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

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Space, property, and propriety in urban England

The public space in medieval towns and cities was shaped and influenced by the private spaces that surrounded it. The private was, like the public, a complex domain; many interests coexisted there. The pressures of population gowth and commercial development fragmented individual holdings and created overlapping layers of claims to particular spaces. Neighbors' interests also impinged; the enjoyment of the private was far from exclusive. Elaborate codes of property rights and legal procedures evolved as a fundamental part of urban custom. When the property market declined in the later Middle Ages, however, practices changed, and new ways of defining and describing private property emerged

Could a rabies incursion spread in the northern Australian dingo population? Development of a spatial stochastic simulation model.

Australia, home to the iconic dingo, is currently free from canine rabies. However northern Australia, including Indigenous communities with large free-roaming domestic dog populations, is at increased risk of rabies incursion from nearby Indonesia. We developed a novel agent-based stochastic spatial rabies spread model to evaluate the potential spread of rabies within the dingo population of the Northern Peninsula Area (NPA) region of northern Australia. The model incorporated spatio-temporal features specific to this host-environment system, including landscape heterogeneity, demographic fluctuations, dispersal movements and dingo ecological parameters-such as home range size and density-derived from NPA field studies. Rabies spread between dingo packs in nearly 60% of simulations. In such situations rabies would affect a median of 22 dingoes (approximately 14% of the population; 2.5-97.5 percentiles: 2-101 dingoes) within the study area which covered 1,131 km2, and spread 0.52 km/week for 191 days. Larger outbreaks occurred in scenarios in which an incursion was introduced during the dry season (vs. wet season), and close to communities (vs. areas with high risk of interaction between dingoes and hunting community dogs). Sensitivity analyses revealed that home range size and duration of infectious clinical period contributed most to the variance of outputs. Although conditions in the NPA would most likely not support a sustained propagation of the disease in the dingo population, due to the predicted number of infected dingoes following a rabies incursion and the proximity of Indigenous communities to dingo habitat, we conclude that the risk for human transmission could be substantial

Student Approaches and Performance in Element Sequencing Tasks Using 2D and Augmented Reality Formats

In civil and construction engineering education research, a focus has been on using 3D models to support students’ design comprehension. Despite this trend, the predominant mode of design communication in the industry relies on 2D plans and specifications, which typically supersede other modes of communication. Rather than focusing on the presentation of less common 3D content as an input to support students’ understanding of a design, this paper explores more common 2D inputs, but compares different visualization formats of student output in two educational interventions. In the first intervention, students document a construction sequence for wood-framed elements in a 2D worksheet format. In the second, students work with the same wood-framed design, but document their sequence through an augmented reality (AR) format where their physical interactions move full-scale virtual elements as if they were physically constructing the wood frame. Student approaches and performance were analyzed using qualitative attribute coding of video, audio, and written documentation of the student experience. Overall, results showed that the 2D worksheet format was simple to implement and was not mentally demanding to complete, but often corresponded with a lack of critical checks and a lack of mistake recognition from the students. The AR approach challenged students more in terms of cognitive load and completion rates but showed the potential for facilitating mistake recognition and self-remediation through visualization. These results suggest that when students are tasked with conceptualizing construction sequences from 2D documentation, the cognitive challenges associated with documenting a sequence in AR may support their recognition of their own mistakes in ways that may not be effectively supported through 2D documentation as an output for documenting and planning a construction sequence. The results presented in this paper provide insights on student tendencies, behaviors, and perceptions related to defining construction sequences from 2D documentation in order for educators to make informed decisions regarding the use of similar learning activities to prepare their students for understanding the 2D design documents used in industry

Detection of Copy Number Variants by Short Multiply Aggregated Sequence Homologies.

Chromosomal microarray testing is indicated for patients with diagnoses including unexplained developmental delay or intellectual disability, autism spectrum disorders, and multiple congenital anomalies. The short multiply aggregated sequence homologies (SMASH) genomic assay is a novel next-generation sequencing technology that performs copy number analysis at resolution similar to high-coverage whole genome sequencing but requires far less capacity. We benchmarked the performance of SMASH on a panel of genomic DNAs containing known copy number variants (CNVs). SMASH was able to detect pathogenic copy number variants of ≥10 kb in 77 of 77 samples. No pathogenic events were seen in 32 of 32 controls, indicating 100% sensitivity and specificity for detecting pathogenic CNVs >10 kb. Repeatability (interassay precision) and reproducibility (intra-assay precision) were assessed with 13 samples and showed perfect concordance. We also established that SMASH had a limit of detection of 20% for detection of large mosaic CNVs. Finally, we analyzed seven blinded specimens by SMASH analysis and successfully identified all pathogenic events. These results establish the efficacy of the SMASH genomic assay as a clinical test for the detection of pathogenic copy number variants at a resolution comparable to chromosomal microarray analysis

Sphingosine-1-Phosphate Levels Are Higher in Male Patients with Non-Classic Fabry Disease

International audienceFabry disease is an X-linked lysosomal disease in which defects in the alpha-galactosidase A enzyme activity lead to the ubiquitous accumulation of glycosphingolipids. Whereas the classic disease is characterized by neuropathic pain, progressive renal failure, white matter lesions, cerebral stroke, and hypertrophic cardiomyopathy (HCM), the non-classic phenotype, also known as cardiac variant, is almost exclusively characterized by HCM. Circulating sphingosine-1-phosphate (S1P) has controversially been associated with the Fabry cardiomyopathy. We measured serum S1P levels in 41 patients of the FFABRY cohort. S1P levels were higher in patients with a non-classic phenotype compared to those with a classic phenotype (200.3 [189.6–227.9] vs. 169.4 ng/mL [121.1–203.3], p = 0.02). In a multivariate logistic regression model, elevated S1P concentration remained statistically associated with the non-classic phenotype (OR = 1.03; p < 0.02), and elevated lysoGb3 concentration with the classic phenotype (OR = 0.95; p < 0.03). S1P levels were correlated with interventricular septum thickness (r = 0.46; p = 0.02). In a logistic regression model including S1P serum levels, phenotype, and age, age remained the only variable significantly associated with the risk of HCM (OR = 1.25; p = 0.001). S1P alone was not associated with cardiac hypertrophy but with the cardiac variant. The significantly higher S1P levels in patients with the cardiac variant compared to those with classic Fabry suggest the involvement of distinct pathophysiological pathways in the two phenotypes. S1P dosage could allow the personalization of patient management