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

Chronic pancreatitis: evaluation of pancreatic exocrine function with MR pancreatography after secretin stimulation.

PURPOSE: To compare duodenal filling seen at magnetic resonance (MR) pancreatography after secretin stimulation and biochemical parameters determined with the intraductal secretin test (IDST) for evaluation of pancreatic exocrine function. MATERIALS AND METHODS: MR pancreatography after secretin stimulation and IDST were performed in 41 patients with chronic pancreatitis (group 1) and eight patients with other pancreatic disease (group 2). A control group (group 3, n = 28) underwent MR pancreatography after secretin stimulation only. MR pancreatograms were acquired before and every 30 seconds for 10 minutes after secretin injection. Duodenal filling was graded from least amount of filling (grade 1) to normal filling (grade 3) on the last MR pancreatogram. Pancreatic exocrine function was determined at IDST. Main pancreatic ductal diameter was compared between groups 1 and 3. RESULTS: All ductal diameters were significantly larger in group 1 (P <.001). The maximal diameter variation after secretin stimulation was significantly higher in the control group (P =.001). Pancreatic exocrine function parameters determined at IDST were significantly lower in patients with grade 1 duodenal filling than in those with grade 2 or 3 (P <.05). Maximal bicarbonate concentration alone was independently associated with all grades of duodenal filling (P =.007). The sensitivity and specificity of reduced duodenal filling for assessment of reduced pancreatic exocrine function were 72% and 87%, respectively. CONCLUSION: Duodenal filling grade determined at MR pancreatography after secretin stimulation allows specific estimation of pancreatic exocrine function.Comparative StudyJournal Articleinfo:eu-repo/semantics/publishe

Traitement de l'hypertension portale. Recommandations. Club Francophone pour l'Etude de l'Hypertension Portale.

Journal ArticleReviewinfo:eu-repo/semantics/publishe

Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes.

International audienceA major challenge in transplantation medicine is controlling the very strong immune responses to foreign antigens that are responsible for graft rejection. Although immunosuppressive drugs efficiently inhibit acute graft rejection, a substantial proportion of patients suffer chronic rejection that ultimately leads to functional loss of the graft. Induction of immunological tolerance to transplants would avoid rejection and the need for lifelong treatment with immunosuppressive drugs. Tolerance to self-antigens is ensured naturally by several mechanisms; one major mechanism depends on the activity of regulatory T lymphocytes. Here we show that in mice treated with clinically acceptable levels of irradiation, regulatory CD4+CD25+Foxp3+ T cells stimulated in vitro with alloantigens induced long-term tolerance to bone marrow and subsequent skin and cardiac allografts. Regulatory T cells specific for directly presented donor antigens prevented only acute rejection, despite hematopoietic chimerism. By contrast, regulatory T cells specific for both directly and indirectly presented alloantigens prevented both acute and chronic rejection. Our findings demonstrate the potential of appropriately stimulated regulatory T cells for future cell-based therapeutic approaches to induce lifelong immunological tolerance to allogeneic transplants