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Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60–0·87 for MACE; 0·79, 0·64–0·98 for the heart failure composite endpoint; 0·76, 0·59–0·97 for cardiovascular death; and 0·81, 0·66–1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49–0·87 for MACE; 0·79, 0·58–1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51–0·91 for MACE; 0·75, 0·52–1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. Novo Nordisk.

Extreme temperatures associated with climate change are expected to impact the physiology and fertility of a variety of insects, including honey bees. Most previous work on this topic has focused on female honey bees (workers and queens), and comparatively little research has investigated how heat exposure affects males (drones). To address this gap, we tested body mass, viral infections, and population origin as predictors of drone survival and sperm viability in a series of heat challenge assays. We found that individual body mass was highly influential, with heavier drones being more likely to survive a heat challenge (4 h at 42°C) than smaller drones. In a separate experiment, we compared the survival of Northern California and Southern California drones in response to the same heat challenge (4 h at 42°C), and found that Southern Californian drones ― which are enriched for African ancestry ― were more likely to survive a heat challenge than drones originating from Northern California. To avoid survivor bias, we conducted sperm heat challenges using in vitro assays and found remarkable variation in sperm heat resilience among drones sourced from different commercial beekeeping operations, with some exhibiting no reduction in sperm viability after heat challenge and others exhibiting a 75% reduction in sperm viability. Further investigating potential causal factors for such variation, we found no association between drone mass and viability of sperm in in vitro sperm heat challenge assays, but virus inoculation (with Israeli acute paralysis virus) exacerbated the negative effect of heat on sperm viability. These experiments establish a vital framework for understanding the importance of population origin and comorbidities for drone heat sensitivity.

Renal M2-like macrophages have critical roles in tissue repair, stimulating tubule cell proliferation and, if they remain, fibrosis. M2-like macrophages have also been implicated in promoting cyst expansion in mouse models of autosomal dominant polycystic kidney disease (ADPKD). While renal macrophages have been documented in human ADPKD, there are no studies in autosomal recessive polycystic kidney disease (ARPKD). Here we evaluated the specific phenotype of renal macrophages and their disease-impacting effects on cystic epithelial cells. We found an abundance of M2-like macrophages in the kidneys of patients with either ADPKD or ARPKD and in the cystic kidneys of cpk mice, a model of ARPKD. Renal epithelial cells from either human ADPKD cysts or noncystic human kidneys promote differentiation of naive macrophages to a distinct M2-like phenotype in culture. Reciprocally, these immune cells stimulate the proliferation of renal tubule cells and microcyst formation in vitro. Further, depletion of macrophages from cpk mice indicated that macrophages contribute to PKD progression regardless of the genetic etiology. Thus, M2-like macrophages are two-pronged progression factors in PKD, promoting cyst cell proliferation, cyst growth, and fibrosis. Agents that block the emergence of these cells or their effects in the cystic kidney may be effective therapies for slowing PKD progression.

Extreme temperatures associated with climate change are expected to impact the physiology and fertility of a variety of insects, including honey bees. Most previous work on this topic has focused on female honey bees (workers and queens), and comparatively little research has investigated how heat exposure affects males (drones). To address this gap, we tested body mass, viral infections, and population origin as predictors of drone survival and sperm viability in a series of heat challenge assays. We found that individual body mass was highly influential, with heavier drones being more likely to survive a heat challenge (4 h at 42°C) than smaller drones. In a separate experiment, we compared the survival of Northern California and Southern California drones in response to the same heat challenge (4 h at 42°C), and found that Southern Californian drones -- which are enriched for African ancestry -- were more likely to survive a heat challenge than drones originating from Northern California. To avoid survivor bias, we conducted sperm heat challenges using in vitro assays and found remarkable variation in sperm heat resilience among drones sourced from different commercial beekeeping operations, with some exhibiting no reduction in sperm viability after heat challenge and others exhibiting a 75% reduction in sperm viability. Further investigating potential causal factors for such variation, we found no association between drone mass and viability of sperm in in vitro sperm heat challenge assays, but virus inoculation (with Israeli acute paralysis virus) exacerbated the negative effect of heat on sperm viability. These experiments establish a vital framework for understanding the importance of population origin and comorbidities for drone heat sensitivity.

Precise identification of drinking and smoking patterns during pregnancy is crucial to better understand the risk to the fetus. The purpose of this manuscript is to describe the methodological approach used to define prenatal drinking and smoking trajectories from a large prospective pregnancy cohort, and to describe maternal characteristics associated with different exposure patterns. In the Safe Passage Study, detailed information regarding quantity, frequency, and timing of exposure was self-reported up to four times during pregnancy and at 1 month post-delivery. Exposure trajectories were developed using data from 11,692 pregnancies (9912 women) where pregnancy outcome was known. Women were from three diverse populations: white (23%) and American Indian (17%) in the Northern Plains, US, and mixed ancestry (59%) in South Africa (other/not specified [1%]). Group-based trajectory modeling was used to identify 5 unique drinking trajectories (1 none/minimal, 2 quitting groups, 2 continuous groups) and 7 smoking trajectories (1 none/minimal, 2 quitting groups, 4 continuous groups). Women with pregnancies assigned to the low- or high-continuous drinking groups were less likely to have completed high school and were more likely to have enrolled in the study in the third trimester, be of mixed ancestry, or be depressed than those assigned to the none/minimal or quit-drinking groups. Results were similar when comparing continuous smokers to none/minimal and quit-smoking groups. Further, women classified as high- or low-continuous drinkers were more likely to smoke at moderate-, high-, and very high-continuous levels, as compared to women classified as non-drinkers and quitters. This is the first study of this size to utilize group-based trajectory modeling to identify unique prenatal drinking and smoking trajectories. These trajectories will be used in future analyses to determine which specific exposure patterns subsequently manifest as poor peri- and postnatal outcomes. •Group-based trajectory modeling identified prenatal drinking and smoking patterns.•Five unique drinking trajectories (1 none/min, 2 quit, 2 continuous) are identified.•Seven unique smoking trajectories (1 none/min, 2 quit, 4 continuous) are identified.•Continuous patterns linked with profiles (e.g., less educated, more depressed) are identified.•Future analyses will link trajectories to peri- and postnatal outcomes.

ObjectiveTo determine normative values for heart rate patterns in healthy fetuses.MethodsThis research is from the Safe Passage Study conducted by the Prenatal Alcohol and SIDS and Stillbirth (PASS) Network. A standardized protocol assessed fetal heart rate (FHR), heart rate variability (HRV), and movement from 1655 fetuses at three-time points during gestation (20–24 weeks, 28–32 weeks, 34–38 weeks gestation).ResultsFHR decreased while HRV increased over gestation. At the latter two ages, males had significantly lower FHR than females while there were no sex differences in FHR at 20–24 weeks. When accounting for the fetal state during late gestation (34–28 weeks), we found that males had significantly lower FHR than females in the active fetal state only.ConclusionResults demonstrate significant state, gestational age, and sex-related changes in cardiac activity, somatic activity, and autonomic function as the fetus approaches birth.

Extreme temperatures associated with climate change are expected to impact the physiology and fertility of a variety of insects, including honey bees. Most previous work has focused on female honey bees, and comparatively little research has investigated how heat exposure affects males (drones). To address this gap, we tested how body mass, viral infections, Africanization, and geographic origin (including stocks from Australia, California, and Ukraine as well as diverse locations within British Columbia, Canada) influenced drone and sperm heat tolerance. We found that individual body size was highly influential, with heavier drones being more likely to survive a heat challenge than smaller drones. Drones originating from feral colonies in Southern California (which are enriched for African genetics) were also more likely to survive a heat challenge than drones originating from commercially-supplied Californian stock. We found no association between drone mass and thermal tolerance of sperm over time in an in vitro challenge assay, but experimental viral infection decreased the heat tolerance of sperm. Overall, there is ample variation in sperm heat tolerance, with sperm from some groups displaying remarkable heat resilience and sperm from others being highly sensitive, with additional factors influencing heat tolerance of the drones themselves.