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

Gastroduodenal ulceration in dogs with liver disease

Abstract Background Liver disease is frequently cited as a cause of gastroduodenal ulceration (GDU) in dogs but studies regarding GDU and liver disease are limited. Objectives To document the presence of GDU in dogs with liver disease. Animals Forty dogs that underwent liver biopsy, computed tomographic (CT) angiography or both at the University of Florida Small Animal Hospital to diagnose congenital or acquired liver disease. Methods Cross‐sectional study. Dogs had gastroduodenoscopy performed with photographic and video documentation in a standardized fashion. Lesions (hemorrhage, erosions, ulcers) in the esophagus, stomach, and duodenum were scored based on a grading scale. Presence of esophageal varices was recorded. Dogs were categorized into 4 groups according to cause of liver disease (inflammatory disease, cirrhosis, congenital, other). Presence or absence of ulcers, erosions or both as well as total endoscopic scores were compared among groups. Results Forty dogs were enrolled with the following distribution: 13 congenital, 13 inflammatory, 3 cirrhosis, and 11 other. Four dogs had GDU (10%; 95% confidence interval [CI], 3%‐24%) and 6 dogs had erosions (15%; 95% CI, 6%‐30%). No difference was found in total endoscopic score (P = .21) or in the proportion of dogs with ulcers, erosions or both versus those without (P = .25) among the groups. Conclusions and Clinical Importance Gastroduodenal ulceration was found in 10% of dogs with liver disease in this population. Additional studies are warranted to confirm these findings in larger numbers of dogs with specific disease etiologies

Deep red emitting heteroleptic Ir(III) complexes that incorporate unsymmetrical 4-quinoline carboxylic acid derived ligands

Six disubstituted ligands based upon 2-(2′-pyridinyl/pyrazinyl)quinoline-4-carboxylic acids have been synthesised, solvent-free, in one step from a range of commercially available isatin derivatives. These species behave as ancillary chelating ligands for Ir(III) complexes of the form [Ir(C^N)2(N^N)]PF6 (where C^N=cyclometalating ligand; N^N=2-(2′-pyridinyl/pyrazinyl)quinoline-4-carboxylic acids). An X-ray crystallographic study on one complex shows a distorted octahedral geometry wherein a cis-C,C and trans-N,N coordination mode is observed for the cyclometalating ligands. DFT calculations predicted that variations in N^N ligand from 2,2′-bipyridine to L1–6 should localise the LUMO on to the Ln ligand and that the complexes are predicted to display MLCT/LLCT character. All complexes displayed luminescence in the deep red part of the visible region (674–679 nm) and emit from triplet states, but with little apparent tuning as a function of L1–6. Further time-resolved transient absorption spectroscopy supports the participation of these triplet states to the excited state character.</p

Glomerular abnormalities in children undergoing orthotopic liver transplantation

A prospective study of renal function was undertaken on an unselected group of 8 children with chronic progressive liver disease on whom a renal biopsy was performed subsequently at the time of orthotopic liver transplantation. Two patients had abnormal urinalyses and 2 elevated urinary albumin/creatinine ratios. The remainder had no clinical evidence of renal dysfunction. All had normal serum creatinine concentrations. Glomerular abnormalities were present in all renal biopsies and were of two types: hepatic glomerulosclerosis (n = 5) and minor glomerular abnormalities (n = 3). IgM immunofluorescence was present in all biopsies and IgA in 6. Elevated serum immunoglobulin levels were observed in all patients, with IgM elevation in 6, IgA in 4 and IgG in 6. C3 and/or C4 were reduced in 5 patients and increased circulating immune complexes containing IgM were noted in 4. The clinical significance of these cirrhosis-associated glomerular abnormalities can only be established by long-term follow-up studies after orthotopic liver transplantation

Long-term (180-Day) outcomes in critically Ill patients with COVID-19 in the REMAP-CAP randomized clinical trial

Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months