Reduction in the cumulative effect of stress-induced inbreeding depression due to intragenerational purging in Drosophila melanogaster

Environmental stress generally exacerbates the harmful effects of inbreeding and it has been proposed that this could be exploited in purging deleterious alleles from threatened inbred populations. However, understanding what factors contribute to variability in the strength of inbreeding depression (ID) observed across adverse environmental conditions remains a challenge. Here, we examined how the nature and timing of stress affects ID and the potential for purging using inbred and outbred Drosophila melanogaster larvae exposed to biotic (larval competition, bacteria infection) and abiotic (ethanol, heat) stressors compared with unstressed controls. ID was measured during (larval survival) and after (male mating success) stress exposure. The level of stress imposed by each stressor was approximately equal, averaging a 42% reduction in outbred larval survival relative to controls. All stressors induced on average the same ID, causing a threefold increase in lethal equivalents for larval survival relative to controls. However, stress-induced ID in larval success was followed by a 30% reduction in ID in mating success of surviving males. We propose that this fitness recovery is due to ‘intragenerational purging' whereby fitness correlations facilitate stress-induced purging that increases the average fitness of survivors in later life history stages. For biotic stressors, post-stress reductions in ID are consistent with intragenerational purging, whereas for abiotic stressors, there appeared to be an interaction between purging and stress-induced physiological damage. For all stressors, there was no net effect of stress on lifetime ID compared with unstressed controls, undermining the prediction that stress enhances the effectiveness of population-level purging across generations

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo