Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant

Investigation of hospital discharge cases and SARS-CoV-2 introduction into Lothian care homes

Background The first epidemic wave of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in Scotland resulted in high case numbers and mortality in care homes. In Lothian, over one-third of care homes reported an outbreak, while there was limited testing of hospital patients discharged to care homes. Aim To investigate patients discharged from hospitals as a source of SARS-CoV-2 introduction into care homes during the first epidemic wave. Methods A clinical review was performed for all patients discharges from hospitals to care homes from 1st March 2020 to 31st May 2020. Episodes were ruled out based on coronavirus disease 2019 (COVID-19) test history, clinical assessment at discharge, whole-genome sequencing (WGS) data and an infectious period of 14 days. Clinical samples were processed for WGS, and consensus genomes generated were used for analysis using Cluster Investigation and Virus Epidemiological Tool software. Patient timelines were obtained using electronic hospital records. Findings In total, 787 patients discharged from hospitals to care homes were identified. Of these, 776 (99%) were ruled out for subsequent introduction of SARS-CoV-2 into care homes. However, for 10 episodes, the results were inconclusive as there was low genomic diversity in consensus genomes or no sequencing data were available. Only one discharge episode had a genomic, time and location link to positive cases during hospital admission, leading to 10 positive cases in their care home. Conclusion The majority of patients discharged from hospitals were ruled out for introduction of SARS-CoV-2 into care homes, highlighting the importance of screening all new admissions when faced with a novel emerging virus and no available vaccine

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

A geospatial dataset for U.S. hurricane storm surge and sea-level rise vulnerability: Development and case study applications

The consequences of future sea-level rise for coastal communities are a priority concern arising from anthropogenic climate change. Here, previously published methods are scaled up in order to undertake a first pass assessment of exposure to hurricane storm surge and sea-level rise for the U.S. Gulf of Mexico and Atlantic coasts. Sea-level rise scenarios ranging from +0.50 to +0.82 m by 2100 increased estimates of the area exposed to inundation by 4–13% and 7–20%, respectively, among different Saffir-Simpson hurricane intensity categories. Potential applications of these hazard layers for vulnerability assessment are demonstrated with two contrasting case studies: potential exposure of current energy infrastructure in the U.S. Southeast and exposure of current and future housing along both the Gulf and Atlantic Coasts. Estimates of the number of Southeast electricity generation facilities potentially exposed to hurricane storm surge ranged from 69 to 291 for category 1 and category 5 storms, respectively. Sea-level rise increased the number of exposed facilities by 6–60%, depending on the sea-level rise scenario and the intensity of the hurricane under consideration. Meanwhile, estimates of the number of housing units currently exposed to hurricane storm surge ranged from 4.1 to 9.4 million for category 1 and category 4 storms, respectively, while exposure for category 5 storms was estimated at 7.1 million due to the absence of landfalling category 5 hurricanes in the New England region. Housing exposure was projected to increase 83–230% by 2100 among different sea-level rise and housing scenarios, with the majority of this increase attributed to future housing development. These case studies highlight the utility of geospatial hazard information for national-scale coastal exposure or vulnerability assessment as well as the importance of future socioeconomic development in the assessment of coastal vulnerability

Automated Built-Up Infrastructure Land Cover Extraction Using Index Ensembles with Machine Learning, Automated Training Data, and Red Band Texture Layers

Automated built-up infrastructure classification is a global need for planning. However, individual indices have weaknesses, including spectral confusion with bare ground, and computational requirements for deep learning are intensive. We present a computationally lightweight method to classify built-up infrastructure. We use an ensemble of spectral indices and a novel red-band texture layer with global thresholds determined from 12 diverse sites (two seasonally varied images per site). Multiple spectral indexes were evaluated using Sentinel-2 imagery. Our texture metric uses the red band to separate built-up infrastructure from spectrally similar bare ground. Our evaluation produced global thresholds by evaluating ground truth points against a range of site-specific optimal index thresholds across the 24 images. These were used to classify an ensemble, and then spectral indexes, texture, and stratified random sampling guided training data selection. The training data fit a random forest classifier to create final binary maps. Validation found an average overall accuracy of 79.95% (±4%) and an F1 score of 0.5304 (±0.07). The inclusion of the texture metric improved overall accuracy by 14–21%. A comparison to site-specific thresholds and a deep learning-derived layer is provided. This automated built-up infrastructure mapping framework requires only public imagery to support time-sensitive land management workflows

Automated Training Data Generation from Spectral Indexes for Mapping Surface Water Extent with Sentinel-2 Satellite Imagery at 10 m and 20 m Resolutions

This study presents an automated methodology to generate training data for surface water mapping from a single Sentinel-2 granule at 10 m (4 band, VIS/NIR) or 20 m (9 band, VIS/NIR/SWIR) resolution without the need for ancillary training data layers. The 20 m method incorporates an ensemble of three spectral indexes with optimal band thresholds, whereas the 10 m method achieves similar results using fewer bands and a single spectral index. A spectrally balanced and randomly generated set of training data based on the index values and optimal thresholds is used to fit machine learning classifiers. Statistical validation compares the 20 m ensemble-only method to the 20 m ensemble method with a random forest classifier. Results show the 20 m ensemble-only method had an overall accuracy of 89.5% (±1.7%), whereas the ensemble method combined with the random forest classifier performed better, with a ~4.8% higher overall accuracy: 20 m method (94.3% (±1.3%)) with optimal spectral index and SWIR thresholds of −0.03 and 800, respectively, and 10 m method (93.4% (±1.5%)) with optimal spectral index and NIR thresholds of −0.01 and 800, respectively. Comparison of other supervised classifiers trained automatically with the framework typically resulted in less than 1% accuracy improvement compared with the random forest, suggesting that training data quality is more important than classifier type. This straightforward framework enables accurate surface water classification across diverse geographies, making it ideal for development into a decision support tool for water resource managers

Use of the posterior auricular artery for indirect bypass in moyamoya: A pediatric case series

Introduction:Encephaloduroarteriosynangiosis (EDAS) for moyamoya is predominantly performed using a branch of the superficial temporal artery (STA) as the donor artery. At times, other branches of the external carotid artery are better suited for EDAS than is the STA. There is little information in the literature concerning using the posterior auricular artery (PAA) for EDAS in the pediatric age-group. In this case series, we review our experience using the PAA for EDAS in children and adolescents. Case presentations:We describe the presentations, imaging, and outcomes of 3 patients in whom the PAA was used for EDAS, as well our surgical technique. There were no complications. All 3 patients were confirmed to have radiologic revascularization from their surgeries. All patients also had improvement of their preoperative symptoms, and no patient has had a stroke postoperatively. Conclusion:The PAA is a viable option for use as a donor artery in EDAS for the treatment of moyamoya in children and adolescents

Discovery of the 1-naphthylamine biodegradation pathway reveals a broad-substrate-spectrum enzyme catalyzing 1-naphthylamine glutamylation

1-Naphthylamine (1NA), which is harmful to human and aquatic animals, has been used widely in the manufacturing of dyes, pesticides, and rubber antioxidants. Nevertheless, little is known about its environmental behavior and no bacteria have been reported to use it as the growth substrate. Herein, we describe a pathway for 1NA degradation in the isolate Pseudomonas sp. strain JS3066, determine the structure and mechanism of the enzyme NpaA1 that catalyzes the initial reaction, and reveal how the pathway evolved. From genetic and enzymatic analysis, a five gene-cluster encoding a dioxygenase system was determined to be responsible for the initial steps in 1NA degradation through glutamylation of 1NA. The γ-glutamylated 1NA was subsequently oxidized to 1,2-dihydroxynaphthalene which was further degraded by the well-established pathway of naphthalene degradation via catechol. A glutamine synthetase-like (GS-like) enzyme (NpaA1) initiates 1NA glutamylation, and this enzyme exhibits a broad substrate selectivity toward a variety of anilines and naphthylamine derivatives. Structural analysis revealed that the aromatic residues in the 1NA entry tunnel and the V201 site in the large substrate-binding pocket significantly influence NpaA1’s substrate preferences. The findings enhance understanding of degrading polycyclic aromatic amines, and will also enable the application of bioremediation at naphthylamine contaminated sites

Proteomic Characterization of Yersinia pestis Virulence

The Yersinia pestis proteome was studied as a function of temperature and calcium by two-dimensional differential gel electrophoresis. Over 4,100 individual protein spots were detected, of which hundreds were differentially expressed. A total of 43 differentially expressed protein spots, representing 24 unique proteins, were identified by mass spectrometry. Differences in expression were observed for several virulence-associated factors, including catalase-peroxidase (KatY), murine toxin (Ymt), plasminogen activator (Pla), and F1 capsule antigen (Caf1), as well as several putative virulence factors and membrane-bound and metabolic proteins. Differentially expressed proteins not previously reported to contribute to virulence are candidates for more detailed mechanistic studies, representing potential new virulence determinants