The COVID STEROID 2 Trial Group IMPORTANCE A daily dose with 6 mg of dexamethasone is recommended for up to 10 days in patients with severe and critical COVID-19, but a higher dose may benefit those with more severe disease. OBJECTIVE To assess the effects of 12 mg/d vs 6 mg/d of dexamethasone in patients with COVID-19 and severe hypoxemia. DESIGN, SETTING, AND PARTICIPANTS A multicenter, randomized clinical trial was conducted between August 2020 and May 2021 at 26 hospitals in Europe and India and included 1000 adults with confirmed COVID-19 requiring at least 10 L/min of oxygen or mechanical ventilation. End of 90-day follow-up was on August 19, 2021. INTERVENTIONS Patients were randomized 1:1 to 12 mg/d of intravenous dexamethasone (n = 503) or 6 mg/d of intravenous dexamethasone (n = 497) for up to 10 days. MAIN OUTCOMES AND MEASURESThe primary outcome was the number of days alive without life support (invasive mechanical ventilation, circulatory support, or kidney replacement therapy) at 28 days and was adjusted for stratification variables. Of the 8 prespecified secondary outcomes, 5 are included in this analysis (the number of days alive without life support at 90 days, the number of days alive out of the hospital at 90 days, mortality at 28 days and at 90 days, and Ն1 serious adverse reactions at 28 days). RESULTSOf the 1000 randomized patients, 982 were included (median age, 65 [IQR, 55-73] years; 305 [31%] women) and primary outcome data were available for 971 (491 in the 12 mg of dexamethasone group and 480 in the 6 mg of dexamethasone group). The median number of days alive without life support was 22.0 days (IQR, 6.0-28.0 days) in the 12 mg of dexamethasone group and 20.5 days (IQR, 4.0-28.0 days) in the 6 mg of dexamethasone group (adjusted mean difference, 1.3 days [95% CI, 0-2.6 days]; P = .07). Mortality at 28 days was 27.1% in the 12 mg of dexamethasone group vs 32.3% in the 6 mg of dexamethasone group (adjusted relative risk, 0.86 [99% CI, 0.68-1.08]). Mortality at 90 days was 32.0% in the 12 mg of dexamethasone group vs 37.7% in the 6 mg of dexamethasone group (adjusted relative risk, 0.87 [99% CI, 0.70-1.07]). Serious adverse reactions, including septic shock and invasive fungal infections, occurred in 11.3% in the 12 mg of dexamethasone group vs 13.4% in the 6 mg of dexamethasone group (adjusted relative risk, 0.83 [99% CI, 0.54-1.29]).CONCLUSIONS AND RELEVANCE Among patients with COVID-19 and severe hypoxemia, 12 mg/d of dexamethasone compared with 6 mg/d of dexamethasone did not result in statistically significantly more days alive without life support at 28 days. However, the trial may have been underpowered to identify a significant difference.

Rationale: The feasibility and safety of awake prone positioning and its impact on outcomes in non-intubated patients with acute respiratory distress syndrome secondary to COVID-19 is unknown. Results of the observational studies published during this pandemic have been conflicting. In this context, we conducted a multi-center, parallel group, randomized controlled feasibility study on awake prone positioning in non-intubated patients with COVID-19 pneumonia requiring supplemental oxygen. Methods: 60 patients with acute hypoxic respiratory failure secondary to COVID-19 pneumonia requiring 4 or more liters of oxygen to maintain a saturation of ≥92% were recruited in this study. Thirty patients each were randomized to either standard care or awake prone group. Patients randomized to the prone group were encouraged to self-prone for at least 6 hours a day. The primary outcome was the proportion of patients adhering to the protocol in each group. Results: In the prone group, 43% (13 out of 30) of patients were able to self-prone for 6 or more hours a day. In the supine group, 47% (14 out of 30) were completely supine and 53% spent some hours in the prone position, but none exceeded 6 hours. There was no significant difference in any of the secondary outcomes between the 2 groups and there were no adverse events. Conclusions: Awake prone positioning in non-intubated patients with acute hypoxic respiratory failure is feasible and safe under clinical trial conditions. The results of our feasibility study will potentially help in the design of larger definitive trials to address this key knowledge gap.

In high energy density, low porosity, lithium-ion battery electrodes, the underlying microstructural tortuosity controls the macroscopic charge capacity, average lithium-ion diffusivity, and macroscopic resistivity of the cell, particularly at high discharge rates and power densities. In this paper, an analytical framework is presented to extend widely used empirical tortuosity relations such as the Bruggemann relation to incorporate the effects of the mesoscale tortuosity through analytical integration along the width of the electrode (in the limit of high porosities), and integration along a statistically representative tortuous path (in the limit of low porosities). The framework presented herein enables to establish analytical tortuosity-porosity relations that combine the constitutive properties of the individual components. As an example application, the macroscopic tortuosity-porosity relation of a mixture of two porous particle systems of widely different length scales and well-known individual tortuosity constitutive equations, one displaying mesoscale porosity (the carbon black-electrolyte mixture) and a second one displaying microporosity (the electrochemically active phase), are combined into a self-consistent macroscopic tortuosity expression that is in agreement with recently reported empirical measures of tortuosity.

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Background The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men.

Background The coronavirus disease 2019 (COVID‐19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low‐dose corticosteroids have proven clinical benefit in patients with severe COVID‐19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID‐19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID‐19 is unclear. Methods The COVID STEROID 2 trial is an investigator‐initiated, international, parallel‐grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID‐19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all‐cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health‐related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. Discussion The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID‐19 patients with severe hypoxia with important implications for patients, their relatives and society.

Background Coronavirus disease 2019 (COVID‐19) can lead to severe hypoxic respiratory failure and death. Corticosteroids decrease mortality in severely or critically ill patients with COVID‐19. However, the optimal dose remains unresolved. The ongoing randomised COVID STEROID 2 trial investigates the effects of higher vs lower doses of dexamethasone (12 vs 6 mg intravenously daily for up to 10 days) in 1,000 adult patients with COVID‐19 and severe hypoxia. Methods This protocol outlines the rationale and statistical methods for a secondary, pre‐planned Bayesian analysis of the primary outcome (days alive without life support at day 28) and all secondary outcomes registered up to day 90. We will use hurdle‐negative binomial models to estimate the mean number of days alive without life support in each group and present results as mean differences and incidence rate ratios with 95% credibility intervals (CrIs). Additional count outcomes will be analysed similarly and binary outcomes will be analysed using logistic regression models with results presented as probabilities, relative risks and risk differences with 95% CrIs. We will present probabilities of any benefit/harm, clinically important benefit/harm and probabilities of effects smaller than pre‐defined clinically minimally important differences for all outcomes analysed. Analyses will be adjusted for stratification variables and conducted using weakly informative priors supplemented by sensitivity analyses using sceptic priors. Discussion This secondary, pre‐planned Bayesian analysis will supplement the primary, conventional analysis and may help clinicians, researchers and policymakers interpret the results of the COVID STEROID 2 trial while avoiding arbitrarily dichotomised interpretations of the results. Trial registration ClinicalTrials.gov: NCT04509973; EudraCT: 2020‐003363‐25.

Purpose:We assessed long-term outcomes of dexamethasone 12 mg versus 6 mg given daily for up to 10 days in patients with coronavirus disease 2019 (COVID-19) and severe hypoxaemia. Methods:We assessed 180-day mortality and health-related quality of life (HRQoL) using EuroQoL (EQ)-5D-5L index values and EQ visual analogue scale (VAS) in the international, stratified, blinded COVID STEROID 2 trial, which randomised 1000 adults with confirmed COVID-19 receiving at least 10 L/min of oxygen or mechanical ventilation in 26 hospitals in Europe and India. In the HRQoL analyses, higher values indicated better outcomes, and deceased patients were given a score of zero. Results:We obtained vital status at 180 days for 963 of 982 patients (98.1%) in the intention-to-treat population, EQ-5D-5L index value data for 922 (93.9%) and EQ VAS data for 924 (94.1%). At 180 days, 164 of 486 patients (33.7%) had died in the 12 mg group versus 184 of 477 (38.6%) in the 6 mg group [adjusted risk difference − 4.3%; 99% confidence interval (CI) − 11.7-3.0; relative risk 0.89; 0.72-1.09; P = 0.13]. The adjusted mean differences between the 12 mg and the 6 mg groups in EQ-5D-5L index values were 0.06 (99% CI − 0.01 to 0.12; P = 0.10) and in EQ VAS scores 4 (− 3 to 10; P = 0.22).