The Origin of a New Sex Chromosome by Introgression between Two Stickleback Fishes.

Introgression is increasingly recognized as a source of genetic diversity that fuels adaptation. Its role in the evolution of sex chromosomes, however, is not well known. Here, we confirm the hypothesis that the Y chromosome in the ninespine stickleback, Pungitius pungitius, was established by introgression from the Amur stickleback, P. sinensis. Using whole genome resequencing, we identified a large region of Chr 12 in P. pungitius that is diverged between males and females. Within but not outside of this region, several lines of evidence show that the Y chromosome of P. pungitius shares a most recent common ancestor not with the X chromosome, but with the homologous chromosome in P. sinensis. Accumulation of repetitive elements and gene expression changes on the new Y are consistent with a young sex chromosome in early stages of degeneration, but other hallmarks of Y chromosomes have not yet appeared. Our findings indicate that porous species boundaries can trigger rapid sex chromosome evolution

Effects of dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial

Background: Goals of management in patients with heart failure and reduced ejection fraction include reducing death and hospitalizations, and improving health status (symptoms, physical function, and quality of life). In the DAPA-HF trial (Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure), sodium–glucose cotransporter-2 inhibitor, dapagliflozin, reduced death and hospitalizations, and improved symptoms in patients with heart failure and reduced ejection fraction. In this analysis, we examine the effects of dapagliflozin on a broad range of health status outcomes, using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Methods: KCCQ was evaluated at randomization, 4 and 8 months. Patients were divided by baseline KCCQ total symptom score (TSS); Cox proportional hazards models examined the effects of dapagliflozin on clinical events across these subgroups. We also evaluated the effects of dapagliflozin on KCCQ-TSS, clinical summary score, and overall summary score. Responder analyses were performed to compare proportions of dapagliflozin versus placebo-treated patients with clinically meaningful changes in KCCQ at 8 months. Results: A total of 4443 patients had available KCCQ at baseline (median KCCQ-TSS, 77.1 [interquartile range, 58.3–91.7]). The effects of dapagliflozin vs placebo on reducing cardiovascular death or worsening heart failure were consistent across the range of KCCQ-TSS (lowest to highest tertile: hazard ratio, 0.70 [95% CI, 0.57–0.86]; hazard ratio, 0.77 [95% CI, 0.61–0.98]; hazard ratio, 0.62 [95% CI, 0.46–0.83]; P for heterogeneity=0.52). Patients treated with dapagliflozin had greater improvement in mean KCCQ-TSS, clinical summary score, and overall summary score at 8 months (2.8, 2.5 and 2.3 points higher versus placebo; P<0.0001 for all). Fewer patients treated with dapagliflozin had a deterioration in KCCQ-TSS (odds ratio, 0.84 [95% CI, 0.78–0.90]; P<0.0001); and more patients had at least small, moderate, and large improvements (odds ratio, 1.15 [95% CI, 1.08–1.23]; odds ratio, 1.15 [95% CI, 1.08–1.22]; odds ratio, 1.14 [95% CI, 1.07–1.22]; number needed to treat=14, 15, and 18, respectively; P<0.0001 for all; results consistent for KCCQ clinical summary score and overall summary score). Conclusions: Dapagliflozin reduced cardiovascular death and worsening heart failure across the range of baseline KCCQ, and improved symptoms, physical function, and quality of life in patients with heart failure and reduced ejection fraction. Furthermore, dapagliflozin increased the proportion of patients experiencing at least small, moderate, and large improvements in health status; these effects were clinically important

Dapagliflozin in HFrEF Patients Treated With Mineralocorticoid Receptor Antagonists An Analysis of DAPA-HF

OBJECTIVES The purpose of this study was to assess the efficacy and safety of dapagliflozin in patients taking or not taking an mineralocorticoid receptor antagonist (MRA) at baseline in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial. BACKGROUND MRAs and sodium glucose co-transporter 2 inhibitors each have diuretic activity, lower blood pressure, and reduce glomerular filtration rate (GFR). Therefore, it is important to investigate the safety, as well as efficacy, of their combination. METHODS A total of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) were randomized to placebo or dapagliflozin 10mg daily. The efficacy of dapagliflozin on the primary composite outcome (cardiovascular death or episode of worsening heart failure) and its components was examined according to MRA use, as were predefined safety outcomes. RESULTS A total of 3,370 patients (71%) were treated with an MRA and they were younger (65 vs. 69 years of age), less often from North America (9% vs. 26%), had worse New York Heart Association functional class (35% vs. 25% in class III/ IV), lower left ventricular ejection fraction (30.7% vs. 31.9%) and systolic blood pressure (120.3 vs. 125.5 mm Hg), but higher estimated GFR (67.1 vs. 62.6 ml/min/1.73 m(2)), than patients not taking an MRA. The benefit of dapagliflozin compared with placebo was similar in patients taking or not taking an MRA: hazard ratio: 0.74 (95% confidence interval [CI]: 0.63 to 0.87) versus 0.74 (95% CI: 0.57 to 0.95), respectively, for the primary endpoint (p value for interaction - 0.97); similar findings were observed for secondary endpoints. In both MRA subgroups, safety outcomes were similar in patients randomized to dapagliflozin or placebo. CONCLUSIONS Dapagliflozin was similarly efficacious and safe in patients with HFrEF taking or not taking an MRA, supporting the use of both drugs together. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124) (C)2021 Published by Elsevier on behalf of the American College of Cardiology Foundation

Communications Biophysics

Contains research objectives, summary of research and reports on two research project.National Institutes of Health (Grant 5 PO1 GM14940-03)National Institutes of Health (Grant 5 TO1 GM01555-03)National Aeronautics and Space Administration (Grant NGL 22-009-304

Genome-Wide Association Study of Peripheral Artery Disease

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (P-associationPeer reviewe

Cost-effectiveness of In-home Automated External Defibrillators for Individuals at Increased Risk of Sudden Cardiac Death

In-home automated external defibrillators (AEDs) are increasingly recommended as a means for improving survival of cardiac arrests that occur at home. The current study was conducted to explore the relationship between individuals' risk of cardiac arrest and cost-effectiveness of in-home AED deployment. Design : Markov decision model employing a societal perspective. Patients : Four hypothetical cohorts of American adults 60 years of age at progressively greater risk for sudden cardiac death (SCD): 1) all adults (annual probability of SCD 0.4%); 2) adults with multiple SCD risk factors (probability 2%); 3) adults with previous myocardial infarction (probability 4%); and 4) adults with ischemic cardiomyopathy unable to receive an implantable defibrillator (probability 6%). Intervention : Strategy 1: individuals suffering an in-home cardiac arrest were treated with emergency medical services equipped with AEDs (EMS-D). Strategy 2: individuals suffering an in-home cardiac arrest received initial treatment with an in-home AED, followed by EMS. Results : Assuming cardiac arrest survival rates of 15% with EMS-D and 30% with AEDs, the cost per quality-adjusted life-year gained (QALY) of providing in-home AEDs to all adults 60 years of age is $216,000. Costs of providing in-home AEDs to adults with multiple risk factors (2$132,000, $104,000, and$88,000, respectively. Conclusions : The cost-effectiveness of in-home AEDs is intimately linked to individuals' risk of SCD. However, providing in-home AEDs to all adults over age 60 appears relatively expensive.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72168/1/j.1525-1497.2005.40247.x.pd

Communications Biophysics

Contains research objectives, summary of research and reports on three research projects.National Institutes of Health (Grant 5 PO1 GM14940-04)National Institutes of Health (Grant 5 TOl GM01555-04)National Aeronautics and Space Administration (Grant NGL 22-009-304

Communications Biophysics

Contains research objectives, summary of research and reports on four research projects.National Institutes of Health (Grant 5 P01 GM14940-05)National Institutes of Health (Grant 5 TOl GM01555-05)National Aeronautics and Space Administration (Grant NGL 22-009-304)B-D ElectrodyneBoston City Hospital Purchase Order 1065

Implantable or External Defibrillators for Individuals at Increased Risk of Cardiac Arrest: Where Cost-Effectiveness Hits Fiscal Reality

Objcetives:  Implantable cardioverter defibrillators (ICDs) are highly effective at preventing cardiac arrest, but their availability is limited by high cost. Automated external defibrillators (AEDs) are likely to be less effective, but also less expensive. We used decision analysis to evaluate the clinical and economic trade-offs of AEDs, ICDs, and emergency medical services equipped with defibrillators (EMS-D) for reducing cardiac arrest mortality. Methods:  A Markov model was developed to compare the cost-effectiveness of three strategies in adults meeting entry criteria for the MADIT II Trial: strategy 1, individuals experiencing cardiac arrest are treated by EMS-D; strategy 2, individuals experiencing cardiac arrest are treated with an in-home AED; and strategy 3, individuals receive a prophylactic ICD. The model was then used to quantify the aggregate societal benefit of these three strategies under the conditions of a constrained federal budget. Results:  Compared with EMS-D, in-home AEDs produced a gain of 0.05 quality-adjusted life-years (QALYs) at an incremental cost of $5225 ($104,500 per QALY), while ICDs produced a gain of 0.90 QALYs at a cost of $114,660 ($127,400 per QALY). For every $1 million spent on defibrillators, 1.7 additional QALYs are produced by purchasing AEDs (9.6 QALYs/$million) instead of ICDs (7.9 QALYs/$million). Results were most sensitive to defibrillator complication rates and effectiveness, defibrillator cost, and adults’ risk of cardiac arrest. Conclusions:  Both AEDs and ICDs reduce cardiac arrest mortality, but AEDs are significantly less expensive and less effective. If financial constraints were to lead to rationing of defibrillators, it might be preferable to provide more people with a less effective and less expensive intervention (in-home AEDs) instead of providing fewer people with a more effective and more costly intervention (ICDs).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74790/1/j.1524-4733.2006.00118.x.pd