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

Pilot of an advanced liver disease nurse education programme and its intersection with emerging models of advanced hepatology nursing practice

INTRODUCTION: Advanced liver disease (ALD) and liver cancer are a growing public health issue. Burdensome treatments for Hepatitis C once consumed nursing resources. However, as new treatments shift Hepatitis C care from specialist to generalist practice, hepatology nurses are freed to diversify their skills to meet the growing burden of ALD and liver cancer. Internationally, there are limited examples of hepatology education programmes to address and assess core ALD nurse capability. AIM: To explore acceptability and feasibility of a pilot ALD education and mentoring programme, and its impact on nurse capability and emerging models of advanced hepatology nurse practice. METHODS: Phase 1 surveyed nurses’ attitudes towards ALD training and identified learning needs. This informed curriculum and assessments comprising 9-months of formal hepatologist mentoring, face-to-face and online learning, hands-on skill development and clinical placement. Phase 2, through survey and interview, evaluated relevance of, and satisfaction with curriculum, nurse/hepatologist experience of mentorship, and local issues impacting course participation. In Phase 3, Schuler’s model of advanced practice guided semi-structured interviews with nurses and hepatologists, and descriptive, qualitative analysis was grounded in Fawcett’s nursing metaparadigm. RESULTS: There was great interest in the programme, it was rated highly acceptable, feasible and relevant to ALD practice. Under mentorship, nurses developed educational initiatives and local policies, and gave examples of nurse-led, patient-centered, holistic models of advanced ALD practice. Participants revealed the person with ALD as socially disadvantaged, with substance use disorders and communication challenges. Their health embodied complex body needs. Their environment lacked ALD services, particularly in rural/regional settings, heightening stigma and discrimination. Emerging models of ALD nursing practice responded by listening to the whole story, being non-judgmental, being a lynch pin and building networks and lines of referral. CONCLUSION: The programme was acceptable, feasible and effective in building capability for advanced nursing practice. Future work may confirm the impact of education and advanced practice on ALD service access and outcomes

Constitutional 11p15 abnormalities, including heritable imprinting center mutations, cause nonsyndromic Wilms tumor

Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor(1-3). We explored their possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor

Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus

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