Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Genome-wide analysis of DNA methylation in clones and nonclones of two different breeds: Holstein and Japanese black

National audienc

Investigation of inter-individual epigenetic variability in bovine clones: a high throughput study

Adresse Présente de Daniel Le Bourhis: Physiologie de la Reproduction et des Comportements, INRA ToursReprogramming the somalie cel! to totipotency can be obtained following the transfert ofits nucleus into an enucleated oocyte (cloning). We are using cattle clones as a mode!to assess the interindividual epigenetic variability and its consequences on phenotypes, including agronomical relevant traits and developmental pathologies. Indeed, the developmental defects frequently associated with cloning could be related to the insufficient extent of reprogramming, leading to long tenu consequences on phenotypes. To identifY epigenomic pattems affected by incomplete reprogramming, we used immunoprecipitation of methylated DNA followed by hybridization on a new bovine promoter microarray (MeDIP-chip). The microarray targets the upstream region (-2,000 to +1,360 bp) of21,416 genes (UMD3.1 assembly). We first focused on liver, because overgrowth of this organ is often observed in clones. The microarray has been hybridized with MeDIP sampies from livers of normal Holstein animais (4 perinatal controis and 8 adults, obtained by artificial insemination and all healthy) and livers of Holstein clones (7 perinatal clones, either stillborn or suffering from severe pathologies, and 7 adult clones, with normal to pathological phenotypes). After normalization of the data, enriched probes were identified using ChiPmix. Results of exploratory analysis, including correlation clustering, Principal ComponentAnalysis (PCA) and Independent ComponentAnalysis (ICA), will be presented. A statistical test based on differences in the spatial distribution of the enriched probes revealed that most of the promoters exhibit a clustered distribution of the enriched probes. This local enriclnnent shows interindividual variability for sorne of the promoters, which are currently being identified and validated

Altered DNA methylation associated with an abnormal liver phenotype in a cattle model with a high incidence of perinatal pathologies

Cloning enables the generation of both clinically normal and pathological individuals from the same donor cells, and may therefore be a DNA sequence-independent driver of phenotypic variability. We took advantage of cattle clones with identical genotypes but different developmental abilities to investigate the role of epigenetic factors in perinatal mortality, a complex trait with increasing prevalence in dairy cattle. We studied livers from pathological clones dying during the perinatal period, clinically normal adult clones with the same genotypes as perinatal clones and conventional age-matched controls. The livers from deceased perinatal clones displayed histological lesions, modifications to quantitative histomorphometric and metabolic parameters such as glycogen storage and fatty acid composition, and an absence of birth-induced maturation. In a genome-wide epigenetic analysis, we identified DNA methylation patterns underlying these phenotypic alterations and targeting genes relevant to liver metabolism, including the type 2 diabetes gene TCF7L2. The adult clones were devoid of major phenotypic and epigenetic abnormalities in the liver, ruling out the effects of genotype on the phenotype observed. These results thus provide the first demonstration of a genome-wide association between DNA methylation and perinatal mortality in cattle, and highlight epigenetics as a driving force for phenotypic variability in farmed animals

Investigation of inter-individual epigenetic variability in bovine clones: A high throughput study

Reprogramming the differentiated cell to totipotency can be achieved following the introduction of its nucleus into an enucleated oocyte, a procedure known as cloning. We used cattle clones as a pertinent model to assess the inter-individual epigenetic variability and its consequences on phenotypes, including agronomically relevant traits and developmental pathologies. Indeed, the developmental defects frequently associated with cloning could be related to the insufficient extent of reprogramming, leading to perturbations of the nuclear microenvironment of the early embryo, with long-term consequences on the phenotype. Immunoprecipitation of methylated DNA following hybridization on a new bovine-specific tiling array (MeDIP-chip) was used to describe the epigenomic patterns affected by incomplete reprogramming. We first focused on the liver, because overgrowth of this organ is, to a certain extent, bound to global foetal overgrowth, which is often observed in clones. The microarray represents the 21 416 bovine genes currently annotated (UMD3.1 genome assembly). Each gene was tiled by 34 probes, on average, spanning upstream regions from –2000 to +1360 bp relative to the transcription start site. This microarray was hybridized with MeDIP samples from livers of normal Holstein animals obtained by AI (4 perinatal controls and 8 adults: 2 males and 10 females) and livers of female Holstein clones (7 perinatal clones from 2 different genotypes, either stillborn or suffering from severe pathologies, and 7 adult clones from 3 different genotypes, with normal to pathological phenotypes). After normalization of the data, enriched probes were identified using the ChIPmix method (Martin-Magniette et al. 2008 Bioinformatics) and located on the Ensembl Genome Browser. Results of exploratory analysis, including correlation clustering, principal components analysis (PCA), and independent components analysis (ICA), will be presented. A statistical test based on differences in the spatial distribution of the enriched probes along promoters was applied to the data, to associate epigenetic signatures to specific parameters (cloning, phenotype, stage, and genotype). Most promoters with more than 5 enriched probes across individuals showed a clustered distribution of the enriched probes. This local enrichment was highly conserved among individuals for 96% of the promoters, suggesting that most of the methylated regions were common to all animals. More interestingly, the distributions of the enriched probes showed inter-individual variability for 4% of the promoters in all samples. The identification and validation of these promoters is currently in progress

Cloning disrupts the methylation signatures associated to age in cattle

Reprogramming the differentiated cell to totipotency can be obtained following the introduction of its nucleus into an enucleated oocyte, a procedure known as cloning. We are using cattle clones as a model to assess the inter-individual epigenetic variability and its consequences on phenotypes, including agronomical relevant traits and developmental pathologies. Indeed, the developmental defects frequently associated with cloning could be related to the insufficient extent of reprogramming, leading to perturbations of the nuclear microenvironment of the early embryo with long term consequences. To identify epigenomic patterns affected by incomplete reprogramming, we used immunoprecipitation of methylated DNA followed by hybridization on a new bovine promoter microarray (MeDIP-chip). The microarray targets the upstream region (-2000 to +1360bp) of 21416 genes (UMD3.1 assembly). We first focused on liver, because overgrowth of this organ is often observed in clones. The microarray has been hybridized with MeDIP samples from livers of normal Holstein animals (4 perinatal controls and 8 adults, obtained by artificial insemination and all healthy) and livers of Holstein clones (7 perinatal clones, either stillborn or suffering from severe pathologies, and 7 adult clones, with normal to pathological phenotypes). After normalization of the data, enriched probes were identified using ChIPmix (Martin-Magniette et al., 2008). Results of exploratory analysis, including correlation clustering, Principal Component Analysis (PCA) and Independent Component Analysis (ICA), will be presented. A statistical test based on differences in the spatial distribution of the enriched probes was used to identify Differentially Methylated Regions (DMR) related to age and cloning. In age-related DMR, we show that cloning erases the methylation signatures associated to age. Conversely, analysis of cloning-related DMR revealed that bovine clones behave like adults independently of their age

MR, 18F-FDG, and 18F-AV45 PET Correlate With AD PSEN1 Original Phenotype.

International audienceWe report the case of a 37-year-old man suffering from insidious visual agnosia and spastic paraparesis due to a PSEN1 mutation. His mother was diagnosed with Alzheimer disease after a biopsy. He was assessed by multimodal neuroimaging, including new in vivo positron emission tomography amyloid imaging (F-AV45). His data were compared with those from healthy participants and patients with sporadic predemential Alzheimer disease. He exhibited posterior cortical thickness reduction, posterior hypometabolism, and increased amyloid ligand uptake in the posterior cortex and the striatum. We show that F-AV45 positron emission tomography allows visualization of the unusual pattern of amyloid deposits that co-localize with cortical atrophy in this genetic form of Alzheimer disease

Conséquences tardives de perturbations épigénétiques précoces : exemple des clones bovins

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Conséquences tardives de perturbations épigénétiques précoces : exemple des clones bovins

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