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

A search for loci contributing to acquisition of peak bone mass

Background: Low peak bone mass is an important risk factor for osteoporotic fracture. Despite heritability of 50-85%, genetic studies have failed to identify a significant susceptibility locus. With advances in genotyping technologies, a genome-wide association (GWA) approach now allows an unbiased search for genetic determinants. Aim: To perform a GWA study using pooled DNA samples (as the cost of individual genotyping is prohibitive) to identify genetic loci associated with bone accrual in a cohort where all known confounding factors could be accounted for Methods: The Young Hearts 2000 Project carried out an in-depth survey of 1700 Northern Irish secondary school children. PIXI DXA scans of wrist and heel were performed and blood was collected. 1318 subjects had complete data available within separate age/sex groups: 12yr boys and girls, 15yr old boys and girls. BMD measurements were ranked after adjustments for age, BMI and pubertal status. Within each group, 50 subjects with the highest (controls) and 50 subjects with the lowest (cases) corrected BMD scores were selected giving a total of 400. DNA was extracted manually from stored buffy coat and pooled DNA was analysed using Illumina's HumanHap550 Genotyping BeadChip. The raw data for each SNP was compared between high and low BMD pools. Results: Clusters of SNPs that showed the greatest differences between high and low BMD pools were at Chr7 - GRM8, Chr8 - SGCZ, Chr15 - TRPM7 and Chr16 - TRAP1. These differences were confirmed on individual genotyping with p-values<0.05 for the SNPs within GRM8, SGCZ and TRAP 1. The SGCZ region showed the strongest association with BMD across the age groups. The TRAP 1 region was confirmed in replication pools. These genes each have described activity in bone and therefore are reasonable candidates for association with bone accrual and warrant further replication studies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo