Inventory of available data and data sources and proposal for data collection on vector‐borne zoonoses in animals

n/

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial

Background: 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. Methods: 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. Findings: 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. Interpretation: 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. Funding: Novo Nordisk

Characterisation of androstenone metabolism in pig liver in relation to boar taint

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Effect of testosterone, estrone sulphate and androstenone on 3β-hydroxysteroid dehydrogenase protein expression in primary cultured hepatocytes

Androstenone (5α-androst-16-en-3-one) is a steroid pheromone, excessive accumulation of which in pig adipose tissue contributes to the phenomenon of "boar taint". The incidence of boar taint increases with age and weight of entire male pigs. One of the reasons for the excessive accumulation of androstenone in adipose tissue of some pigs is a low rate of androstenone degradation in pig liver, which is related to defective expression of the androstenone-metabolising enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD). The mechanism regulating 3β-HSD expression in pig liver remains unclear. The present study investigated the effects of the sex steroids testosterone, estrone sulphate and androstenone on the expression of 3β-HSD protein using primary cultured hepatocytes as a model system. The study was performed on hepatocytes from pigs of two weight/age groups: "lighter weight" (average carcass weight 70kg, age 21weeks) and "heavier weight" (average carcass weight 92kg, age 26weeks). Testosterone at the range of concentrations from 5 to 100nM induced 3β-HSD expression in "lighter weight" pigs but not in "heavier weight" animals. In contrast, estrone sulphate (5 to 100nM) and androstenone (5 to 500nM) induced 3β-HSD expression only in "heavier weight" but not "lighter weight" pigs. Induction of 3β-HSD expression by the sex steroids was protein-synthesis-dependent. Overall this study demonstrates for the first time that sex steroids are involved in regulation of 3β-HSD protein expression in primary cultured pig hepatocytes and that the effect of sex steroids depends on age and weight of animals. The results of this work might contribute to understanding the mechanism controlling androstenone deposition in pigs. © 2007 Elsevier B.V. All rights reserved

Breed-associated variations in the sequence of the pig 3β- hydroxysteroid dehydrogenase gene

The entire sequence of the pig 3β-hydroxysteroid dehydrogenase (3β-HSD) gene has recently become known. This gene is deemed to be important in androstenone metabolism in pig liver, and its defective expression has been shown to be related to androstenone accumulation in adipose tissue and the development of boar taint. The aim of the present work was to do the following: 1) define the structure of the pig 3β-HSD gene and 2) compare 3β-HSD DNA sequences from pigs of different breeds, which vary in adipose tissue androstenone levels, with the purpose of identifying a polymorphism that might be responsible for differential 3β-HSD expression. The 5′ flanking and the coding region of 3β-HSD were cloned and sequenced by conventional techniques. The 3β-HSD coding regions were identical in pigs of different breeds and in animals with high and low androstenone levels. Significant sequence variations were found in the 5′ flanking region of the 3β-HSD gene, where differences in the number of TTAT repeats and 3 SNP were observed. The SNP were associated with the number of the TTAT repeats. These variations in the DNA sequence of the 3β-HSD gene were not associated with the androstenone level in s.c. adipose tissue but were breed-dependent. The results of this work might be used for detection of the presence of Meishan genes in Western pig breeds, especially if the phenotype is not clearly established. © 2007 American Society of Animal Science. All rights reserved

Relationship between the expression of hepatic but not testicular 3β-hydroxysteroid dehydrogenase with androstenone deposition in pig adipose tissue

This study investigated the relationship between expression of hepatic and testicular 3/3-hydroxysteroid dehydrogenase (3/3-HSD) and accumulation of androstenone in adipose tissue because of its relation to boar taint. The experiments were performed on 13 Large White (50%) × Landrace (50%) and Meishan (25%) × Large White (25%) × Landrace (50%), pigs, which differed in the level of backfat androstenone. Our previous work showed that the major product of the hepatic androstenone metabolism is 3β-androstenol. In this study, the formation of 3β-androstenol was inhibited by the specific 3β-HSD inhibitor trilostane. These results are the first direct confirmation that 3β-HSD is the enzyme responsible for androstenone metabolism in the pig. The expression of the hepatic but not testicular 3β-HSD protein showed a negative relationship with the level of backfat androstenone (r2 = 0.64; P 0.05) and was lower compared with the hepatic 3β-HSD expression. Cloning and sequencing of the 3β-HSD coding regions established that the hepatic and testicular 3β-HSD cDNA have identical sequences, which were 98% similar to the human 3β-HSD isoform I. It is suggested that expression of a single 3β-HSD gene is regulated by different mechanisms in pig liver and testis. The liver-specific regulation of 3β-HSD expression contributes to the low rate of hepatic androstenone metabolism and therefore can be considered as one of the factors regulating deposition of androstenone in pig adipose tissue and subsequent development of boar taint. ©2006 American Society of Animal Science. All rights reserved

Development of the CMS detector for the CERN LHC Run 3

International audienceSince the initial data taking of the CERN LHC, the CMS experiment has undergone substantial upgrades and improvements. This paper discusses the CMS detector as it is configured for the third data-taking period of the CERN LHC, Run 3, which started in 2022. The entire silicon pixel tracking detector was replaced. A new powering system for the superconducting solenoid was installed. The electronics of the hadron calorimeter was upgraded. All the muon electronic systems were upgraded, and new muon detector stations were added, including a gas electron multiplier detector. The precision proton spectrometer was upgraded. The dedicated luminosity detectors and the beam loss monitor were refurbished. Substantial improvements to the trigger, data acquisition, software, and computing systems were also implemented, including a new hybrid CPU/GPU farm for the high-level trigger