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BACKGROUND: Post-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID. METHODS: We conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30-85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo. Participants, investigators, care providers, and outcomes assessors were masked to study group assignment. The primary outcome was severe COVID-19 by day 14, and those data have been published previously. Because the trial was delivered remotely nationwide, the a priori primary sample was a modified intention-to-treat sample, meaning that participants who did not receive any dose of study treatment were excluded. Long COVID diagnosis by a medical provider was a prespecified, long-term secondary outcome. This trial is complete and is registered with ClinicalTrials.gov, NCT04510194. FINDINGS: Between Dec 30, 2020, and Jan 28, 2022, 6602 people were assessed for eligibility and 1431 were enrolled and randomly assigned. Of 1323 participants who received a dose of study treatment and were included in the modified intention-to-treat population, 1126 consented for long-term follow-up and completed at least one survey after the assessment for long COVID at day 180 (564 received metformin and 562 received matched placebo; a subset of participants in the metformin vs placebo trial were also randomly assigned to receive ivermectin or fluvoxamine). 1074 (95%) of 1126 participants completed at least 9 months of follow-up. 632 (56·1%) of 1126 participants were female and 494 (43·9%) were male; 44 (7·0%) of 632 women were pregnant. The median age was 45 years (IQR 37-54) and median BMI was 29·8 kg/m2 (IQR 27·0-34·2). Overall, 93 (8·3%) of 1126 participants reported receipt of a long COVID diagnosis by day 300. The cumulative incidence of long COVID by day 300 was 6·3% (95% CI 4·2-8·2) in participants who received metformin and 10·4% (7·8-12·9) in those who received identical metformin placebo (hazard ratio [HR] 0·59, 95% CI 0·39-0·89; p=0·012). The metformin beneficial effect was consistent across prespecified subgroups. When metformin was started within 3 days of symptom onset, the HR was 0·37 (95% CI 0·15-0·95). There was no effect on cumulative incidence of long COVID with ivermectin (HR 0·99, 95% CI 0·59-1·64) or fluvoxamine (1·36, 0·78-2·34) compared with placebo. INTERPRETATION: Outpatient treatment with metformin reduced long COVID incidence by about 41%, with an absolute reduction of 4·1%, compared with placebo. Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost, and safe. FUNDING: Parsemus Foundation; Rainwater Charitable Foundation; Fast Grants; UnitedHealth Group Foundation; National Institute of Diabetes, Digestive and Kidney Diseases; National Institutes of Health; and National Center for Advancing Translational Sciences.

OBJECTIVES: Recent research has helped define the complex pathways in sepsis, affording new opportunities for advancing diagnostics tests. Given significant advances in the field, a group of academic investigators from emergency medicine, intensive care, pathology, and pharmacology assembled to develop consensus around key gaps and potential future use for emerging rapid host response diagnostics assays in the emergency department (ED) setting. METHODS: A modified Delphi study was conducted that included 26 panelists (expert consensus panel) from multiple specialties. A smaller steering committee first defined a list of Delphi statements related to the need for and future potential use of a hypothetical sepsis diagnostic test in the ED. Likert scoring was used to assess panelists agreement or disagreement with statements. Two successive rounds of surveys were conducted and consensus for statements was operationally defined as achieving agreement or disagreement of 75% or greater. RESULTS: Significant gaps were identified related to current tools for assessing risk of sepsis in the ED. Strong consensus indicated the need for a test providing an indication of the severity of dysregulated host immune response, which would be helpful even if it did not identify the specific pathogen. Although there was a relatively high degree of uncertainty regarding which patients would most benefit from the test, the panel agreed that an ideal host response sepsis test should aim to be integrated into ED triage and thus should produce results in less than 30 minutes. The panel also agreed that such a test would be most valuable for improving sepsis outcomes and reducing rates of unnecessary antibiotic use. CONCLUSION: The expert consensus panel expressed strong consensus regarding gaps in sepsis diagnostics in the ED and the potential for new rapid host response tests to help fill these gaps. These finding provide a baseline framework for assessing key attributes of evolving host response diagnostic tests for sepsis in the ED.

BackgroundReduced cholesterol levels are associated with increased organ failure and mortality in sepsis. Cholesterol levels may vary by infection type (gram negative vs positive), possibly reflecting differences in cholesterol-mediated bacterial clearance.MethodsThis was a secondary analysis of a combined data set of 2 prospective cohort studies of adult patients meeting Sepsis-3 criteria. Infection types were classified as gram negative, gram positive, or culture negative. We investigated quantitative (levels) and qualitative (dysfunctional high-density lipoprotein [HDL]) cholesterol differences. We used multivariable logistic regression to control for disease severity.ResultsAmong 171 patients with sepsis, infections were gram negative in 67, gram positive in 46, and culture negative in 47. Both gram-negative and gram-positive infections occurred in 11 patients. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and HDL cholesterol (HDL-C) levels were lower for culture-positive sepsis at enrollment (TC, P < .001; LDL-C, P < .001; HDL-C, P = .011) and persisted after controlling for disease severity. Similarly, cholesterol levels were lower among culture-positive patients at 48 hours (TC, P = .012; LDL-C, P = .029; HDL-C, P = .002). Triglyceride (TG) levels were lower at enrollment (P =.033) but not at 48 hours (P = .212). There were no differences in dysfunctional HDL. Among bacteremic patients, cholesterol levels were lower at enrollment (TC, P = .010; LDL-C, P = .010; HDL-C, P ≤ .001; TG, P = .005) and at 48 hours (LDL-C, P = .027; HDL-C, P < .001; TG, P = .020), except for 48 hour TC (P = .051). In the bacteremia subgroup, enrollment TC and LDL-C were lower for gram-negative versus gram-positive infections (TC, P = .039; LDL-C, P = .023).ConclusionCholesterol levels are significantly lower among patients with culture-positive sepsis and bacteremia.

PURPOSE: Microbial infection stimulates neutrophil/macrophage/monocyte extracellular trap formation, which leads to the release of citrullinated histone H3 (CitH3) catalyzed by peptidylarginine deiminase (PAD) 2 and 4. Understanding these molecular mechanisms in the pathogenesis of septic shock will be an important next step for developing novel diagnostic and treatment modalities. We sought to determine the expression of CitH3 in patients with septic shock, and to correlate CitH3 levels with PAD2/PAD4 and clinically relevant outcomes. METHODS: Levels of CitH3 were measured in serum samples of 160 critically ill patients with septic and non-septic shock, and healthy volunteers. Analyses of clinical and laboratory characteristics of patients were conducted. RESULTS: Levels of circulating CitH3 at enrollment were significantly increased in septic shock patients (n = 102) compared to patients hospitalized with non-infectious shock (NIC) (n = 32, p

Introduction: The coronavirus disease 2019 (COVID-19) pandemic has been shown to increase levels of psychological distress among healthcare workers. Little is known, however, about specific positive and negative individual and organizational factors that affect the mental health of emergency physicians (EP) during COVID-19. Our objective was to assess these factors in a broad geographic sample of EPs in the United States.  Methods: We conducted an electronic, prospective, cross-sectional national survey of EPs from October 6–December 29, 2020. Measures assessed negative mental health outcomes (depression, anxiety, post-traumatic stress, and insomnia), positive work-related outcomes, and strategies used to cope with COVID-19. After preliminary analyses and internal reliability testing, we performed four separate three-stage hierarchical multiple regression analyses to examine individual and organizational predictive factors for psychological distress.  Results: Response rate was 50%, with 517 EPs completing the survey from 11 different sites. Overall, 85% of respondents reported negative psychological effects due to COVID-19. Participants reported feeling more stressed (31%), lonelier (26%), more anxious (25%), more irritable (24%) and sadder (17.5%). Prevalence of mental health conditions was 17% for depression, 13% for anxiety, 7.5% for post-traumatic stress disorder (PTSD), and 18% for insomnia. Regular exercise decreased from 69% to 56%, while daily alcohol use increased from 8% to 15%. Coping strategies of behavioral disengagement, self-blame, and venting were significant predictors of psychological distress, while humor and positive reframing were negatively associated with psychological distress.  Conclusion: Emergency physicians have experienced high levels of psychological distress during the COVID-19 pandemic. Those using avoidant coping strategies were most likely to experience depression, anxiety, insomnia, and PTSD, while humor and positive reframing were effective coping strategies.

ObjectiveLack of empathic communication between providers and patients may contribute to low value diagnostic testing in emergency care. Accordingly, we measured the perception of physician empathy and trust in patients undergoing low-value computed tomography (CT) in the emergency department (ED).MethodsMulticenter study of ED patients undergoing CT scanning, acknowledged by ordering physicians as unlikely to show an emergent condition. Near the end of their visit, patients completed the Jefferson Scale of Patient Perception of Physician Empathy (JSPPPE), Trust in Physicians Survey (TIPS), and the Group Based Medical Mistrust Scale (GBMMS). We stratified results by patient demographics including gender, race, and education.ResultsWe enrolled 305 participants across 9 sites with diverse geographic, racial, and ethnic representation. The median scores (interquartile ranges) for the JSPPPE, TIPS, and GBMMS for all patients were 29 (24-33.5), 55 (47-62), and 18 (12-29). Compared with white patients, nonwhite patients had similar JSPPPE and TIPS scores but had higher (worse) GBMMS scores. Females had significantly lower JSPPPE and TIPS scores than males, and scores were lower (worse) in females with college degrees. Patients in the lowest tier of educational status had the highest (better) JSPPPE and TIPS scores. Scores were invariant with physician characteristics.ConclusionAmong patients undergoing low-value CT scanning in the ED, the degree of patient perception of physician empathy and trust varied based on the patients' level of education and gender. Given this variation, an intervention to increase patient perception of physician empathy should contain individualized strategies to address these subgroups, rather than a one-size-fits-all approach.

For a variety of reasons including cheap computing, widespread adoption of electronic medical records, digitalization of imaging and biosignals, and rapid development of novel technologies, the amount of health care data being collected, recorded, and stored is increasing at an exponential rate. Yet despite these advances, methods for the valid, efficient, and ethical utilization of these data remain underdeveloped. Emergency care research, in particular, poses several unique challenges in this rapidly evolving field. A group of content experts was recently convened to identify research priorities related to barriers to the application of data science to emergency care research. These recommendations included: 1) developing methods for cross-platform identification and linkage of patients; 2) creating central, deidentified, open-access databases; 3) improving methodologies for visualization and analysis of intensively sampled data; 4) developing methods to identify and standardize electronic medical record data quality; 5) improving and utilizing natural language processing; 6) developing and utilizing syndrome or complaint-based based taxonomies of disease; 7) developing practical and ethical framework to leverage electronic systems for controlled trials; 8) exploring technologies to help enable clinical trials in the emergency setting; and 9) training emergency care clinicians in data science and data scientists in emergency care medicine. The background, rationale, and conclusions of these recommendations are included in the present article.

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.

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. There was an error on Figure 1. Faculty Shift Card. The top card originally stated, “What should this faculty member do to improve their procedural teaching skills? Select all that apply.” This should be revised to, “What should this faculty member do to improve their clinical decision making teaching skills?  Select all that apply.”

Background Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. Methods COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. Results The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (−0.56 log10 copies/mL; 95% confidence interval [CI], −1.05 to −.06; P =.027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI,.55 to.94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI,.36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. Conclusions In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. Clinical Trials Registration NCT04510194. [ABSTRACT FROM AUTHOR]