Background: The role of remdesivir inThe primary outcome was in-hospital 24.8% and 28.2%, respectively (95% CI the treatment of patients in hospital mortality. Secondary outcomes 0.72 to 1.07). For patients not mechanwith COVID-19 remains ill defined in a included changes in clinical severity, ically ventilated at baseline, the need for global context. The World Health Organ-oxygen-and ventilator-free days (at mechanical ventilation was 8.0% in those ization Solidarity randomized controlled 28 d), incidence of new oxygen or assigned remdesivir, and 15.0% in those trial (RCT) evaluated remdesivir in mechanical ventilation use, duration of receiving standard of care (RR 0.53, 95% CI patients across many countries, with hospital stay, and adverse event rates. 0.38 to 0.75). Mean oxygen-free and Canada enrolling patients using anWe performed a priori subgroup analy-ventilator-free days at day 28 were 15.9 expanded data collection format in the ses according to duration of symptoms (± standard deviation [SD] 10.5) and 21.4 Canadian Treatments for COVID-19 before enrolment, age, sex and severity (± SD 11.3) in those receiving remdesivir (CATCO) trial. We report on the Canad-of symptoms on presentation. and 14.2 (± SD 11) and 19.5 (± SD 12.3) in ian findings, with additional demo-those receiving standard of care (p = 0.006 graphics, characteristics and clinical Results: Across 52 Canadian hospitals, and 0.007, respectively). There was no difoutcomes, to explore the potential for we randomized 1282 patients between ference in safety events of new dialysis, differential effects across different Aug. 14, 2020, and Apr. 1, 2021, to remde-change in creatinine, or new hepatic dyshealth care systems.sivir (n = 634) or standard of care (n = function between the 2 groups. 648). Of these, 15 withdrew consent or Methods: We performed an open-label, were still in hospital, for a total sample of Interpretation: Remdesivir, when compragmatic RCT in Canadian hospitals, in 1267 patients. Among patients assigned pared with standard of care, has a modest conjunction with the Solidarity trial. We to receive remdesivir, in-hospital mortal-but significant efect on outcomes imporrandomized patients to 10 days of rem-ity was 18.7%, compared with 22.6% in tant to patients and health systems, such desivir (200 mg intravenously [IV] on day the standard-of-care arm (relative risk as the need for mechanical ventilation. 0, followed by 100 mg IV daily), plus[RR] 0.83 (95% confidence interval [CI] Trial registration: ClinicalTrials.gov, no. standard care, or standard care alone. 0.67 to 1.03), and 60-day mortality was NCT04330690.

ACE (angiotensin-converting enzyme)-2 as the target for SARS-CoV-2 also negatively regulates the renin-angiotensin system. Pathological activation of ADAM17 (A disintegrin and metalloproteinase-17) may potentiate inflammation and diminish ACE2-mediated tissue protection through proteolytic shedding, contributing to SARS-CoV-2 pathogenesis. We aim to examine plasma soluble ACE2 and angiotensin profiles in relation to outcomes by enrolling consecutive patients admitted for COVID-19 with baseline blood collection at admission and repeated sampling at 7 days. The primary outcome was 90-day mortality, and secondary outcomes were the incidence of end-organ injuries. Overall, 242 patients were included, the median age was 63 (52–74) years, 155 (64.0%) were men, and 57 (23.6%) patients reached the primary end point. Baseline soluble ACE2 was elevated in COVID-19 but was not associated with disease severity or mortality. In contrast, an upward trajectory of soluble ACE2 at repeat sampling was independently associated with an elevated risk of mortality and incidence of acute myocardial injury and circulatory shock. Similarly, an increase in soluble tumor necrosis factor receptor levels was also associated with adverse outcomes. Plasma Ang I, Ang 1-7 (angiotensin 1–7) levels, and the Ang 1-7/Ang II (angiotensin II) ratio were elevated during SARS-CoV-2 infection related to downregulation of ACE activity at baseline. Moreover, patients having an upward trajectory of soluble ACE2 were characterized by an imbalance in the Ang 1-7/Ang II ratio. The observed dysregulation of ACE2 and angiotensin peptides with disease progression suggest a potential role of ADAM17 inhibition and enhancing the beneficial Ang 1-7/Mas axis to improve outcomes against SARS-CoV-2 infection.

The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. In this study, we observed massive elevation of plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls (HCs). By using the receiver operating characteristic (ROC) curve, we found that a baseline of 2,042 pg/ml plasma Gal-9 can differentiate SARS-CoV-2-infected from noninfected individuals with high specificity/sensitivity (95%). Analysis of 30 cytokines and chemokines detected a positive correlation of the plasma Gal-9 with C-reactive protein (CRP) and proinflammatory cytokines/chemokines such as interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), IP-10, MIP-1α, and MCP-1 but an inverse correlation with transforming growth factor β (TGF-β) in COVID-19 patients. In agreement, we found enhanced production of IL-6 and TNF-α by monocytes and NK cells of COVID-19 patients once treated with the recombinant human Gal-9 in vitro. Also, we observed that although the cell-membrane expression of Gal-9 on monocytes does not change in COVID-19 patients, those with higher Gal-9 expression exhibit an activated phenotype. Furthermore, we noted significant downregulation of surface Gal-9 in neutrophils from COVID-19 patients compared to HCs. Our further investigations indicated that immune activation following SARS-CoV-2 infection results in Gal-9 shedding from neutrophils. The strong correlation of Gal-9 with proinflammatory mediators suggests that inhibition of Gal-9 may severe as a therapeutic approach in COVID-19 infection. Besides, the plasma Gal-9 measurement may be used as a surrogate diagnostic biomarker in COVID-19 patients. IMPORTANCE The outbreak of SARS-CoV-2 infection has enormously impacted our lives. Clinical evidence has implicated the emergence of cytokine release syndrome as the prominent cause of mortality in COVID-19 patients. We observed substantial elevation of the plasma Galectin-9 (Gal-9) in COVID-19 patients compared to healthy controls. Gal-9 is an abundant protein in many immune and nonimmune cells. We found that Gal-9 detection assay can differentiate SARS-CoV-2-infected from noninfected individuals with a specificity/sensitivity of 95%. Importantly, we found a positive correlation of the plasma Gal-9 with a wide range of proinflammatory biomarkers in COVID-19 patients. In agreement, we found enhanced expression and production of such proinflammatory molecules by immune cells of COVID-19 patients once treated with Gal-9 in vitro. Our results propose Gal-9 as an important contributing factor in cytokine release syndrome; therefore, Gal-9 inhibition may serve as a beneficial therapeutic approach by suppressing the hyperimmune activation in COVID-19 patients.

Background. The prevalence of patients supported with home mechanical ventilation (HMV) for chronic respiratory failure has increased. However, the clinical outcomes associated with HMV are largely unknown. Methods. We performed a systematic review of studies evaluating patients receiving HMV for indications other than obstructive lung disease, reporting at least one clinically relevant outcome including health-related quality of life (HRQL) measured by validated tools; hospitalization requirements; caregiver burden; and health service utilization. We searched MEDLINE, EMBASE, CINAHL, the Cochrane library, clinical trial registries, proceedings from selected scientific meetings, and bibliographies of retrieved citations. Results. We included 1 randomized control trial (RCT) and 25 observational studies of mixed methodological quality involving 4425 patients; neuromuscular disorders (NMD) (n = 1687); restrictive thoracic diseases (RTD) (n = 481); obesity hypoventilation syndrome (OHS) (n = 293); and others (n = 748). HRQL was generally described as good for HMV users. Mental rather than physical HRQL domains were rated higher, particularly where physical assessment was limited. Hospitalization rates and days in hospital appear to decrease with implementation of HMV. Caregiver burden associated with HMV was generally high; however, it is poorly described. Conclusion. HRQL and need for hospitalization may improve after establishment of HMV. These inferences are based on relatively few studies of marked heterogeneity and variable quality.

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