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

Cerebrovascular assessment of patients undergoing shoulder surgery in beach chair position using a multiparameter transcranial Doppler approach.

Although the beach-chair position (BCP) is widely used during shoulder surgery, it has been reported to associate with a reduction in cerebral blood flow, oxygenation, and risk of brain ischaemia. We assessed cerebral haemodynamics using a multiparameter transcranial Doppler-derived approach in patients undergoing shoulder surgery. 23 anaesthetised patients (propofol (2 mg/kg)) without history of neurologic pathology undergoing elective shoulder surgery were included. Arterial blood pressure (ABP, monitored with a finger-cuff plethysmograph calibrated at the auditory meatus level) and cerebral blood flow velocity (FV, monitored in the middle cerebral artery) were recorded in supine and in BCP. All subjects underwent interscalene block ipsilateral to the side of FV measurement. We evaluated non-invasive intracranial pressure (nICP) and cerebral perfusion pressure (nCPP) calculated with a black-box mathematical model; critical closing pressure (CrCP); diastolic closing margin (DCM-pressure reserve available to avoid diastolic flow cessation); cerebral autoregulation index (Mxa); pulsatility index (PI). Significant changes occured for DCM [mean decrease of 6.43 mm Hg (p = 0.01)] and PI [mean increase of 0.11 (p = 0.05)]. ABP, FV, nICP, nCPP and CrCP showed a decreasing trend. Cerebral autoregulation was dysfunctional (Mxa > 0.3) and PI deviated from normal ranges (PI > 0.8) in both phases. ABP and nCPP values were low (< 60 mm Hg) in both phases. Changes between phases did not result in CrCP reaching diastolic ABP, therefore DCM did not reach critical values (≤ 0 mm Hg). BCP resulted in significant cerebral haemodynamic changes. If left untreated, reduction in cerebral blood flow may result in brain ischaemia and post-operative neurologic deficit.ICM+ software is licensed by the University of Cambridge, Cambridge Enterprise Ltd. MC and PS have a financial interest in a part of its licensing fee. The procedure of non-invasive ICP assessment is distributed as a plug-in for ICM+ monitoring software. BS and MC have financial interest in its licensing fee. The remaining authors declare no conflict of interest. Cambridge Commonwealth, European & International Trust Scholarship, University of Cambridge provided financial support in the form of Scholarship funding for DC. Woolf Fisher Trust provided financial support in the form of Scholarship funding for JD. NIHR Brain Injury Healthcare Technology Co-operative, Cambridge, UK, provided financial support in the form of equipment funding for DC and MC. The sponsors had no role in the design or conduct of this manuscript

The genomic and phenotypic diversity of Schizosaccharomyces pombe.

Natural variation within species reveals aspects of genome evolution and function. The fission yeast Schizosaccharomyces pombe is an important model for eukaryotic biology, but researchers typically use one standard laboratory strain. To extend the usefulness of this model, we surveyed the genomic and phenotypic variation in 161 natural isolates. We sequenced the genomes of all strains, finding moderate genetic diversity (π = 3 × 10(-3) substitutions/site) and weak global population structure. We estimate that dispersal of S. pombe began during human antiquity (∼340 BCE), and ancestors of these strains reached the Americas at ∼1623 CE. We quantified 74 traits, finding substantial heritable phenotypic diversity. We conducted 223 genome-wide association studies, with 89 traits showing at least one association. The most significant variant for each trait explained 22% of the phenotypic variance on average, with indels having larger effects than SNPs. This analysis represents a rich resource to examine genotype-phenotype relationships in a tractable model

Genomic reconstruction of the SARS-CoV-2 epidemic in England

AbstractThe evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus leads to new variants that warrant timely epidemiological characterization. Here we use the dense genomic surveillance data generated by the COVID-19 Genomics UK Consortium to reconstruct the dynamics of 71 different lineages in each of 315 English local authorities between September 2020 and June 2021. This analysis reveals a series of subepidemics that peaked in early autumn 2020, followed by a jump in transmissibility of the B.1.1.7/Alpha lineage. The Alpha variant grew when other lineages declined during the second national lockdown and regionally tiered restrictions between November and December 2020. A third more stringent national lockdown suppressed the Alpha variant and eliminated nearly all other lineages in early 2021. Yet a series of variants (most of which contained the spike E484K mutation) defied these trends and persisted at moderately increasing proportions. However, by accounting for sustained introductions, we found that the transmissibility of these variants is unlikely to have exceeded the transmissibility of the Alpha variant. Finally, B.1.617.2/Delta was repeatedly introduced in England and grew rapidly in early summer 2021, constituting approximately 98% of sampled SARS-CoV-2 genomes on 26 June 2021.</jats:p

Maternal and neonatal outcomes after caesarean delivery in the African Surgical Outcomes Study: a 7-day prospective observational cohort study.

BACKGROUND: Maternal and neonatal mortality is high in Africa, but few large, prospective studies have been done to investigate the risk factors associated with these poor maternal and neonatal outcomes. METHODS: A 7-day, international, prospective, observational cohort study was done in patients having caesarean delivery in 183 hospitals across 22 countries in Africa. The inclusion criteria were all consecutive patients (aged ≥18 years) admitted to participating centres having elective and non-elective caesarean delivery during the 7-day study cohort period. To ensure a representative sample, each hospital had to provide data for 90% of the eligible patients during the recruitment week. The primary outcome was in-hospital maternal mortality and complications, which were assessed by local investigators. The study was registered on the South African National Health Research Database, number KZ_2015RP7_22, and on ClinicalTrials.gov, number NCT03044899. FINDINGS: Between February, 2016, and May, 2016, 3792 patients were recruited from hospitals across Africa. 3685 were included in the postoperative complications analysis (107 missing data) and 3684 were included in the maternal mortality analysis (108 missing data). These hospitals had a combined number of specialist surgeons, obstetricians, and anaesthetists totalling 0·7 per 100 000 population (IQR 0·2-2·0). Maternal mortality was 20 (0·5%) of 3684 patients (95% CI 0·3-0·8). Complications occurred in 633 (17·4%) of 3636 mothers (16·2-18·6), which were predominantly severe intraoperative and postoperative bleeding (136 [3·8%] of 3612 mothers). Maternal mortality was independently associated with a preoperative presentation of placenta praevia, placental abruption, ruptured uterus, antepartum haemorrhage (odds ratio 4·47 [95% CI 1·46-13·65]), and perioperative severe obstetric haemorrhage (5·87 [1·99-17·34]) or anaesthesia complications (11·47 (1·20-109·20]). Neonatal mortality was 153 (4·4%) of 3506 infants (95% CI 3·7-5·0). INTERPRETATION: Maternal mortality after caesarean delivery in Africa is 50 times higher than that of high-income countries and is driven by peripartum haemorrhage and anaesthesia complications. Neonatal mortality is double the global average. Early identification and appropriate management of mothers at risk of peripartum haemorrhage might improve maternal and neonatal outcomes in Africa. FUNDING: Medical Research Council of South Africa.Medical Research Council of South Africa

The ASOS Surgical Risk Calculator: development and validation of a tool for identifying African surgical patients at risk of severe postoperative complications

Background: The African Surgical Outcomes Study (ASOS) showed that surgical patients in Africa have a mortality twice the global average. Existing risk assessment tools are not valid for use in this population because the pattern of risk for poor outcomes differs from high-income countries. The objective of this study was to derive and validate a simple, preoperative risk stratification tool to identify African surgical patients at risk for in-hospital postoperative mortality and severe complications. Methods: ASOS was a 7-day prospective cohort study of adult patients undergoing surgery in Africa. The ASOS Surgical Risk Calculator was constructed with a multivariable logistic regression model for the outcome of in-hospital mortality and severe postoperative complications. The following preoperative risk factors were entered into the model; age, sex, smoking status, ASA physical status, preoperative chronic comorbid conditions, indication for surgery, urgency, severity, and type of surgery. Results: The model was derived from 8799 patients from 168 African hospitals. The composite outcome of severe postoperative complications and death occurred in 423/8799 (4.8%) patients. The ASOS Surgical Risk Calculator includes the following risk factors: age, ASA physical status, indication for surgery, urgency, severity, and type of surgery. The model showed good discrimination with an area under the receiver operating characteristic curve of 0.805 and good calibration with c-statistic corrected for optimism of 0.784. Conclusions: This simple preoperative risk calculator could be used to identify high-risk surgical patients in African hospitals and facilitate increased postoperative surveillance. © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.Medical Research Council of South Africa gran