Behavioural adaptive variation in the striped mouse Rhabdomys

A thesis submitted to the Faculty of Science, University of the Witwatersrand, Johannesburg, in fulfilment of the requirements for the degree of Doctor of Philosophy, 2017Under current and previous global climate change, environments are changing and have changed at a rapid rate. Species with the potential to undergo adaptive radiation are likely to survive environmental change. The genus Rhabdomys is widespread in southern Africa, occurring along the east-west rainfall gradient in South Africa. Rhabdomys may have undergone adaptive radiations in the past, which may have resulted in the current suite of species in various habitats of different aridity. Some Rhabdomys species also occur in sympatry in some locations in South Africa. The aim of my study was to investigate adaptive variation in Rhabdomys by studying the behaviour of 5 populations, representing 3 Rhabdomys species, across South Africa. Using selected taxa, my approach was, firstly, to describe variation in two traits, personality and spatial cogntion, well known for showing environmentally-linked (i.e. adaptive) variation. Secondly, I manipulated the development of exploratory and anxiety behaviour to assess the limits of the adaptive variation (i.e. test the nature of the reaction norm of the characters measured). I first established the taxon-level personality of 4 taxa (2 sympatric) in 5 standard behavioural tests. Generally, the semi-desert living R. pumilio was the boldest together, surprisingly, with R. d. dilectus occurring in grasslands of central South Africa, contradicting previously published results. Comparatively, R. bechuanae from central South Africa and R. dilectus from far north-eastern South Africa, also occurring in grasslands were less bold, even though R. bechuanae is sympatric with R. dilectus in central South Africa. My data indicate adaptive variation at the extreme populations and possibly character displacement in the sympatric populations. In the next chapter, I investigated whether early rearing environment shapes exploratory behaviour and anxiety responses of R. pumilio and R. bechuanae. I predicted that using an interspecies cross-fostering protocol would reveal a gene x environment interaction on behaviour, so that fostered offspring would display an intermediate behaviour phenotype compared to their non-fostered siblings. I showed that a novel rearing environment mostly did not influence the adult behaviour of cross-fostered inidividuals. This indicates genetic constraints on exploratory behaviour and anxiety responses. Next, I tested whether physical rearing environment shapes exploratory behaviour and anxiety responses. I reared semidesert R. pumilio, sympatric R. bechuanae and R. dilectus and allopatric R. bechuanae under either no cover or high cover for 2 generations. The taxa were mostly similar and altering the phyical housing condition did not alter behaviour, but there were small differences between the taxa in exploratory behaviour. In the final experimental chapter, I established whether the environment predicts the spatial cognition in semi-desert R. pumilio, sympatric R. bechuanae and R. dilectus and an allopatric population of R. dilectus from far north-eastern South Africa. The populations showed very similar performance in a modified Barnes maze, indicating a possible phylogenetic constraint on spatial cognition. Overall, my study suggests that there is adaptive variation in personality but not spatial cognition. In contrast to previous studies in the genus, alterations to the social and physical environments failed to separate out genetic and environmental effects (i.e. reaction norm) that would potentially provide the mechanisms for adaptive variation within and between species. The similarity in spatial cognition between taxa and similar responses to environmental modification indicate phylogenetic constraints on traits that were predicted to vary geographically.XL201

The behaviour of two sub-species of the striped mouse Rhabdomys: the role of phylogeny and the environment

MSc., Faculty of Science, University of the Witwatersrand, 2011The role of phylogeny and environmental influences on behaviour were investigated in two sub-species of Rhabdomys dilectus: R. d. chakae and R. d. dilectus. I compared populations of the two sub-species that occur about 70 km apart in superficially similar grasslands, south of Johannesburg (Walkers Fruit Farms) and at Irene in Gauteng Province, South Africa. The vegetation characteristics of the localities were assessed by measuring aerial cover, cover density, amount of dead material, and the maximum and minimum plant height. I studied the maintenance (non-social) and social behaviour of the sub-species in captivity. Three maintenance behaviours were studied: diel activity in an open arena, activity in an enclosed maze and in a modified plus maze. Social behaviour was studied by investigating the stress response of juvenile males after removal from their family groups and being placed in a plus maze, and the tolerance of unfamiliar same-sex consub-specifics in staged dyadic encounters. My results indicate that there were differences in the vegetation at the localities, most notably in the level of cover, which was greater at Irene (R. d. dilectus) than at Walkers Fruit Farms (R. d. chakae). Both sub-species displayed similar activity profiles (diurnal and crepuscular) and similar levels of activity in an enclosed maze. However, R. d. dilectus showed high levels of anxiety in an open arena and in a plus maze. The sub-species showed similar social behaviours: males of both sub-species that were removed from their family groups at the onset of weaning showed a lower stress response compared to the social sister species R. pumilio. Social interactions of same-sex intra-sub-specifics were mostly similar between the sub-species but there were slight discrepancies in behaviour associated with mating. Surprisingly, there were higher levels of amicability in all dyads than predicted by the solitary lifestyle of the two sub-species in nature. Behavioural differences (anxiety response) may be due to divergence in allopatry because of differences in vegetation characteristics. The similarities in activity profile and social behaviours could be explained by phylogenetic inertia or by similar selection pressures in similar environments

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Background: In an era of shifting global agendas and expanded emphasis on non-communicable diseases and injuries along with communicable diseases, sound evidence on trends by cause at the national level is essential. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides a systematic scientific assessment of published, publicly available, and contributed data on incidence, prevalence, and mortality for a mutually exclusive and collectively exhaustive list of diseases and injuries. Methods: GBD estimates incidence, prevalence, mortality, years of life lost (YLLs), years lived with disability (YLDs), and disability-adjusted life-years (DALYs) due to 369 diseases and injuries, for two sexes, and for 204 countries and territories. Input data were extracted from censuses, household surveys, civil registration and vital statistics, disease registries, health service use, air pollution monitors, satellite imaging, disease notifications, and other sources. Cause-specific death rates and cause fractions were calculated using the Cause of Death Ensemble model and spatiotemporal Gaussian process regression. Cause-specific deaths were adjusted to match the total all-cause deaths calculated as part of the GBD population, fertility, and mortality estimates. Deaths were multiplied by standard life expectancy at each age to calculate YLLs. A Bayesian meta-regression modelling tool, DisMod-MR 2.1, was used to ensure consistency between incidence, prevalence, remission, excess mortality, and cause-specific mortality for most causes. Prevalence estimates were multiplied by disability weights for mutually exclusive sequelae of diseases and injuries to calculate YLDs. We considered results in the context of the Socio-demographic Index (SDI), a composite indicator of income per capita, years of schooling, and fertility rate in females younger than 25 years. Uncertainty intervals (UIs) were generated for every metric using the 25th and 975th ordered 1000 draw values of the posterior distribution. Findings: Global health has steadily improved over the past 30 years as measured by age-standardised DALY rates. After taking into account population growth and ageing, the absolute number of DALYs has remained stable. Since 2010, the pace of decline in global age-standardised DALY rates has accelerated in age groups younger than 50 years compared with the 1990–2010 time period, with the greatest annualised rate of decline occurring in the 0–9-year age group. Six infectious diseases were among the top ten causes of DALYs in children younger than 10 years in 2019: lower respiratory infections (ranked second), diarrhoeal diseases (third), malaria (fifth), meningitis (sixth), whooping cough (ninth), and sexually transmitted infections (which, in this age group, is fully accounted for by congenital syphilis; ranked tenth). In adolescents aged 10–24 years, three injury causes were among the top causes of DALYs: road injuries (ranked first), self-harm (third), and interpersonal violence (fifth). Five of the causes that were in the top ten for ages 10–24 years were also in the top ten in the 25–49-year age group: road injuries (ranked first), HIV/AIDS (second), low back pain (fourth), headache disorders (fifth), and depressive disorders (sixth). In 2019, ischaemic heart disease and stroke were the top-ranked causes of DALYs in both the 50–74-year and 75-years-and-older age groups. Since 1990, there has been a marked shift towards a greater proportion of burden due to YLDs from non-communicable diseases and injuries. In 2019, there were 11 countries where non-communicable disease and injury YLDs constituted more than half of all disease burden. Decreases in age-standardised DALY rates have accelerated over the past decade in countries at the lower end of the SDI range, while improvements have started to stagnate or even reverse in countries with higher SDI. Interpretation: As disability becomes an increasingly large component of disease burden and a larger component of health expenditure, greater research and developm nt investment is needed to identify new, more effective intervention strategies. With a rapidly ageing global population, the demands on health services to deal with disabling outcomes, which increase with age, will require policy makers to anticipate these changes. The mix of universal and more geographically specific influences on health reinforces the need for regular reporting on population health in detail and by underlying cause to help decision makers to identify success stories of disease control to emulate, as well as opportunities to improve. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes