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

Acute Blood Pressure and Outcome After Intracerebral Hemorrhage: The VISTA-ICH Cohort

BACKGROUND: Recent clinical trials suggest that it is safe to acutely lower systolic blood pressure (BP) to 140 mm Hg after ICH, but uncertainty remains regarding optimal management. We sought to better define the link between BP and outcome in ICH patients using data from the Virtual International Stroke Trials Archive (VISTA). METHODS: We performed a retrospective analysis of patients of the VISTA-ICH trials. We measured the strength of association between systolic and diastolic BP various components at different timepoints with unfavorable 3 month-outcome, defined as death or moderate-to-severe disability at 3 months (mRS of 4-6), after adjustment for known confounders. We also dichotomized BP values obtained at 24 h at different thresholds to better define an optimal treatment target. The association of BP with hematoma expansion (HE) was also analyzed. RESULTS: A total of 384 patients were included. Higher BP at 24 hours was associated with unfavorable outcome for systolic BP (OR 1.16, 95% C.I. 1.07-1.25), pulse pressure (OR 1.13, 95% C.I. 1.03-1.24), and diastolic BP (OR 1.11, 95% C.I. 1.01-1.23) per 10 mm Hg increment. The association between higher BP at 24 h and unfavorable outcome remained significant down to \u3e140 mm Hg. Elevated systolic BP at 24 h was also associated with HE (OR 1.11, 95% C.I. 1.02-1.21 per 10 mm Hg increment). CONCLUSION: Elevated BP after ICH at 24 h is associated with poor outcome. Our results support the practice of targeting a systolic BP of 140 mm Hg

Surface Cooling System for Fever Control in Neurocritical Care Patients: A Pilot Study

OBJECTIVES: Fever occurs in up to 50% of critically-ill patients with acute neurological injury. Small temperature elevations have been correlated with increased morbidity and mortality in this patient population. We sought to evaluate a novel single-use surface cooling system for the treatment of fever in patients with acute brain injury. PATIENTS AND METHODS: We conducted a retrospective analysis of a prospective product evaluation using the EMCOOLS Flex.Pad™ system for acute fever (≥38.3 °C) in our 16-bed neuro-ICU. Four refrigerated pads (-18 °C) were applied to the chest, back, and anterior thighs. Core temperature (bladder) was continuously recorded over 4 h, and the highest Bedside Shivering Assessment Scale (BSAS) score was recorded hourly. RESULTS: Twelve subjects were included in the analysis. Mean age was 55 ± 9 years, 9 patients were men, and mean weight was 85 ± 12 kg. The most common primary diagnoses were subarachnoid (N = 5) and intracerebral (N = 4) hemorrhage. Application of the EMCOOLS system resulted in a linear 1.3 ± 0.6 °C drop (T0avg=38.9 (0)C, T90avg=37.6 (0)C, P=0.0032) in mean temperature over 90min, followed by a plateau with only one subject rebounding to \u3e38 degrees C within 4h. Normothermia (\u3c38.0 (0)C) was achieved in all but one patient (92%) in an average of 65min. Comatose patients displayed a non-significantly higher degree of cooling at 90min than did awake subjects (DeltaTcoma=1.74 degrees C vs DeltaTawake=0.74 degrees C hr(-1), P=0.067). There was no observed skin irritation upon removal of the device for any patients. CONCLUSION: The EMCOOLs system is a well-tolerated, safe and effective short-term intervention for control of fever in neurological patients. Future studies are needed to compare efficacy of the EMCOOLs to other devices and interventions

Desmopressin administration and rebleeding in subarachnoid hemorrhage: analysis of an observational prospective database

OBJECTIVE Rebleeding remains a frequent and catastrophic event leading to poor outcome after subarachnoid hemorrhage (SAH). Reduced platelet function after the initial bleed is associated with higher risk of early rebleeding. Desmopressin (DDAVP) is a well-known hemostatic agent, and recent guidelines already suggest its use in individuals exposed to antiplatelet drugs. The authors hypothesized that DDAVP administration in patients with SAH at admission would be associated with lower risks of rebleeding.METHODSThe authors performed an observational cohort study of patients enrolled in the Columbia University SAH Outcome Project between August 1996 and July 2015. The authors compared the rate of rebleeding between patients who were and those who were not treated with DDAVP. After adjustment for known predictors, logistic regression was used to measure the association between treatment with DDAVP and risks of rebleeding.RESULTSAmong 1639 patients with SAH, 12% were treated with DDAVP. The main indication for treatment was suspected exposure to an antiplatelet agent. The overall incidence of rebleeding was 9% (1% among patients treated with DDAVP compared with 8% among those not treated). After adjustment for antiplatelet use and known predictors, treatment with DDAVP was associated with a 45% reduction in the risks of rebleeding (adjusted OR 0.55, 95% CI 0.27-0.97). DDAVP was associated with a higher incidence of hyponatremia but not with thrombotic events or delayed cerebral ischemia.CONCLUSIONSTreatment with DDAVP was associated with a lower risk of rebleeding among patients with SAH. These findings support further study of DDAVP as first-line therapy for medical hemostasis in patients with SAH

Representações digitais e interação incorporada: um estudo etnográfico de práticas científicas de modelagem computacional

O objetivo deste trabalho é discutir como objetos virtuais participam interativamente da produção do conhecimento na prática científica. O artigo baseia-se numa observação etnográfica de uma equipe interdisciplinar de cientistas, cujo trabalho envolve modelagem computacional de transferência de calor na próstata humana. A etnografia constatou que, embora visualizações científicas sejam pensadas como uma forma de "simplificar" a apreensão de dados, há um intenso trabalho interpretativo necessário para alcançar sentidos compartilhados a respeito das imagens. Tais sentidos são construídos a partir de comunicação oral e de interações incorporadas com objetos virtuais no decorrer das interações entre os cientistas. Uma melhor compreensão dessas práticas interpretativas é importante na medida em que o uso de visualizações digitais em 3D e de modelos computacionais ganha importância na ciência contemporânea. Tais técnicas são crescentemente utilizadas não somente para descrever verdades sobre a natureza, mas como ferramentas poderosas de intervenção no mundo.<br>This text discusses how virtual objects participate interactively in the production of knowledge in scientific practice. The article is based on the ethnographic observation of an interdisciplinary team of scientists whose work involves computer modelling of heat transfer in the human prostate. The ethnography found that although scientific imaging may be considered a form of 'simplifying' the apprehension of data, an intense interpretative process is required to achieve shared meanings concerning the images. These meanings are constructed through oral communication and embodied interactions with virtual objects during the interactions between scientists. A better understanding of these interpretative practices is needed given the growing importance of the use of 3D digital imaging and computational models in contemporary science. These techniques are increasingly used not only to describe truths about nature, but also as powerful tools for intervening in the world

Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: Beyond Vasospasm and Towards a Multifactorial Pathophysiology

PURPOSE OF REVIEW: Delayed cerebral ischemia (DCI) is common after subarachnoid hemorrhage (SAH) and represents a significant cause of poor functional outcome. DCI was mainly thought to be caused by cerebral vasospasm; however, recent clinical trials have been unable to confirm this hypothesis. Studies in humans and animal models have since supported the notion of a multifactorial pathophysiology of DCI. This review summarizes some of the main mechanisms under investigation including cerebral vascular dysregulation, microthrombosis, cortical spreading depolarizations, and neuroinflammation. RECENT FINDINGS: Recent guidelines have differentiated between DCI and angiographic vasospasm and have highlighted roles of the microvasculature, coagulation and fibrinolytic systems, cortical spreading depressions, and the contribution of the immune system to DCI. Many therapeutic interventions are underway in both preclinical and clinical studies to target these novel mechanisms as well as studies connecting these mechanisms to one another. Summary: Clinical trials to date have been largely unsuccessful at preventing or treating DCI after SAH. The only successful pharmacologic intervention is the calcium channel antagonist, nimodipine. Recent studies have provided evidence that cerebral vasospasm is not the sole contributor to DCI and that additional mechanisms may play equal if not more important roles

Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions

© 2020, The Author(s). The availability of high-quality RNA-sequencing and genotyping data of post-mortem brain collections from consortia such as CommonMind Consortium (CMC) and the Accelerating Medicines Partnership for Alzheimer’s Disease (AMP-AD) Consortium enable the generation of a large-scale brain cis-eQTL meta-analysis. Here we generate cerebral cortical eQTL from 1433 samples available from four cohorts (identifying >4.1 million significant eQTL for >18,000 genes), as well as cerebellar eQTL from 261 samples (identifying 874,836 significant eQTL for >10,000 genes). We find substantially improved power in the meta-analysis over individual cohort analyses, particularly in comparison to the Genotype-Tissue Expression (GTEx) Project eQTL. Additionally, we observed differences in eQTL patterns between cerebral and cerebellar brain regions. We provide these brain eQTL as a resource for use by the research community. As a proof of principle for their utility, we apply a colocalization analysis to identify genes underlying the GWAS association peaks for schizophrenia and identify a potentially novel gene colocalization with lncRNA RP11-677M14.2 (posterior probability of colocalization 0.975)