Molecular evolutionary consequences of island colonization

Island endemics are expected to have low effective population sizes (Ne), first because some may experience population bottlenecks when they are founded, and second because they have restricted ranges. Therefore, we expect island species to have reduced genetic diversity, inefficient selection, and reduced adaptive potential compared with their mainland counterparts. We used both polymor- phism and substitution data to address these predictions, improving on the approach of recent studies that only used substitution data. This allowed us to directly test the assumption that island species have small values of Ne. We found that island species had significantly less genetic diversity than mainland species; however, this pattern could be attributed to a subset of island species that appeared to have undergone a recent population bottleneck. When these species were excluded from the analysis, island and mainland species had similar levels of genetic diversity, despite island species occupying considerably smaller areas than their mainland counterparts. We also found no overall difference between island and mainland species in terms of the effectiveness of selection or the mutation rate. Our evidence suggests that island colonization has no lasting impact on molecular evolution. This surprising result highlights gaps in our knowledge of the relationship between census and effective population size

Future Libraries, Archives, and Museums in Excavation (FLAME) - A Podcast Series of the CLIR Curated Futures Project

Our podcast series holds the microphone up to archivists, scholars, and museum staff who work with collections pertaining to BIPOC (Black, Indigenous, and people of color) communities. Thus far, two paths have emerged: (1) reinterpreting archival, library, museum content that come from predominantly white colonial perspectives; and (2) introducing underrepresented BIPOC narratives into the mainstream. Such efforts have already been evolving in local BIPOC libraries, archives, and museums, in neighborhoods, and in tribal communities. In speaking with BIPOC scholars, archivists, librarians and non-BIPOC allies, many have recommended establishing contact with the communities to whom the collections belong, making sure that they have gained full agency over the life cycle and uses of the materials that pertain to BIPOC cultures and points of view. We aim to understand how their archival practices provide more agency for BIPOC communities, differing from those practiced by the “first” university systems. In short, our work sits at the juncture of both a re-definition (especially for Predominantly White institutions) and a continuingly strengthened construction of archives (for BIPOC communities)

Genome scanning of behavioral selection in a canine olfactory detection breeding cohort

Research on working dogs is growing rapidly due to increasing global demand. Here we report genome scanning of the risk of puppies being eliminated for behavioral reasons prior to entering the training phase of the US Transportation Security Administration\u27s (TSA) canine olfactory detection breeding and training program through 2013. Elimination of dogs for behavioral rather than medical reasons was based on evaluations at three, six, nine and twelve months after birth. Throughout that period, the fostered dogs underwent standardized behavioral tests at TSA facilities, and, for a subset of tests, dogs were tested in four different environments. Using methods developed for family studies, we performed a case-control genome wide association study (GWAS) of elimination due to behavioral observation and testing results in a cohort of 528 Labrador Retrievers (2002-2013). We accounted for relatedness by including the pedigree as a covariate and maximized power by including individuals with phenotype, but not genotype, data (approximately half of this cohort). We determined genome wide significance based on Bonferroni adjustment of two quasi-likelihood score tests optimized for either small or nearly-fully penetrant effect sizes. Six loci were significant and five suggestive, with approximately equal numbers of loci for the two tests and frequencies of loci with single versus multiple mapped markers. Several loci implicate a single gene, including CHD2, NRG3 and PDE1A which have strong relevance to behavior in humans and other species. We briefly discuss how expanded studies of canine breeding programs could advance understanding of learning and performance in the mammalian life course. Although human interactions and other environmental conditions will remain critical, our findings suggest genomic breeding selection could help improve working dog populations

Diel Temperature and pH Variability Scale With Depth Across Diverse Coral Reef Habitats

Coral reefs are facing intensifying stressors, largely due to global increases in seawater temperature and decreases in pH. However, there is extensive environmental variability within coral reef ecosystems, which can impact how organisms respond to global trends. We deployed spatial arrays of autonomous sensors across distinct shallow coral reef habitats to determine patterns of spatiotemporal variability in seawater physicochemical parameters. Temperature and pH were positively correlated over the course of a day due to solar heating and light‐driven metabolism. The mean temporal and spatial ranges of temperature and pH were positively correlated across all sites, with different regimes of variability observed in different reef types. Ultimately, depth was a reliable predictor of the average diel ranges in both seawater temperature and pH. These results demonstrate that there is widespread environmental variability on diel timescales within coral reefs related to water column depth, which needs to be included in assessments of how global change will locally affect reef ecosystems

Nearly neutral evolution across the Drosophila melanogaster genome

Under the nearly neutral theory of molecular evolution, the proportion of effectively neutral mutations is expected to depend upon the effective population size (Ne). Here, we investigate whether this is the case across the genome of Drosophila melanogaster using polymorphism data from North American and African lines. We show that the ratio of the number of nonsynonymous and synonymous polymorphisms is negatively correlated to the number of synonymous polymorphisms, even when the nonindependence is accounted for. The relationship is such that the proportion of effectively neutral nonsynonymous mutations increases by ∼45% as Ne is halved. However, we also show that this relationship is steeper than expected from an independent estimate of the distribution of fitness effects from the site frequency spectrum. We investigate a number of potential explanations for this and show, using simulation, that this is consistent with a model of genetic hitchhiking: Genetic hitchhiking depresses diversity at neutral and weakly selected sites, but has little effect on the diversity of strongly selected sites

A facilitated home-based cardiac rehabilitation intervention for people with heart failure and their caregivers:a research programme including the REACH-HF RCT

Background: Rates of participation in centre (hospital)-cardiac rehabilitation by patients with heart failure are suboptimal. Heart failure has two main phenotypes differing in underlying pathophysiology: Heart failure with reduced ejection fraction is characterised by depressed left ventricular systolic function (‘reduced ejection fraction’), whereas heart failure with preserved ejection fraction is diagnosed after excluding other causes of dyspnoea with normal ejection fraction. This programme aimed to develop and evaluate a facilitated home-based cardiac rehabilitation intervention that could increase the uptake of cardiac rehabilitation while delivering the clinical benefits of centre-based cardiac rehabilitation. Objectives: To develop an evidence-informed, home-based, self-care cardiac rehabilitation programme for patients with heart failure and their caregivers [the REACH-HF (Rehabilitation Enablement in Chronic Heart Failure) intervention]. To conduct a pilot randomised controlled trial to assess the feasibility of a full trial of the clinical effectiveness and cost-effectiveness of the REACH-HF intervention in addition to usual care in patients with heart failure with preserved ejection fraction. To assess the short- and long-term clinical effectiveness and cost-effectiveness of the REACH-HF intervention in addition to usual care in patients with heart failure with reduced ejection fraction and their caregivers. Design: Intervention mapping to develop the REACH-HF intervention; uncontrolled feasibility study; pilot randomised controlled trial in those with heart failure with preserved ejection fraction; randomised controlled trial with a trial-based cost-effectiveness analysis in those with heart failure with reduced ejection fraction; qualitative studies including process evaluation; systematic review of cardiac rehabilitation in heart failure; and modelling to assess long-term cost-effectiveness (in those with heart failure with reduced ejection fraction). Setting: Four centres in England and Wales (Birmingham, Cornwall, Gwent and York); one centre in Scotland (Dundee) for a pilot randomised controlled trial. Participants: Adults aged ≥ 18 years with heart failure with reduced ejection fraction (left ventricular ejection fraction &lt; 45%) for the main randomised controlled trial (n = 216), and those with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥ 45%) for the pilot randomised controlled trial (n = 50). Intervention: A self-care, facilitated cardiac rehabilitation manual was offered to patients (and participating caregivers) at home over 12 weeks by trained health-care professionals in addition to usual care or usual care alone. Main outcome measures: The primary outcome was disease-specific health-related quality of life measured using the Minnesota Living with Heart Failure Questionnaire at 12 months. Secondary outcomes included deaths and hospitalisations. Results: The main randomised controlled trial recruited 216 participants with heart failure with reduced ejection fraction and 97 caregivers. A significant and clinically meaningful between-group difference in the Minnesota Living with Heart Failure Questionnaire score (primary outcome) at 12 months (–5.7 points, 95% confidence interval –10.6 to –0.7 points) favoured the REACH-HF intervention (p = 0.025). Eight (4%) patients (four in each group) had died at 12 months. There was no significant difference in hospital admissions, at 12 months, with 19 participants in the REACH-HF intervention group having at least one hospital admission, compared with 24 participants in the control group (odds ratio 0.72, 95% confidence interval 0.35 to 1.51; p = 0.386). The mean cost of the intervention was £418 per participant with heart failure with reduced ejection fraction. The costs at 12 months were, on average, £401 higher in the intervention group than in the usual care alone group. Model-based economic evaluation, extrapolating from the main randomised controlled trial in those with heart failure with reduced ejection fraction over 4 years, found that adding the REACH-HF intervention to usual care had an estimated mean cost per participant of £15,452 (95% confidence interval £14,240 to £16,780) and a mean quality-adjusted lifeyear gain of 4.47 (95% confidence interval 3.83 to 4.91) years, compared with £15,051 (95% confidence interval £13,844 to £16,289) and 4.24 (95% confidence interval 4.05 to 4.43) years, respectively, for usual care alone. This gave an incremental cost per quality-adjusted life-year of £1721. The probabilistic sensitivity analysis indicated 78% probability that the intervention plus usual care versus usual care alone has a cost-effectiveness below the willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained. The intervention was well received by participants with heart failure with reduced ejection fraction and those with heart failure with preserved ejection fraction, as well as their caregivers. Both randomised controlled trials recruited to target, with &gt; 85% retention at follow-up. Limitations: Key limitations included (1) lack of blinding – given the nature of the intervention and the control we could not mask participants to treatments, so our results may reflect participant expectation bias; (2) that we were not able to capture consistent participant-level data on level of intervention adherence; (3) that there may be an impact on the generalisability of findings due to the demographics of the trial patients, as most were male (78%) and we recruited only seven people from ethnic minorities. Conclusions: Evaluation of the comprehensive, facilitated, home-based REACH-HF intervention for participants with heart failure with reduced ejection fraction and caregivers indicated clinical effectiveness in terms of health-related quality of life and patient self-care but no other secondary outcomes. Although the economic analysis conducted alongside the full randomised controlled trial did not produce significant differences on the EuroQol-5 Dimensions or in quality-adjusted life-years, economic modelling suggested greater cost-effectiveness of the intervention than usual care. Our REACH-HF intervention offers a new evidence-based cardiac rehabilitation option that could increase uptake of cardiac rehabilitation in patients with heart failure not attracted to or able to access hospital-based programmes. Future work: Systematic collection of real-world data would track future changes in uptake of and adherence to alternative cardiac rehabilitation interventions in heart failure with reduced ejection fraction and increase understanding of how changes in service delivery might affect clinical and health economic outcomes. The findings of our pilot randomised controlled trial in patients with heart failure with preserved ejection fraction support progression to a full multicentre randomised controlled trial. </p

Allogeneic stem cell transplantation for chronic lymphocytic leukemia in the era of novel agents.

Although novel agents (NAs) have improved outcomes for patients with chronic lymphocytic leukemia (CLL), a subset will progress through all available NAs. Understanding outcomes for potentially curative modalities including allogeneic hematopoietic stem cell transplantation (alloHCT) following NA therapy is critical while devising treatment sequences aimed at long-term disease control. In this multicenter, retrospective cohort study, we examined 65 patients with CLL who underwent alloHCT following exposure to ≥1 NA, including baseline disease and transplant characteristics, treatment preceding alloHCT, transplant outcomes, treatment following alloHCT, and survival outcomes. Univariable and multivariable analyses evaluated associations between pre-alloHCT factors and progression-free survival (PFS). Twenty-four-month PFS, overall survival (OS), nonrelapse mortality, and relapse incidence were 63%, 81%, 13%, and 27% among patients transplanted for CLL. Day +100 cumulative incidence of grade III-IV acute graft-vs-host disease (GVHD) was 24%; moderate-severe GVHD developed in 27%. Poor-risk disease characteristics, prior NA exposure, complete vs partial remission, and transplant characteristics were not independently associated with PFS. Hematopoietic cell transplantation-specific comorbidity index independently predicts PFS. PFS and OS were not impacted by having received NAs vs both NAs and chemoimmunotherapy, 1 vs ≥2 NAs, or ibrutinib vs venetoclax as the line of therapy immediately pre-alloHCT. AlloHCT remains a viable long-term disease control strategy that overcomes adverse CLL characteristics. Prior NAs do not appear to impact the safety of alloHCT, and survival outcomes are similar regardless of number of NAs received, prior chemoimmunotherapy exposure, or NA immediately preceding alloHCT. Decisions about proceeding to alloHCT should consider comorbidities and anticipated response to remaining therapeutic options

A facilitated home-based cardiac rehabilitation intervention for people with heart failure and their caregivers:a research programme including the REACH-HF RCT

Background: Rates of participation in centre (hospital)-cardiac rehabilitation by patients with heart failure are suboptimal. Heart failure has two main phenotypes differing in underlying pathophysiology: Heart failure with reduced ejection fraction is characterised by depressed left ventricular systolic function (‘reduced ejection fraction’), whereas heart failure with preserved ejection fraction is diagnosed after excluding other causes of dyspnoea with normal ejection fraction. This programme aimed to develop and evaluate a facilitated home-based cardiac rehabilitation intervention that could increase the uptake of cardiac rehabilitation while delivering the clinical benefits of centre-based cardiac rehabilitation. Objectives: To develop an evidence-informed, home-based, self-care cardiac rehabilitation programme for patients with heart failure and their caregivers [the REACH-HF (Rehabilitation Enablement in Chronic Heart Failure) intervention]. To conduct a pilot randomised controlled trial to assess the feasibility of a full trial of the clinical effectiveness and cost-effectiveness of the REACH-HF intervention in addition to usual care in patients with heart failure with preserved ejection fraction. To assess the short- and long-term clinical effectiveness and cost-effectiveness of the REACH-HF intervention in addition to usual care in patients with heart failure with reduced ejection fraction and their caregivers. Design: Intervention mapping to develop the REACH-HF intervention; uncontrolled feasibility study; pilot randomised controlled trial in those with heart failure with preserved ejection fraction; randomised controlled trial with a trial-based cost-effectiveness analysis in those with heart failure with reduced ejection fraction; qualitative studies including process evaluation; systematic review of cardiac rehabilitation in heart failure; and modelling to assess long-term cost-effectiveness (in those with heart failure with reduced ejection fraction). Setting: Four centres in England and Wales (Birmingham, Cornwall, Gwent and York); one centre in Scotland (Dundee) for a pilot randomised controlled trial. Participants: Adults aged ≥ 18 years with heart failure with reduced ejection fraction (left ventricular ejection fraction &lt; 45%) for the main randomised controlled trial (n = 216), and those with heart failure with preserved ejection fraction (left ventricular ejection fraction ≥ 45%) for the pilot randomised controlled trial (n = 50). Intervention: A self-care, facilitated cardiac rehabilitation manual was offered to patients (and participating caregivers) at home over 12 weeks by trained health-care professionals in addition to usual care or usual care alone. Main outcome measures: The primary outcome was disease-specific health-related quality of life measured using the Minnesota Living with Heart Failure Questionnaire at 12 months. Secondary outcomes included deaths and hospitalisations. Results: The main randomised controlled trial recruited 216 participants with heart failure with reduced ejection fraction and 97 caregivers. A significant and clinically meaningful between-group difference in the Minnesota Living with Heart Failure Questionnaire score (primary outcome) at 12 months (–5.7 points, 95% confidence interval –10.6 to –0.7 points) favoured the REACH-HF intervention (p = 0.025). Eight (4%) patients (four in each group) had died at 12 months. There was no significant difference in hospital admissions, at 12 months, with 19 participants in the REACH-HF intervention group having at least one hospital admission, compared with 24 participants in the control group (odds ratio 0.72, 95% confidence interval 0.35 to 1.51; p = 0.386). The mean cost of the intervention was £418 per participant with heart failure with reduced ejection fraction. The costs at 12 months were, on average, £401 higher in the intervention group than in the usual care alone group. Model-based economic evaluation, extrapolating from the main randomised controlled trial in those with heart failure with reduced ejection fraction over 4 years, found that adding the REACH-HF intervention to usual care had an estimated mean cost per participant of £15,452 (95% confidence interval £14,240 to £16,780) and a mean quality-adjusted lifeyear gain of 4.47 (95% confidence interval 3.83 to 4.91) years, compared with £15,051 (95% confidence interval £13,844 to £16,289) and 4.24 (95% confidence interval 4.05 to 4.43) years, respectively, for usual care alone. This gave an incremental cost per quality-adjusted life-year of £1721. The probabilistic sensitivity analysis indicated 78% probability that the intervention plus usual care versus usual care alone has a cost-effectiveness below the willingness-to-pay threshold of £20,000 per quality-adjusted life-year gained. The intervention was well received by participants with heart failure with reduced ejection fraction and those with heart failure with preserved ejection fraction, as well as their caregivers. Both randomised controlled trials recruited to target, with &gt; 85% retention at follow-up. Limitations: Key limitations included (1) lack of blinding – given the nature of the intervention and the control we could not mask participants to treatments, so our results may reflect participant expectation bias; (2) that we were not able to capture consistent participant-level data on level of intervention adherence; (3) that there may be an impact on the generalisability of findings due to the demographics of the trial patients, as most were male (78%) and we recruited only seven people from ethnic minorities. Conclusions: Evaluation of the comprehensive, facilitated, home-based REACH-HF intervention for participants with heart failure with reduced ejection fraction and caregivers indicated clinical effectiveness in terms of health-related quality of life and patient self-care but no other secondary outcomes. Although the economic analysis conducted alongside the full randomised controlled trial did not produce significant differences on the EuroQol-5 Dimensions or in quality-adjusted life-years, economic modelling suggested greater cost-effectiveness of the intervention than usual care. Our REACH-HF intervention offers a new evidence-based cardiac rehabilitation option that could increase uptake of cardiac rehabilitation in patients with heart failure not attracted to or able to access hospital-based programmes. Future work: Systematic collection of real-world data would track future changes in uptake of and adherence to alternative cardiac rehabilitation interventions in heart failure with reduced ejection fraction and increase understanding of how changes in service delivery might affect clinical and health economic outcomes. The findings of our pilot randomised controlled trial in patients with heart failure with preserved ejection fraction support progression to a full multicentre randomised controlled trial. </p