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

Isolation and Evaluation of the Enantiospecific Antitubercular Activity of a Novel Triazole Compound

Cyclohex-3-enyl(5-phenyl-4H-1,2,4-triazol-3-yl)methanol (MSDRT 12) is a novel triazole-based antitubercular compound with two chiral centers. To evaluate the enantiospecific antitubercular activity, the four stereoisomers were isolated using preparative chiral chromatography and the individual stereoisomers were evaluated using the resazurin microtiter assay method (REMA) and a microbroth dilution technique against the Mycobacterium tuberculosis H37Rv strain. Isomer III of MSDRT 12 was found to be the most potent with a minimum inhibitory concentration (MIC) of 0.78 μg/mL, Isomer II had a MIC of 12.5 μg/mL, and isomers I and IV showed no activity. The diastereomeric mixture of MSDRT 12 showed a MIC of 3.125 μg/mL and isoniazid, used as the standard drug, showed a MIC of 0.4 μg/mL. This confirms the necessity of screening individual enantiomers for their pharmacological activity early in the discovery phase to identify the most potent isomer for further development efforts

Dynamic adsorption of DMMP over synthetic zeolite-Alpha

AbstractZeolite-Alpha was synthesized under hydrothermal and static conditions and was characterized by N2 BET surface area, XRD, SEM–EDAX analysis, NH3-TPD and FTIR. The dynamic adsorption experiments were carried out on a TPD plus Chemisorption system (Micrometrics ASAP 2920 unit). Adsorption was found to be high initially and it then decreases with an increase in the injected volume. It was found that adsorption increases with an increase in contact time between DMMP and zeolite-Alpha only up to 8h after which it remains almost constant. Desorption pattern was analyzed which shows two types of peaks, sharp peak with onset temperature of around 30°C which represents desorption of physisorbed DMMP and a broad peak with the onset temperature of around 110°C which represents the desorption of strongly chemisorbed DMMP

C3G Regulates STAT3, ERK, Adhesion Signaling, and Is Essential for Differentiation of Embryonic Stem Cells

SummaryC3G (RAPGEF1), engaged in multiple signaling pathways, is essential for the early development of the mouse. In this study, we have examined its role in mouse embryonic stem cell self-renewal and differentiation. C3G null cells generated by CRISPR mediated knock-in of a targeting vector exhibited enhanced clonogenicity and long-term self-renewal. They did not differentiate in response to LIF withdrawal when compared to the wild type ES cells and were defective for lineage commitment upon teratoma formation in vivo. Gene expression analysis of C3G KO cells showed misregulated expression of a large number of genes compared with WT cells. They express higher levels of self-renewal factors like KLF4 and ESRRB and show high STAT3 activity, and very low ERK activity compared to WT cells. Reintroduction of C3G expression in a KO line partially reverted expression of ESRRB, and KLF4, and ERK activity similar to that seen in WT cells. The expression of self-renewal factors was persistent for a longer time, and induction of lineage-specific markers was not seen when C3G KO cells were induced to form embryoid bodies. C3G KO cells showed poor adhesion and significantly reduced levels of pFAK, pPaxillin, and Integrin-β1, in addition to downregulation of the cluster of genes involved in cell adhesion, compared to WT cells. Our results show that C3G is essential for the regulation of STAT3, ERK, and adhesion signaling, to maintain pluripotency of mouse embryonic stem cells and enable their lineage commitment for differentiation. Graphical abstract</jats:p