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

Surveillance versus ablation for incidentally diagnosed small renal tumours: the SURAB feasibility RCT

Background: There is uncertainty around the appropriate management of small renal tumours. Treatments include partial nephrectomy, ablation and active surveillance. Objectives: To explore the feasibility of a randomised trial of ablation versus active surveillance. Design: Two-stage feasibility study: stage 1 – clinician survey and co-design work; and stage 2 – randomised feasibility study with qualitative and economic components. Methods: Stage 1 – survey of radiologists and urologists, and development of patient information materials. Stage 2 – patients identified across eight UK centres with small renal tumours (< 4 cm) were randomised (1 : 1 ratio) to ablation or active surveillance in an unblinded manner. Randomisation was carried out by a central computer system. The primary objective was to determine willingness to participate and to randomise a target of 60 patients. The qualitative and economic data were collected separately. Results: The trial was conducted across eight centres, with a site-specific period of recruitment ranging from 3 to 11 months. Of the 154 patients screened, 36 were eligible and were provided with study details. Seven agreed to be randomised and one patient was found ineligible following biopsy results. Six patients (17% of those eligible) were randomised: three patients received ablation and no serious adverse events were recorded. The 3- and 6-month data were collected for four (67%) and three (50%) out of the six patients, respectively. The qualitative substudy identified factors directly impacting on the recruitment of this trial. These included patient and clinician preferences, organisational factors (variation in clinical pathway) and standard treatment not included. The health economic questionnaire was designed and piloted; however, the sample size of recruited patients was insufficient to draw a conclusion on the feasibility of the health economics. Conclusions: The trial did not meet the criteria for progression and the recruitment rate was lower than hypothesised, demonstrating that a full trial is presently not possible. The qualitative study identified factors that led to variation in recruitment across the sites. Implementation of organisational and operational measures can increase recruitment in any future trial. There was insufficient information to conduct a full economic analysis. Trial registration: Current Controlled Trials ISRCTN31161700. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 81. See the NIHR Journals Library website for further project information

THREE INTERESTING CASES OF GALL STONE ILEUS WITH SPECIAL REFERENCE TO ITS MECHANISM IN THE FORMATION OF A CHOLEDOCHAL-DUODENAL COMMUNICATION

<div><p>We use a spatially explicit biogeochemical end-to-end ecosystem model, Atlantis, to simulate impacts from the Deepwater Horizon oil spill and subsequent recovery of fish guilds. Dose-response relationships with expected oil concentrations were utilized to estimate the impact on fish growth and mortality rates. We also examine the effects of fisheries closures and impacts on recruitment. We validate predictions of the model by comparing population trends and age structure before and after the oil spill with fisheries independent data. The model suggests that recruitment effects and fishery closures had little influence on biomass dynamics. However, at the assumed level of oil concentrations and toxicity, impacts on fish mortality and growth rates were large and commensurate with observations. Sensitivity analysis suggests the biomass of large reef fish decreased by 25% to 50% in areas most affected by the spill, and biomass of large demersal fish decreased even more, by 40% to 70%. Impacts on reef and demersal forage caused starvation mortality in predators and increased reliance on pelagic forage. Impacts on the food web translated effects of the spill far away from the oiled area. Effects on age structure suggest possible delayed impacts on fishery yields. Recovery of high-turnover populations generally is predicted to occur within 10 years, but some slower-growing populations may take 30+ years to fully recover.</p></div

Impacts of the Deepwater Horizon Oil Spill Evaluated Using an End-to-End Ecosystem Model

We use a spatially explicit biogeochemical end-to-end ecosystem model, Atlantis, to simulate impacts from the Deepwater Horizon oil spill and subsequent recovery of fish guilds. Dose-response relationships with expected oil concentrations were utilized to estimate the impact on fish growth and mortality rates. We also examine the effects of fisheries closures and impacts on recruitment. We validate predictions of the model by comparing population trends and age structure before and after the oil spill with fisheries independent data. The model suggests that recruitment effects and fishery closures had little influence on biomass dynamics. However, at the assumed level of oil concentrations and toxicity, impacts on fish mortality and growth rates were large and commensurate with observations. Sensitivity analysis suggests the biomass of large reef fish decreased by 25% to 50% in areas most affected by the spill, and biomass of large demersal fish decreased even more, by 40% to 70%. Impacts on reef and demersal forage caused starvation mortality in predators and increased reliance on pelagic forage. Impacts on the food web translated effects of the spill far away from the oiled area. Effects on age structure suggest possible delayed impacts on fishery yields. Recovery of high-turnover populations generally is predicted to occur within 10 years, but some slower-growing populations may take 30+ years to fully recover

Atlantis polygon geometry.

<p>Shaded polygons: heavily impacted areas, asterisk: site of oil spill, triangles: reef survey sites.</p

Absolute biomass reduction for no oil versus oil scenario for grouper guild.

<p>Biomass minima is shown occurring at 10 months after the oil spill. Oil simulation [K1000 <i>β</i>363].</p

Condition factor of grouper guild.

<p>Condition factor is represented as reserve:structural Nitrogen ratio. High rN/sN indicates good body condition. Dotted line: no oil scenario, solid line: oiled [K1000 <i>β</i>363].</p