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

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

The Role of Arthroscopy After Total Ankle Replacement.

Alongside advances and trends in foot and ankle surgery, arthroscopy provides a minimally invasive option in exploring and addressing pain after total ankle replacement (TAR). It is not uncommon for patients to develop pain months or even years after TAR implantation for both fixed and mobile-bearing designs. Arthroscopic debridement of gutter pain can provide successful outcomes in the hands of the experienced arthroscopist. Surgeon preference and experience will dictate the threshold for intervention, approach, and tool selection. This article provides a brief look into the background, indications, technique, limitations, and outcomes for arthroscopy after TAR

Time to Revision After Periprosthetic Joint Infection in Total Ankle Arthroplasty: A Systematic Review.

While not a common complication after total ankle arthroplasty (TAA), periprosthetic joint infection (PJI) presents a significant risk of implant failure. The primary aim of this systematic review was to evaluate time to revision after PJI in patients who had undergone TAA. An extensive search strategy via electronic databases initially captured 11,608 citations that were evaluated for relevance. Ultimately, 12 unique articles studying 3040 implants met inclusion criteria. The time to revision surgery due to PJI was recorded for each study and a weighted average obtained. The prevalence of PJI was 1.12% (n = 34). We found that the average time to revision due to PJI was 30.7 months, or approximately 2.6 years after the index TAA procedure. By literature definitions, the majority of cases (91.2%, n = 31) were beyond the acute PJI phase. The population was divided into 2 groups for further analysis of chronic infections. PJIs before the median were classified as early and those after as late chronic. The majority of cases (61.8%) were late chronic with an average time to revision of 44.3 months. A smaller number were early chronic (29.4%) with revision within 10.8 months. After summarizing the rates of infection and times to revision reported in the literature, we suggest modifying the current PJI classification to include early chronic and late chronic subgroups so that the total ankle surgeon is better prepared to prudently diagnose and treat PJIs

Association analysis of DAOA and DAO in bipolar disorder: results from two independent case-control studies

Darya Gaysina, Sarah Cohen-Woods, Philip C. Chow, Livia Martucci, Alexandra Schosser, Harriet A. Ball, Federica Tozzi, Julia Perry, Pierandrea Muglia, James L. Kennedy, Nicole King, John B. Vincent, Sagar V. Parikh, John Strauss, Ian W. Craig, Peter McGuffin and Anne Farme

Pharmacokinetics and Pharmacodynamics of Omarigliptin, a Once-weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, after Single and Multiple Doses in Healthy Subjects

Abstract The pharmacokinetics (PK), and pharmacodynamics (PD) of omarigliptin, a novel once-weekly DPP-4 inhibitor, were assessed following single and multiple doses in healthy subjects. Absorption was rapid and food did not influence single dose PK. Accumulation was minimal and steady state was reached after 2-3 weeks. Weekly AUC and Cmax displayed dose proportionality within the dose range studied at steady state. The average renal clearance of omarigliptin was ~2 L/h. DPP-4 inhibition ranged from ~77-89% at 168 hours following the last of 3 once-weekly doses over the dose range studied. Omarigliptin resulted in ~2-fold increases in weighted average post-prandial active GLP-1. Omarigliptin acts by stabilizing active GLP-1, which is consistent with its mechanism of action as a DPP-4 inhibitor. Administration of omarigliptin was generally well tolerated in healthy subjects, and both the PK and PD profile support once-weekly dosing. A model-based assessment of QTc interval risk from the single ascending dose study indicated low risk of QTc prolongation within the likely clinical dose rangestatus: publishe