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Introduction: In the PINETREE study, early remdesivir treatment reduced risk of coronavirus disease 2019 (COVID-19)-related hospitalizations or all-cause death versus placebo by 87% by day 28 in high-risk, non-hospitalized patients. Here we report results of assessment of heterogeneity of treatment effect (HTE) of early outpatient remdesivir, focusing on time from symptom onset and number of baseline risk factors (RFs). Methods: PINETREE was a double-blind, placebo-controlled trial of non-hospitalized patients with COVID-19 who were randomized within 7 days of symptom onset and had ≥ 1 RF for disease progression (age ≥ 60 years, obesity [body mass index ≥ 30], or certain coexisting medical conditions). Patients received remdesivir intravenously (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. Results: In this subgroup analysis, HTE of remdesivir by time from symptom onset at treatment initiation and number of baseline RFs was not detected. Treatment with remdesivir reduced COVID-19-related hospitalizations independent of stratification by time from symptom onset to randomization. Of patients enrolled ≤ 5 days from symptom onset, 1/201 (0.5%) receiving remdesivir and 9/194 (4.6%) receiving placebo were hospitalized (hazard ratio [HR] 0.10; 95% confidence interval [CI] 0.01–0.82). Of those enrolled at > 5 days from symptom onset, 1/78 (1.3%) receiving remdesivir and 6/89 (6.7%) receiving placebo were hospitalized (HR 0.19; 95% CI 0.02–1.61). Remdesivir was also effective in reducing COVID-19-related hospitalizations when stratified by number of baseline RFs for severe disease. Of patients with ≤ 2 RFs, 0/159 (0.0%) receiving remdesivir and 4/164 (2.4%) receiving placebo were hospitalized; of those with ≥ 3 RFs, 2/120 (1.7%) receiving remdesivir and 11/119 (9.2%) receiving placebo were hospitalized (HR 0.16; 95% CI 0.04–0.73). Conclusions: In the outpatient setting, benefit of remdesivir initiated within 7 days of symptoms appeared to be consistent across patients with RFs. Therefore, it may be reasonable to broadly treat patients with remdesivir regardless of comorbidities. Trial Registration: ClinicalTrials.gov number NCT04501952.

Background Self-Monitoring (SM), the act of observing ones’ own behavior, has been used in substance use treatment because SM may bring conscious awareness to automatized substance use behaviors. Empirical findings regarding SM's effectiveness are mixed. The aim of this study was to synthesize the literature for the efficacy of SM on substance use.Method A literature search was conducted using MEDLINE/PubMed.Results Out of 2,659 citations, 41 studies with 126 analyses were included. Among analyses from studies rated Moderate (n= 24) or Strong (n= 3) quality, SM was shown to have a helpful effect (e.g., reducing substance use) 29% of the time; to have no effect 63.0% of the time; and to be detrimental in 8.0% of analyses. SM's helpful effects were associated with methodological characteristics including longer monitoring and Phone/IVR and EMA/Computer methodologies compared to Paper/Pencil. SM was more helpful in non-treatment-seekers (35.0% of analyses showed SM to be helpful compared to 25.0% of analyses with treatment-seekers).Conclusions Results of this study suggest that SM, under certain circumstances, as the potential to be a low-cost, low-risk research and early intervention strategy for substance users.

AbstractBackground:Self-Monitoring (SM), the act of observing ones’ own behavior, has been used in substance use treatment because SM may bring conscious awareness to automatized substance use behaviors. Empirical findings regarding SM’s effectiveness are mixed. The aim of this study was to synthesize the literature for the efficacy of SM on substance use. Method: A literature search was conducted using MEDLINE/PubMed. Results: Out of 2,659 citations, 41 studies with 126 analyses were included. Among analyses from studies rated Moderate (n = 24) or Strong (n = 3) quality, SM was shown to have a helpful effect (e.g., reducing substance use) 29% of the time; to have no effect 63.0% of the time; and to be detrimental in 8.0% of analyses. SM’s helpful effects were associated with methodological characteristics including longer monitoring and Phone/IVR and EMA/Computer methodologies compared to Paper/Pencil. SM was more helpful in non-treatment-seekers (35.0% of analyses showed SM to be helpful compared to 25.0% of analyses with treatment-seekers). Conclusions: Results of this study suggest that SM, under certain circumstances, as the potential to be a low-cost, low-risk research and early intervention strategy for substance users.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has pleiotropic and systemic effects in some individuals1–3, many others experience milder symptoms. Here, to gain a more comprehensive understanding of the distinction between severe and mild phenotypes in the pathology of coronavirus disease 2019 (COVID-19) and its origins, we performed a whole-blood-preserving single-cell analysis protocol to integrate contributions from all major immune cell types of the blood—including neutrophils, monocytes, platelets, lymphocytes and the contents of the serum. Patients with mild COVID-19 exhibit a coordinated pattern of expression of interferon-stimulated genes (ISGs)3across every cell population, whereas these ISG-expressing cells are systemically absent in patients with severe disease. Paradoxically, individuals with severe COVID-19 produce very high titres of anti-SARS-CoV-2 antibodies and have a lower viral load compared to individuals with mild disease. Examination of the serum from patients with severe COVID-19 shows that these patients uniquely produce antibodies that functionally block the production of the ISG-expressing cells associated with mild disease, by activating conserved signalling circuits that dampen cellular responses to interferons. Overzealous antibody responses pit the immune system against itself in many patients with COVID-19, and perhaps also in individuals with other viral infections. Our findings reveal potential targets for immunotherapies in patients with severe COVID-19 to re-engage viral defence.

Remdesivir 1is an phosphoramidate prodrug that releases the monophosphate of nucleoside GS-441524 (2) into lung cells, thereby forming the bioactive triphosphate 2-NTP. 2-NTP, an analog of ATP, inhibits the SARS-CoV-2 RNA-dependent RNA polymerase replication and transcription of viral RNA. Strong clinical results for 1have prompted interest in oral approaches to generate 2-NTP. Here, we describe the discovery of a 5′-isobutyryl ester prodrug of 2(GS-5245, Obeldesivir, 3) that has low cellular cytotoxicity and 3–7-fold improved oral delivery of 2in monkeys. Prodrug 3is cleaved presystemically to provide high systemic exposures of 2that overcome its less efficient metabolism to 2-NTP, leading to strong SARS-CoV-2 antiviral efficacy in an African green monkey infection model. Exposure-based SARS-CoV-2 efficacy relationships resulted in an estimated clinical dose of 350–400 mg twice daily. Importantly, all SARS-CoV-2 variants remain susceptible to 2, which supports development of 3as a promising COVID-19 treatment.

Evidence-based guidelines for prophylactic antibiotic use in open fractures recommend short-course, narrow-spectrum antibiotics for Gustilo Grade I or II open fractures and broader gram-negative coverage for Grade III open fractures. No studies to date have assessed the impact of these guidelines on infection rates in open fractures. Infection rates before and after the new protocol implementation were examined.