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Background: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic.Methods: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications.Results: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine.Conclusions: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.). [ABSTRACT FROM AUTHOR]

Significant progress has been made in preventing severe COVID-19 disease through the development of vaccines. However, we still lack a validated baseline predictive biologic signature for the development of more severe disease in both outpatients and inpatients infected with SARS-CoV-2. The objective of this study was to develop and externally validate, via 5 international outpatient and inpatient trials and/or prospective cohort studies, a novel baseline proteomic signature, which predicts the development of moderate or severe (vs mild) disease in patients with COVID-19 from a proteomic analysis of 7000 + proteins. The secondary objective was exploratory, to identify (1) individual baseline protein levels and/or (2) protein level changes within the first 2 weeks of acute infection that are associated with the development of moderate/severe (vs mild) disease. For model development, samples collected from 2 randomized controlled trials were used. Plasma was isolated and the SomaLogic SomaScan platform was used to characterize protein levels for 7301 proteins of interest for all studies. We dichotomized 113 patients as having mild or moderate/severe COVID-19 disease. An elastic net approach was used to develop a predictive proteomic signature. For validation, we applied our signature to data from three independent prospective biomarker studies. We found 4110 proteins measured at baseline that significantly differed between patients with mild COVID-19 and those with moderate/severe COVID-19 after adjusting for multiple hypothesis testing. Baseline protein expression was associated with predicted disease severity with an error rate of 4.7% (AUC = 0.964). We also found that five proteins (Afamin, I-309, NKG2A, PRS57, LIPK) and patient age serve as a signature that separates patients with mild COVID-19 and patients with moderate/severe COVID-19 with an error rate of 1.77% (AUC = 0.9804). This panel was validated using data from 3 external studies with AUCs of 0.764 (Harvard University), 0.696 (University of Colorado), and 0.893 (Karolinska Institutet). In this study we developed and externally validated a baseline COVID-19 proteomic signature associated with disease severity for potential use in both outpatients and inpatients with COVID-19., (© 2023. The Author(s).)

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology., Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II., Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022., Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo., Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension., Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo., Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

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: NCT02735707.

Background: Physician empathy has been linked to increased patient satisfaction, improved patient outcomes and reduced provider burnout. Our objective was to test the effectiveness of an educational intervention to improve physician empathy and trust in the ED setting., Methods: Physician participants from six emergency medicine residencies in the US were studied from 2018 to 2019 using a pre-post, quasi-experimental non-equivalent control group design with randomisation at the site level. Intervention participants at three hospitals received an educational intervention, guided by acognitivemap (the 'empathy circle'). This intervention was further emphasised by the use of motivational texts delivered to participants throughout the course of the study. The primary outcome was change in E patient perception of resident empathy (Jefferson scale of patient perception of physician empathy (JSPPPE) and Trust in Physicians Scale (Tips)) before (T1) and 3-6 months later (T2)., Results: Data were collected for 221 residents (postgraduate year 1-4.) In controls, the mean (SD) JSPPPE scores at T1 and T2 were 29 (3.8) and 29 (4.0), respectively (mean difference 0.8, 95% CI: -0.7 to 2.4, p=0.20, paired t-test). In the intervention group, the JSPPPE scores at T1 and T2 were 28 (4.4) and 30 (4.0), respectively (mean difference 1.4, 95% CI: 0.0 to 2.8, p=0.08). In controls, the TIPS at T1 was 65 (6.3) and T2 was 66 (5.8) (mean difference -0.1, 95% CI: -3.8 to 3.6, p=0.35). In the intervention group, the TIPS at T1 was 63 (6.9) and T2 was 66 (6.3) (mean difference 2.4, 95% CI: 0.2 to 4.5, p=0.007). Hierarchical regression revealed no effect of time×group interaction for JSPPPE (p=0.71) nor TIPS (p=0.16)., Conclusion: An educational intervention with the addition of text reminders designed to increase empathic behaviour was not associated with a change in patient-perceived empathy, but was associated with a modest improvement in trust in physicians., Competing Interests: Competing interests: Author JK reports grant money to Indiana University School of Medicine to conduct research conceived and written by JK from Bristol Meyer Squibb and Janssen Pharmaceuticals., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) drugs may modify risk associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Therefore, we assessed whether baseline therapy with ACEIs or ARBs was associated with lower mortality, respiratory failure (noninvasive ventilation or intubation), and renal failure (new renal replacement therapy) in SARS-CoV-2-positive patients. This retrospective registry-based observational cohort study used data from a national database of emergency department patients tested for SARS-CoV-2. Symptomatic emergency department patients were accrued from January to October 2020, across 197 hospitals in the United States. Multivariable analysis using logistic regression evaluated end points among SARS-CoV-2-positive cases, focusing on ACEIs/ARBs and adjusting for covariates. Model performance was evaluated using the c statistic for discrimination and Cox plotting for calibration. A total of 13 859 (99.9%) patients had known mortality status, of whom 2045 (14.8%) died. Respiratory failure occurred in 2485/13 880 (17.9%) and renal failure in 548/13 813 (4.0%) patients with available data. ACEI/ARB status was associated with a 25% decrease in mortality odds (odds ratio [OR], 0.75; 95%CI, 0.59-0.94; P = .011; c = .82). ACEIs/ARBs were not significantly associated with respiratory failure (OR, 0.89; 95%CI, 0.78-1.06; P = .206) or renal failure (OR, 0.75; 95%CI, 0.55-1.04; P = .083). Adjusting for covariates, baseline ACEI/ARB was associated with 25% lower mortality in SARS-CoV-2-positive patients. The potential mechanism for ACEI/ARB mortality modification requires further exploration., (© 2021, The American College of Clinical Pharmacology.)

Background: Data conflict on whether vaccination decreases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load. The objective of this analysis was to compare baseline viral load and symptoms between vaccinated and unvaccinated adults enrolled in a randomized trial of outpatient coronavirus disease 2019 (COVID-19) treatment., Methods: Baseline data from the first 433 sequential participants enrolling into the COVID-OUT trial were analyzed. Adults aged 30-85 with a body mass index (BMI) ≥25 kg/m 2 were eligible within 3 days of a positive SARS-CoV-2 test and <7 days of symptoms. Log 10 polymerase chain reaction viral loads were normalized to human RNase P by vaccination status, by time from vaccination, and by symptoms., Results: Two hundred seventy-four participants with known vaccination status contributed optional nasal swabs for viral load measurement: median age, 46 years; median (interquartile range) BMI 31.2 (27.4-36.4) kg/m 2 . Overall, 159 (58%) were women, and 217 (80%) were White. The mean relative log 10 viral load for those vaccinated <6 months from the date of enrollment was 0.11 (95% CI, -0.48 to 0.71), which was significantly lower than the unvaccinated group ( P  = .01). Those vaccinated ≥6 months before enrollment did not differ from the unvaccinated with respect to viral load (mean, 0.99; 95% CI, -0.41 to 2.40; P  = .85). The vaccinated group had fewer moderate/severe symptoms of subjective fever, chills, myalgias, nausea, and diarrhea (all P  < .05)., Conclusions: These data suggest that vaccination within 6 months of infection is associated with a lower viral load, and vaccination was associated with a lower likelihood of having systemic symptoms., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: To prospectively evaluate a logistic regression-based machine learning (ML) prognostic algorithm implemented in real-time as a clinical decision support (CDS) system for symptomatic persons under investigation (PUI) for Coronavirus disease 2019 (COVID-19) in the emergency department (ED)., Methods: We developed in a 12-hospital system a model using training and validation followed by a real-time assessment. The LASSO guided feature selection included demographics, comorbidities, home medications, vital signs. We constructed a logistic regression-based ML algorithm to predict "severe" COVID-19, defined as patients requiring intensive care unit (ICU) admission, invasive mechanical ventilation, or died in or out-of-hospital. Training data included 1,469 adult patients who tested positive for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) within 14 days of acute care. We performed: 1) temporal validation in 414 SARS-CoV-2 positive patients, 2) validation in a PUI set of 13,271 patients with symptomatic SARS-CoV-2 test during an acute care visit, and 3) real-time validation in 2,174 ED patients with PUI test or positive SARS-CoV-2 result. Subgroup analysis was conducted across race and gender to ensure equity in performance., Results: The algorithm performed well on pre-implementation validations for predicting COVID-19 severity: 1) the temporal validation had an area under the receiver operating characteristic (AUROC) of 0.87 (95%-CI: 0.83, 0.91); 2) validation in the PUI population had an AUROC of 0.82 (95%-CI: 0.81, 0.83). The ED CDS system performed well in real-time with an AUROC of 0.85 (95%-CI, 0.83, 0.87). Zero patients in the lowest quintile developed "severe" COVID-19. Patients in the highest quintile developed "severe" COVID-19 in 33.2% of cases. The models performed without significant differences between genders and among race/ethnicities (all p-values > 0.05)., Conclusion: A logistic regression model-based ML-enabled CDS can be developed, validated, and implemented with high performance across multiple hospitals while being equitable and maintaining performance in real-time validation., Competing Interests: The authors have declared that no competing interests exist.

Emergency medicine (EM) investigators lag in research funding from the National Institutes of Health (NIH) when compared to other specialties. NIH funding determinations are made in part by a process of NIH study section peer review. Low participation by EM investigators in NIH peer review could be one explanation for low levels of NIH funding by EM investigators. The objective of this study was to establish a current-state metric of EM faculty researchers serving on standing NIH study sections from 2019 to 2020. Publicly available lists of NIH study section membership rosters within the Center for Scientific Review and within individual NIH institutions were reviewed for standing members. Committee members listed as being members of a department of emergency medicine were identified as emergency care researchers. Special emphasis panels and ad hoc members were excluded. Members degrees were categorized as PhD, MD (with or without non-PhD degree), MD/PhD, and other. Similar analysis was performed of AHRQ study sections. A total of 6,113 members on NIH study sections were identified. Degrees held by committee members included PhDs 74% (4,547), MDs 14%(883), MD/PhDs 10% (584), and other (99). Twenty (0.3%) NIH study section members were identified as members of an emergency department (ED). A total of 20% (four) held PhDs, 75% (15) held MDs, and 5%(one) held MD/PhD degrees. A total of 25% (five) of EM faculty were pediatric and 75% (15) were adult. Clustering of study sections within similar institutions was noted with 40% (two) of the pediatric faculty at the same institution while 27% (four) of the adult faculty were at the same institution. AHRQ study section review identified 3% (four/127) as members of an ED. Our data show that 20 EM faculty comprised 0.3% of NIH standing study section members and four EM faculty comprised 3% of AHRQ standing study section members from 2019 to 2020 and that these members were clustered at a few institutions., (© 2021 by the Society for Academic Emergency Medicine.)

Competing Interests: Dr. Alhazzani is the Chair of the Guidelines Chapter for the Saudi Critical Care Society and is the chair of the guidelines in intensive care, development and evaluation (GUIDE) Group, McMaster University Canada. Dr. Antonelli received funding from GE, Toray-Estor, Baxter, Pfizer, Orion, Maquet, and Fisher and Paykel; he was on the board of Baxter and Pfizer, and is a member of the executive committee and past president of Società Italiana di Anestesia Rianimazione e Terapia Intensiva (SIAARTI). Dr. French contributed to the ANZICS Guidelines and the National COVID-19 Guidelines. Dr. Machado is a member of the Executive Committee for the Basics Study (for which Baxter provided the drugs and logistics) and AMIB. Dr. McIntyre is a member of the Canadian Critical Care Society and serves on the Surviving Sepsis Campaign Steering Committee. Dr. Ostermann is a council member of the Intensive Care Society UK and member of the Renal Association UK and World Sepsis Alliance. Dr. Prescott is a member of the ATS Critical Care Program Committee. Dr. Simpson is the president-elect and Chair of CHEST, is a member of the board of directors and medical director of Sepsis Alliance, and Chair of the Sepsis Institute Advisory Board. Dr. Wiersinga is a member of ISF, ESCIMID, and SWAB. Dr. Angus received funding from Ferring Pharmaceuticals, Inc and ALung Technologies, Inc. Dr. Beale provides consultancy services for Philips Healthcare with his time billed by his institution. Dr. Beilman is the president of the Surgical Infection Society. Dr. Belley-Cote received grants from Roche and Bayer and is a panel member on the Saudi Critical Care Society COVID-19 Thrombosis Guidelines. Dr. Cecconi is a consultant for Edwards Lifesciences, Cheetah Medical, and Directed Systems and is President of the European Society of Intensive Care Medicine. Dr. Coz is a board member of the American College of Chest Physicians. Dr. De Waele consulted for Accelerate, Bayer, Grifols, Pfizer, and MSD with all honoraria paid to Ghent University; he is a Senior Clinical Investigator with the Research Foundation Flanders. Dr. Dellinger serves as an expert witness on occasional medical legal case reviews. Dr. Doi is a member of the Japanese Society of Intensive Care Medicine. Dr. Du is a member of the Chinese Society of Critical Care Medicine and the Chinese College of Intensive Care Medicine. Dr. Ferrer received funding from Grifols, MSD, Pfizer, Shionogi, Toray, Jafron, and Cytosorbents; he is a member of SEMICYUC. Dr. Gomersall is a member of an educational subgroup of the International Forum of Acute Care Trialists. Dr. Hodgson is a member of the Australian National Health and Medical Research Council guidelines (COVID-19) and leading funded trials in early rehabilitation and ECMO. Dr. Møller contributed to guideline work for DASAIM, SSAI, GUIDE, and ESA. Dr. Iwashyna is a member of the ATS, the NIH, and an informal (unincorporated) organization called the Critical and Acute Illness Recovery Organization. Dr. Jacob co-directs the African Research Collaboration on Sepsis (ARCS, funded by UK National Institute for Health Research, sponsored by Liverpool School of Tropical Medicine), he is Secretary General for the African Sepsis Alliance, and is a technical expert for the World Health Organization panels. Dr. Kleinpell is a board member of the World Federation of Intensive and Critical Care, American Nurses Credentialing Center, and the Tennessee Nurses Association Political Action Committee. Dr. Klompas received funding from Up-to-Date; he is a member of the guidelines committees of the Infectious Disease Society of America (IDSA) and Society of Healthcare Epidemiologists of America (SHEA). Dr. Koh is a member of The Korean Society of Critical Care Medicine, The Korean Academy of Tuberculosis and Respiratory Diseases, The Korean Society of Medical Ethics, and the Asia Ventilation Forum. Dr. Kumar served as an expert witness regarding a lethal dose of narcotics. Dr. Kwizera is president of the Intensive Care Society of Uganda and PRO for the Association of Anesthesiologists of Uganda. Dr. Lobo received funding from Pfizer, MSD, Edwards, and Nestle; she is the principal investigator in new antibiotics research led by CROs/industry; she is a member of the AMIB Executive Board and was elected president for 2020-2021. Dr. McGloughlin is a member of ANZICS (Australian New Zealand Intensive Care Society). Dr. Mehta participated in two non-interventional studies by ISCCM-Hermes and Indicaps. Dr. Mer has been an invited speaker for educational talks in industry-sponsored symposia for which honoraria was received; he is the current Vice President of the Southern African Society of Thrombosis and Haemostasis (SASTH), and is involved in annual congress organization; he is an invited author of the Global guidelines for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Dr. Nunnally is the treasurer of SOCCA, committee member of ASA, NYSSA, IARS, AUA, and SAAAPM and serves on the American College of Critical Care Medicine Board of Regents. Dr. Oczkowski is a member of the European Respiratory Society, and contributed to the High Flow Nasal Cannula Guidelines, the Non-Invasive Ventilation in COPD Guidelines. Dr. Osborn received funding from Viven Inc, Inflammatrix, Beckman, and the Foundation for Barnes Jewish Hospital; she is on the advisory board for Beckman, Inflammatix, and Viven; she is a member of the American College of Emergency Physicians, American College of Chest Physicians, American Medical Association, Society of Academic Emergency Medicine, and American Academy of Emergency Physicians; she served as an expert witness in a case related to viral as compared to bacterial sepsis. Dr. Papathanassoglou is a member of the World Federation of Critical Care Nurses (Editor of Journal) and the Canadian Association of Critical Care Nurses. Dr. Perner received a research grant from Pfizer Denmark. Dr. Puskarich is the co-inventor of a patent to assess L0carnitine drug responsiveness in sepsis (USPO 10330685); he is a member of the Society for Academic Emergency Medicine, American College of Emergency Physicians (ACEP); he was invited to a recently gathered ACEP early sepsis treatment policy task force asked to develop specialty recommendations for early sepsis treatment. Dr. Roberts received funding from MSD, The Medicines Company, Cardeas Pharma, Biomerieux, QPEX, Cipla, and Pfizer; he consulted for MSD, QPEX, Discuva Ltd, Accelerate Diagnostics, Bayer, Biomerieux, UptoDate, and Australian Therapeutic Guidelines; he is a member of the Society of Hospital Pharmacists of Australia Leadership Committees for Critical Care and Infectious Diseases and the Lead of Sepsis Working group for the International Society of Anti-infective Chemotherapy. Dr. Schweickert is a paid consultant to the American College of Physicians (last performed in Spring, 2019). Dr. Seckel volunteers for AACN and is a paid consultant to revise online Critical Care Orientation. Dr. Sevransky received funding from the Marcus Foundation- PI VICTAS Trial and serves on the American College of Critical Care Medicine Board of Regents. Dr. Welte received funding from Astellas, AstraZeneca, Boehringer, Basilea, Bayer, Berlin-Chemie, Grifols, Infectopharm, Mundipharma, MSD, Novartis, Pfizer, DFG, EU, BMBF, and Insmed; he is on the advisory board for AstraZeneca, Boehringer, Bayer, Gilead, GSK, Insmed, Novartis, Pfizer, Roche; he is a member of the European Respiratory Society, German Society of Pneumology, and Paul Ehrlich Gesellschaft. Dr. Zimmerman is a member of the ACP, AACP, and WFPICCS. Dr. Levy is a legal consultant for a few cases involving sepsis and serves as co-chair of the Surviving Sepsis Campaign Steering Committee. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Metformin is the first-line medication for type 2 diabetes, but it also has a long history of improved outcomes in infectious diseases, such as influenza, hepatitis C, and in-vitro assays of zika. In the current Covid-19 pandemic, which has rapidly spread throughout the world, 4 observational studies have been published showing reduced mortality among individuals with home metformin use. There are several potential overlapping mechanisms by which metformin may reduce mortality from Covid-19. Metformin's past anti-infectious benefits have been both against the infectious agent directly, as well as by improving the underlying health of the human host. It is unknown if the lower mortality suggested by observational studies in patients infected with Covid-19 who are on home metformin is due to direct activity against the virus itself, improved host substrate, or both., Competing Interests: DV is employed by the company UnitedHealth Group. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ibrahim, Lowe, Bramante, Shah, Klatt, Sherwood, Aronne, Puskarich, Tamariz, Palacio, Bomberg, Usher, King, Benson, Vojta, Tignanelli and Ingraham.)

In this commentary, we shed light on the role of the mammalian target of rapamycin (mTOR) pathway in viral infections. The mTOR pathway has been demonstrated to be modulated in numerous RNA viruses. Frequently, inhibiting mTOR results in suppression of virus growth and replication. Recent evidence points towards modulation of mTOR in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We discuss the current literature on mTOR in SARS-CoV-2 and highlight evidence in support of a role for mTOR inhibitors in the treatment of coronavirus disease 2019., (© 2020 Wiley Periodicals LLC.)

Background: Circulating complement C3 fragments released during septic shock might contribute to the development of complications such as profound hypotension and disseminated intravascular coagulation. The role of C3 in the course of septic shock varies in the literature, possibly because circulating C3 exists in different forms indistinguishable via traditional ELISA-based methods. We sought to test the relationship between C3 forms, measured by Western blotting with its associated protein size differentiation feature, and clinical outcomes., Methods: Secondary analysis of two prospective cohorts of patients with septic shock: a discovery cohort of 24 patents and a validation cohort of 181 patients. C3 levels were measured by Western blotting in both cohorts using blood obtained at enrollment. Differences between survivors and non-survivors were compared, and the independent prognostic values of C3 forms were assessed., Results: In both cohorts there were significantly lower levels of the C3-alpha chain in non-survivors than in survivors, and persisted after controlling for sequential organ failure assessment score. Area under the receiver operating characteristics to predict survival was 0.65 (95% confidence interval: 0.56-0.75). At a best cutoff value (Youden) of 970.6 μg/mL, the test demonstrated a sensitivity of 68.5% and specificity of 61.5%. At this cutoff point, Kaplan-Meier survival analysis showed that patients with lower levels of C3-alpha chain had significantly lower survival than those with higher levels (P < 0.001)., Conclusion: Circulating C3-alpha chain levels is a significant independent predictor of survival in septic shock patients.

[This corrects West J Emerg Med. 2019 January;20(1):50-57]

Introduction: Formative evaluations of clinical teaching for emergency medicine (EM) faculty are limited. The goal of this study was to develop a behaviorally-based tool for evaluating and providing feedback to EM faculty based on their clinical teaching skills during a shift., Methods: We used a three-phase structured development process. Phase 1 used the nominal group technique with a group of faculty first and then with residents to generate potential evaluation items. Phase 2 included separate focus groups and used a modified Delphi technique with faculty and residents, as well as a group of experts to evaluate the items generated in Phase 1. Following this, residents classified the items into novice, intermediate, and advanced educator skills. Once items were determined for inclusion and subsequently ranked they were built into the tool by the investigators (Phase 3)., Results: The final instrument, the "Faculty Shift Card," is a behaviorally-anchored evaluation and feedback tool used to facilitate feedback to EM faculty about their teaching skills during a shift. The tool has four domains: teaching clinical decision-making; teaching interpersonal skills; teaching procedural skills; and general teaching strategies. Each domain contains novice, intermediate, and advanced sections with 2-5 concrete examples for each level of performance., Conclusion: This structured process resulted in a well-grounded and systematically developed evaluation tool for EM faculty that can provide real-time actionable feedback to faculty and support improved clinical teaching., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. This work was supported by an Education Research grant (EF2016-002) from the Society for Academic Emergency Medicine Foundation.

Precision medicine is an emerging approach to disease treatment and prevention that considers variability in patient genes, environment, and lifestyle. However, little has been written about how such research impacts emergency care. Recent advances in analytical techniques have made it possible to characterize patients in a more comprehensive and sophisticated fashion at the molecular level, promising highly individualized diagnosis and treatment. Among these techniques are various systematic molecular phenotyping analyses (e.g., genomics, transcriptomics, proteomics, and metabolomics). Although a number of emergency physicians use such techniques in their research, widespread discussion of these approaches has been lacking in the emergency care literature and many emergency physicians may be unfamiliar with them. In this article, we briefly review the underpinnings of such studies, note how they already impact acute care, discuss areas in which they might soon be applied, and identify challenges in translation to the emergency department (ED). While such techniques hold much promise, it is unclear whether the obstacles to translating their findings to the ED will be overcome in the near future. Such obstacles include validation, cost, turnaround time, user interface, decision support, standardization, and adoption by end-users., Competing Interests: There are no relevant commercial conflicts of interest., (© 2016 by the Society for Academic Emergency Medicine.)

Background: The emergency medicine milestones were developed to provide more objective resident assessment than current methods. However, little is known about the best practices for applying the milestones in resident assessment., Objective: We examined the utility of end-of-shift evaluations (ESEs) constructed using the milestones in resident assessment., Methods: We developed 14 daily ESEs, each of which included 9 or 10 emergency medicine milestones. Postgraduate year (PGY)-1 and PGY-2 residents were assessed on milestone levels 1 through 3; PGY-3 and PGY-4 residents were assessed on levels 3 through 5. Each milestone was rated on a nominal scale (yes, no, or not applicable). The Clinical Competency Committee combined the ESE data with data from other assessments to determine each resident's proficiency level for the emergency medicine subcompetencies. We used descriptive statistics to summarize resident ESEs and milestone levels. We analyzed differences in ESE score across PGY levels using t tests and analyses of variance., Results: Faculty completed 763 ESEs on 33 residents with a range of 2 to 54 (median=22) ESEs per resident. Faculty rarely (8%, 372 of 4633) rated a resident as not achieving a milestone on the ESEs. Analyses of variance revealed that ESE scores on level 3 milestones did not differ significantly by PGY level. There was poor agreement between ESE scores and Clinical Competency Committee ratings., Conclusions: The ESEs constructed using the milestones resulted in grade or milestone inflation. Our results do not support using milestones as a stand-alone assessment tool.

Implications for practice and research: Wong and colleagues' study improves on current risk stratification models for sepsis. The study's findings may lead to more homogeneous patient populations enrolled into clinical trials, increasing the chance of successful development of novel therapies for sepsis. There are no immediate practice implications, due to clinically unavailable biomarker tests and a cumbersome algorithm.