rather than species, and highlighted the plasticity of movement patterns across and within populations and species. Network analyses assessed the utility and redundancy of each component of the national network, revealing multiple spatial scales of connectivity influenced by the geographic positioning of acoustic receivers. We demonstrate the significance of this nationally coordinated network of receivers to better reveal intra-specific differences in movement profiles and discuss implications for effective management.

Non-governmental organisations (NGOs) play a key role in biodiversity conservation. The majority of these organisations rely on public donations to fund their activities, and therefore fundraising success is a determinant of conservation outcomes. In spite of this integral relationship, the key principals for fundraising success in conservation are still guided by expert opinion and anecdotal evidence, with very few quantitative studies in the literature. Here we assessed the behaviour of monetary donors across twenty-five different species-focused conservation campaigns organised by an NGO conservation and environmental society. The Australian Geographic Society (AGS) carried out fundraising campaigns over a five and half year period using an identical methodology in thirty-four of its country-wide network of outlet shops. AGS owns and operates these shops that sell toys and games related to science and nature. We tested how the following factors influenced monetary donations from members of the public:1) campaign duration, 2) appeal and familiarity of species, 3) species geographic distribution relative to the fundraising location, 4) level of income and education of potential donors, 5) age and gender profile of potential donors. Contrary to past research, we found most of these factors did not significantly influence the amount of donations made to each campaign by members of the public. Larger animals did elicit a significantly higher amount donated per transaction than smaller animals, as did shops located in poorer neighbourhoods. Our study findings contrast with past research that has focused largely on hypothetical donations data collected via surveys, and demonstrates the complexity and case-specific nature of relationships between donor characteristics and spending patterns. The study highlights the value of assessing real-world fundraising campaigns, and illustrates how collaboration between academia and NGOs could be used to better tailor fundraising campaigns to maximise donations from individual citizens.

Polar fishes are at high risk from increasing seawater temperatures. Characterising the physiological responses to such changes may both clarify mechanisms that permit life under extreme conditions and identify limitations in the response to continued global warming. We hypothesised that Notothenia coriiceps would show physiological compensation after an acute exposure to 5°C, and following 6 weeks warm acclimation, compared with ambient temperature (0°C). However, initial tachycardia (22.4±2.8 versus 12.8±1.1 min(-1); P<0.01) was not reversed by acclimation (21.0±1.9 min(-1)). Hyperventilation (45.5±3.1 versus 21.4±2.4 breaths min(-1); P<0.001) showed a modest reduction following acclimation (38.0±2.9 min(-1); P<0.05), while resting oxygen consumption (0.52±0.08 mmol kg(-1) h(-1)) was acutely increased at 5°C (1.07±0.10 mmol kg(-1) h(-1); P<0.001) but unchanged with acclimation. Autonomic blockade showed initial responses were mainly of vagal origin, with little subsequent withdrawal or recovery in long-term heart rate variability after 6 weeks. Given the limited cardiorespiratory capacity to withstand sustained warming, effective physiological compensation probably requires a more prolonged acclimation period., (© 2016. Published by The Company of Biologists Ltd.)

The presence and movements of organisms both reflect and influence the distribution of ecological resources in space and time. The monitoring of animal movement by telemetry devices is being increasingly used to inform management of marine, freshwater and terrestrial ecosystems. Here, we brought together academics, and environmental managers to determine the extent of animal movement research in the Australasian region, and assess the opportunities and challenges in the sharing and reuse of these data. This working group was formed under the Australian Centre for Ecological Analysis and Synthesis (ACEAS), whose overall aim was to facilitate trans-organisational and transdisciplinary synthesis. We discovered that between 2000 and 2012 at least 501 peer-reviewed scientific papers were published that report animal location data collected by telemetry devices from within the Australasian region. Collectively, this involved the capture and electronic tagging of 12 656 animals. The majority of studies were undertaken to address specific management questions; rarely were these data used beyond their original intent. We estimate that approximately half (~500) of all animal telemetry projects undertaken remained unpublished, a similar proportion were not discoverable via online resources, and less than 8.8% of all animals tagged and tracked had their data stored in a discoverable and accessible manner. Animal telemetry data contain a wealth of information about how animals and species interact with each other and the landscapes they inhabit. These data are expensive and difficult to collect and can reduce survivorship of the tagged individuals, which implies an ethical obligation to make the data available to the scientific community. This is the first study to quantify the gap between telemetry devices placed on animals and findings/data published, and presents methods for improvement. Instigation of these strategies will enhance the cost-effectiveness of the research and maximise its impact on the management of natural resources., (Copyright © 2015 Elsevier B.V. All rights reserved.)