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

T and B Cell Subsets Differentially Correlate with Amyloid Deposition and Neurocognitive Function in Patients with Amnestic Mild Cognitive Impairment After One Year of Physical Activity

Individuals with amnestic mild cognitive impairment (aMCI) experience cognitive declines in learning and memory greater than expected for normal aging, and are at a high risk of dementia. We previously reported that sedentary aMCI patients exhibited neuroinflammation that correlated with brain amyloid beta (Aβ) burden, as determined by 18F-florbetapir positron emission tomography (PET). These aMCI patients enrolled in a one-year randomized control trial (AETMCI, NCT01146717) to test the beneficial effects of 12 months of moderate-to-high intensity aerobic exercise training (AET) or stretching/toning (ST) control intervention on neurocognitive function. A subset of aMCI participants had PET imaging, cognitive testing, and immunophenotyping of cerebrospinal fluid (CSF) and peripheral blood after AET or ST interventions. As adaptive immune responses were similar between AET and ST groups, we combined AET/ST into a general \u27physical activity\u27 (PA) group and compared Aβ burden, cognitive function, and adaptive immune cell subsets to sedentary lifestyle before intervention. We found that PAinduced immunomodulation of CD4+ and CD8+ T cells in CSF correlated with changes in Aβ burden in brain regions associated with executive function. Furthermore, after PA, cognitive scores on tests of memory, processing speed, attention, verbal fluency, and executive function were associated with increased percent representation of circulating naïve B cells and CD8+ T cells. We review the literature on aMCI-related cognition and immune changes as they relate to exercise, and highlight how our preliminary data suggest a complex interplay between the adaptive immune system, physical activity, cognition, and Aβ burden in aMCI

Complete Genome Sequences of 44 Arthrobacter

This article reports the complete genome sequences of 44 phages infecting Arthrobacter sp. strain ATCC 21022

Tales of diversity: Genomic and morphological characteristics of forty-six <i>Arthrobacter</i> phages

<div><p>The vast bacteriophage population harbors an immense reservoir of genetic information. Almost 2000 phage genomes have been sequenced from phages infecting hosts in the phylum Actinobacteria, and analysis of these genomes reveals substantial diversity, pervasive mosaicism, and novel mechanisms for phage replication and lysogeny. Here, we describe the isolation and genomic characterization of 46 phages from environmental samples at various geographic locations in the U.S. infecting a single <i>Arthrobacter</i> sp. strain. These phages include representatives of all three virion morphologies, and Jasmine is the first sequenced podovirus of an actinobacterial host. The phages also span considerable sequence diversity, and can be grouped into 10 clusters according to their nucleotide diversity, and two singletons each with no close relatives. However, the clusters/singletons appear to be genomically well separated from each other, and relatively few genes are shared between clusters. Genome size varies from among the smallest of siphoviral phages (15,319 bp) to over 70 kbp, and G+C contents range from 45–68%, compared to 63.4% for the host genome. Although temperate phages are common among other actinobacterial hosts, these <i>Arthrobacter</i> phages are primarily lytic, and only the singleton Galaxy is likely temperate.</p></div

Genome organization of <i>Arthrobacter</i> phage Laroye, Cluster AL.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p

Genome organization of <i>Arthrobacter</i> phage Gordon, Cluster AU.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p

Genome organization of <i>Arthrobacter</i> phage Amigo, Cluster AQ.

<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0180517#pone.0180517.g005" target="_blank">Fig 5</a> for details.</p