Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection.

Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. METHODS: RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. DISCUSSION: RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. REGISTRATION: NCT05172024.

Anti-nucleocapsid antibody levels and pulmonary comorbid conditions are linked to post-COVID-19 syndrome.

BACKGROUNDProlonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.METHODSAdult SARS-CoV-2 reverse transcription PCR-positive (RT-PCR-positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1-3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTSOur cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSIONWe found that all disease severities had a similar risk of developing post-COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.TRIAL REGISTRATIONClinicalTrials.gov, NCT04373148.FUNDINGNIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.

Factors driving burnout and professional fulfillment among emergency medicine residents: A national wellness survey by the Society for Academic Emergency Medicine.

Objectives: This study aimed to identify rates of and contributors to burnout and professional fulfillment among emergency medicine (EM) resident physicians. Methods: This was a cross-sectional, national survey of resident members of the Society for Academic Emergency Medicine (SAEM). Primary outcomes were burnout and professional fulfillment measured using a previously validated instrument with additional domains pertaining to the academic environment. The survey included question domains examining organizational factors (e.g., academic work environment, satisfaction with training, electronic health records, values alignment, and control over schedule) and individual factors (e.g., self-compassion, meaningfulness of clinical work, impact of work on health and personal relationships, perceived appreciation, thoughts of attrition, and expectations of the field of EM). Logistic regression was performed to determine the relationships between the primary outcomes and each domain. Results: The survey was sent electronically to 2641 SAEM resident members. A total of 275 residents completed the survey with a response rate of 10.4%. A total of 151 (55%) respondents were male, and 210 (76%) were White. A total of 132 (48%) residents reported burnout, and 75 (28%) reported professional fulfillment. All organizational and individual factors were significantly associated with both primary outcomes. EM residents reported that meaningfulness of clinical work had the most significant positive association with professional fulfillment (adjusted odds ratio [OR] 2.2 [95% confidence interval {CI} 1.8-2.7]) and negative association with burnout (adjusted OR 0.46 [95% CI 0.37-0.56]). Thoughts of attrition from academics and accurate expectations of EM were also associated with both primary outcomes, with adjusted ORs (95% CIs) of 0.40 (0.21-0.72) and 5.6 (1.9-23.8) for professional fulfillment and 4.1 (2.5-7.1) and 0.19 (0.08-0.40) for burnout, respectively. Conclusions: This study found a high prevalence of burnout and a low prevalence of professional fulfillment among EM residents. Multiple factors were significantly associated with each occupational phenomenon, with meaningfulness of clinical work demonstrating the strongest relationships with burnout and professional fulfillment.

Taking Aim at the Injury Prevention Curriculum: Educating Residents on Talking to Patients About Firearm Injury.

The medical community recognizes that firearm injury is a public health problem. Yet we lack both the tools for and the implementation of evidence-based firearm injury screening and counseling techniques. One reason for these deficits is the lack of clinical training related to engaging patients in firearm injury risk reduction. In this issue, Rickert et al describe a pre-post evaluation of a 2-part firearm injury prevention training curriculum for first-year medical residents at a single academic medical center. Their manuscript serves an important, but still preliminary, step forward for the field of postgraduate medical education on firearm injury and its prevention. Important elements of this project and paper consist of the inclusion of multiple medical disciplines and the use of standardized patients to evaluate participants' learning. This project also points to the need for further growth. We must commit to consistently and conscientiously framing injuries from guns not as "gun violence" but rather as "firearm injuries" to ensure that they are considered squarely in both the public health space and the clinical space. An ideal curriculum would also highlight the importance of trauma-informed care, cultural competency, and antiracist medical practice while countering implicit biases (e.g., toward gun owners, victims of firearm violence, perpetrators of violence). It should address barriers, as well as facilitators, to change. And most importantly, future educational work must evaluate the effect of these trainings on actual clinical practice-and, even better, the efficacy of education in changing behavior and patient-level outcomes.

Drivers of professional fulfillment and burnout among emergency medicine faculty: A national wellness survey by the Society for Academic Emergency Medicine.

BACKGROUND: Professional fulfillment and the mitigation of burnout can enhance clinician well-being and the resiliency of the health care organization. This study examined the extent to which specific individual and workplace factors are associated with professional fulfillment and burnout among a national sample of academic emergency physicians. METHODS: This was a cross-sectional survey of faculty members of the Society for Academic Emergency Medicine. Primary outcomes were professional fulfillment and burnout. The survey also examined individual and workplace factors as well as faculty's thoughts of attrition from academic and clinical medicine. Logistic regression was performed to determine the relationships between each outcome and each factor, respectively. RESULTS: A total of 771 of 3130 faculty completed the survey (response rate 24.6%). A total of 38.7% reported professional fulfillment and 39.1% reported burnout. Meaningfulness of work (odds ratio [OR] 2.2, 95% confidence interval [CI] 1.9-2.5), perceived appreciation (OR 1.9, 95% CI 1.7-2.1), and the academic work environment (OR 1.7, 95% CI 1.5-1.9) had the highest odds of being associated with professional fulfillment. In contrast, low score responses for meaningfulness of work (OR 0.6, 95% CI 0.5-0.6), self-compassion (0.6, 95% CI 0.5-0.6), and control over schedule (OR 0.6, 95% CI 0.6-0.7) were most associated with burnout. Faculty with professional fulfillment were less likely to report plans for attrition from academics (OR 0.1, 95% CI 0.1-0.2) and from clinical medicine (OR 0.2, 95% CI 0.1-0.4). Faculty with burnout were more likely to report plans for attrition from academics (OR 7, 95% CI 4.8-10.4) and clinical medicine (OR 5.7, 95% CI 3.9-8.6). CONCLUSIONS: Individual and workplace factors that contributed to professional fulfillment and burnout were identified, with meaningfulness of clinical work demonstrating the strongest association with both occupational phenomena. Knowledge of which factors are most impactful in promoting professional fulfillment and mitigating burnout may be useful in guiding efforts to enhance clinician well-being.

Feasibility of Specimen Self-collection in Young Children Undergoing SARS-CoV-2 Surveillance for In-Person Learning.

Importance: There is an urgent need to assess the feasibility of COVID-19 surveillance measures in educational settings. Objective: To assess whether young children can feasibly self-collect SARS-CoV-2 samples for surveillance testing over the course of an academic year. Design, Setting, and Participants: This prospective pilot cohort study was conducted from September 10, 2020, to June 10, 2021, at a K-8 school in San Mateo County, California. The research consisted of quantitative data collection efforts: (1) demographic data collected, (2) student sample self-collection error rates, and (3) student sample self-collection time durations. Students were enrolled in a hybrid learning model, a teaching model in which students were taught in person and online, with students having the option to attend virtually as needed. Data were collected under waiver of consent from students participating in weekly SARS-CoV-2 testing. Main Outcomes and Measures: Errors over time for self-collection of nasal swabs such as contaminated swabs and inadequate or shallow swabbing; time taken for sample collection. Results: Of 296 participants, 148 (50.0%) were boys and 148 (50.0%) were girls. A total of 87 participants (29.2%) identified as Asian; 2 (0.6%), Black or African American; 13 (4.4%), Hispanic/Latinx; 103 (34.6%), non-Hispanic White; 87 (29.2%), multiracial; and 6 (2.0%), other. The median school grade was fourth grade. From September 2020 to March 2021, a total of 4203 samples were obtained from 221 students on a weekly basis, while data on error rates were collected. Errors occurred in 2.7% (n = 107; 95% CI, 2.2%-3.2%) of student encounters, with the highest rate occurring on the first day of testing (20 [10.2%]). There was an overall decrease in error rates over time. From April to June 2021, a total of 2021 samples were obtained from 296 students on a weekly basis while data on encounter lengths were collected. Between April and June 2021, 193 encounters were timed. The mean duration of each encounter was 70 seconds (95% CI, 66.4-73.7 seconds). Conclusions and Relevance: Mastery of self-collected lower nasal swabs is possible for children 5 years and older. Testing duration can be condensed once students gain proficiency in testing procedures. Scalability for larger schools is possible if consideration is given to the resource-intensive nature of the testing and the setting's weather patterns.

Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation.

Prostaglandin D2 (PGD2) released from immune cells or other cell types activates its receptors, D prostanoid receptor (DP)1 and 2 (DP1 and DP2), to promote inflammatory responses in allergic and lung diseases. Prostaglandin-mediated inflammation may also contribute to vascular diseases such as abdominal aortic aneurysm (AAA). However, the role of DP receptors in the pathogenesis of AAA has not been systematically investigated. In the present study, DP1-deficient mice and pharmacological inhibitors of either DP1 or DP2 were tested in two distinct mouse models of AAA formation: angiotensin II (AngII) infusion and calcium chloride (CaCl2) application. DP1-deficient mice [both heterozygous (DP1+/-) and homozygous (DP1-/-)] were protected against CaCl2-induced AAA formation, in conjunction with decreased matrix metallopeptidase (MMP) activity and adventitial inflammatory cell infiltration. In the AngII infusion model, DP1+/- mice, but not DP1-/- mice, exhibited reduced AAA formation. Interestingly, compensatory up-regulation of the DP2 receptor was detected in DP1-/- mice in response to AngII infusion, suggesting a potential role for DP2 receptors in AAA. Treatment with selective antagonists of DP1 (laropiprant) or DP2 (fevipiprant) protected against AAA formation, in conjunction with reduced elastin degradation and aortic inflammatory responses. In conclusion, PGD2 signaling contributes to AAA formation in mice, suggesting that antagonists of DP receptors, which have been extensively tested in allergic and lung diseases, may be promising candidates to ameliorate AAA.

Association Between SARS-CoV-2 RNAemia and Postacute Sequelae of COVID-19.

Determinants of Post-Acute Sequelae of COVID-19 are not known. Here we show that 83.3% of patients with viral RNA in blood (RNAemia) at presentation were symptomatic in the post-acute phase. RNAemia at presentation successfully predicted PASC, independent of patient demographics, worst disease severity, and length of symptoms.

Institutional solutions addressing disparities in compensation and advancement of emergency medicine physicians: A critical appraisal of gaps and associated recommendations.

BACKGROUND: Disparities in salary and advancement of emergency medicine (EM) faculty by race and gender have been consistently demonstrated for over three decades. Prior studies have largely focused on individual-level solutions. To identify systems-based interventions, the Society for Academic Emergency Medicine (SAEM) formed the Research Equity Task Force in 2018 with members from multiple academies (the Academy of Academic Chairs in Emergency Medicine [AACEM], the Academy of Academic Administrators in Emergency Medicine [AAAEM], the Academy for Women in Academic Emergency Medicine [AWAEM], and the Academy for Diversity and Inclusion in Emergency Medicine [ADIEM]) and sought recommendations from EM departmental leaders. METHODS: The task force conducted interviews containing both open-ended narrative and closed-ended questions in multiple phases. Phase 1 included a convenience sample of chairs of EM departments across the United States, and phase 2 included vice-chairs and other faculty who lead promotion and advancement. The task force identified common themes from the interviews and then developed three-tiered sets of recommendations (minimal, target, and aspirational) based on participant responses. In phase 3, iterative feedback was collected and implemented on these recommendations from study participants and chairs participating in a national AACEM webinar. RESULTS: In findings from 53 interviews of chairs, vice-chairs, and faculty leaders from across the United States, we noted heterogeneity in the faculty development and promotion processes across institutions. Four main themes were identified from the interviews: the need for a directed, structured promotion process; provision of structured mentorship; clarity on requirements for promotion within tracks; and transparency in salary structure. Recommendations were developed to address gaps in structured mentorship and equitable promotion and compensation. CONCLUSIONS: These recommendations for AEM departments have the potential to increase structured mentorship programs, improve equity in promotion and advancement, and reduce disparities in the AEM workforce. These recommendations have been endorsed by SAEM, AACEM, AWAEM, ADIEM, and AAAEM.

SARS-CoV-2 RNAemia Predicts Clinical Deterioration and Extrapulmonary Complications from COVID-19.

BACKGROUND: The determinants of coronavirus disease 2019 (COVID-19) disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and disease severity, clinical deterioration, and specific EPCs. METHODS: We used quantitative and digital polymerase chain reaction (qPCR and dPCR) to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the emergency department with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression. RESULTS: Of SARS-CoV-2-positive patients, 23.0% (44 of 191) had viral RNA detected in plasma by dPCR, compared with 1.4% (2 of 147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAemic patients were more likely to manifest severe disease (odds ratio, 6.72 [95% confidence interval, 2.45-19.79]), worsening of disease severity (2.43 [1.07-5.38]), and EPCs (2.81 [1.26-6.36]). RNA loads were correlated with maximum severity (r = 0.47 [95% confidence interval, .20-.67]). CONCLUSIONS: dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Because many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.

Establishing a Data Science Unit in an Academic Medical Center: An Illustrative Model.

The field of data science has great potential to address critical questions relevant for academic medical centers. Data science initiatives are consequently being established within academic medicine. At the cornerstone of such initiatives are scientists who practice data science. These scientists include biostatisticians, clinical informaticians, database and software developers, computational scientists, and computational biologists. Too often, however, those involved in the practice of data science are viewed by academic leadership as providing a noncomplex service to facilitate research and further the careers of other academic faculty. The authors contend that the success of data science initiatives relies heavily on the understanding that the practice of data science is a critical intellectual contribution to the overall science conducted at an academic medical center. Further, careful thought by academic leadership is needed for allocation of resources devoted to the practice of data science. At the Stanford University School of Medicine, the authors have developed an innovative model for a data science collaboratory based on 4 fundamental elements: an emphasis on collaboration over consultation, a subscription-based funding mechanism that reflects commitment by key partners, an investment in the career development of faculty who practice data science, and a strong educational component for data science members in team science and for clinical and translational investigators in data science. As data science becomes increasingly essential to learning health systems, centers that specialize in the practice of data science are a critical component of the research infrastructure and intellectual environment of academic medical centers.

Emergency medicine research: 2030 strategic goals.

All academic medical specialties have the obligation to continuously create new knowledge that will improve patient care and outcomes. Emergency medicine (EM) is no exception. Since its origins over 50 years ago, EM has struggled to fulfill its research mission. EM ranks last among clinical specialties in the percentage of medical school faculty who are National Institutes of Health (NIH)-funded principal investigators (PIs; 1.7%) and the percentage of medical school departments with NIH-funded PIs (33%). Although there has been a steady increase in the number of NIH-funded projects and total NIH dollars, the slowing growth in the number of NIH-funded PIs and lack of growth in the number of EM departments with NIH-funded PIs is cause for concern. In response, the Association of Academic Chairs of Emergency Medicine (AACEM) Research Task Force proposes a set of 2030 strategic goals for the EM research enterprise that are based on sustaining historic growth rates in NIH funding. These goals have been endorsed by the AACEM Executive Committee and the boards of Society for Academic Emergency Medicine (SAEM), American College of Emergency Physicians (ACEP), and American Academy of Emergency Medicine (AAEM). The 2030 strategic goals include 200 NIH-funded projects led by 150 EM PIs in at least 50 EM departments with over $100M in annual funding resulting in over 3% of EM faculty being NIH-funded PIs. Achieving these goals will require a targeted series of focused strategies to increase the number of EM faculty who are competitive for NIH funding. This requires a coordinated, intentional effort with investments at the national, departmental, and individual levels. These efforts are ideally led by medical school department chairs, who can create the culture and provide the resources needed to be successful. The specialty of EM has the obligation to improve the health of the public and to fulfill its research mission.

Asthma phenotypes, associated comorbidities, and long-term symptoms in COVID-19.

BACKGROUND: It is unclear whether asthma and its allergic phenotype are risk factors for hospitalization or severe disease from SARS-CoV-2. METHODS: All patients over 28 days old testing positive for SARS-CoV-2 between March 1 and September 30, 2020, were retrospectively identified and characterized through electronic analysis at Stanford. A sub-cohort was followed prospectively to evaluate long-term COVID-19 symptoms. RESULTS: 168,190 patients underwent SARS-CoV-2 testing, and 6,976 (4.15%) tested positive. In a multivariate analysis, asthma was not an independent risk factor for hospitalization (OR 1.12 [95% CI 0.86, 1.45], p = .40). Among SARS-CoV-2-positive asthmatics, allergic asthma lowered the risk of hospitalization and had a protective effect compared with non-allergic asthma (OR 0.52 [0.28, 0.91], p = .026); there was no association between baseline medication use as characterized by GINA and hospitalization risk. Patients with severe COVID-19 disease had lower eosinophil levels during hospitalization compared with patients with mild or asymptomatic disease, independent of asthma status (p = .0014). In a patient sub-cohort followed longitudinally, asthmatics and non-asthmatics had similar time to resolution of COVID-19 symptoms, particularly lower respiratory symptoms. CONCLUSIONS: Asthma is not a risk factor for more severe COVID-19 disease. Allergic asthmatics were half as likely to be hospitalized with COVID-19 compared with non-allergic asthmatics. Lower levels of eosinophil counts (allergic biomarkers) were associated with a more severe COVID-19 disease trajectory. Recovery was similar among asthmatics and non-asthmatics with over 50% of patients reporting ongoing lower respiratory symptoms 3 months post-infection.

A Randomized, Placebo-Controlled Clinical Trial of Bamlanivimab and Etesevimab Together in High-Risk Ambulatory Patients With COVID-19 and Validation of the Prognostic Value of Persistently High Viral Load.

BACKGROUND: Based on interim analyses and modeling data, lower doses of bamlanivimab and etesevimab together (700/1400 mg) were investigated to determine optimal dose and expand availability of treatment. METHODS: This Phase 3 portion of the BLAZE-1 trial characterized the effect of bamlanivimab with etesevimab on overall patient clinical status and virologic outcomes in ambulatory patients ≥12 years old, with mild-to-moderate coronavirus disease 2019 (COVID-19), and ≥1 risk factor for progressing to severe COVID-19 and/or hospitalization. Bamlanivimab and etesevimab together (700/1400 mg) or placebo were infused intravenously within 3 days of patients' first positive COVID-19 test. RESULTS: In total, 769 patients were infused (median age [range]; 56.0 years [12, 93], 30.3% of patients ≥65 years of age and median duration of symptoms; 4 days). By day 29, 4/511 patients (0.8%) in the antibody treatment group had a COVID-19-related hospitalization or any-cause death, as compared with 15/258 patients (5.8%) in the placebo group (Δ[95% confidence interval {CI}] = -5.0 [-8.0, -2.1], P < .001). No deaths occurred in the bamlanivimab and etesevimab group compared with 4 deaths (all COVID-19-related) in the placebo group. Patients receiving antibody treatment had a greater mean reduction in viral load from baseline to Day 7 (Δ[95% CI] = -0.99 [-1.33, -.66], P < .0001) compared with those receiving placebo. Persistently high viral load at Day 7 correlated with COVID-19-related hospitalization or any-cause death by Day 29 in all BLAZE-1 cohorts investigated. CONCLUSIONS: These data support the use of bamlanivimab and etesevimab (700/1400 mg) for ambulatory patients at high risk for severe COVID-19. Evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants will require continued monitoring to determine the applicability of this treatment. CLINICAL TRIALS REGISTRATION: NCT04427501.

Assessment of Allergic and Anaphylactic Reactions to mRNA COVID-19 Vaccines With Confirmatory Testing in a US Regional Health System.

Importance: As of May 2021, more than 32 million cases of COVID-19 have been confirmed in the United States, resulting in more than 615 000 deaths. Anaphylactic reactions associated with the Food and Drug Administration (FDA)-authorized mRNA COVID-19 vaccines have been reported. Objective: To characterize the immunologic mechanisms underlying allergic reactions to these vaccines. Design, Setting, and Participants: This case series included 22 patients with suspected allergic reactions to mRNA COVID-19 vaccines between December 18, 2020, and January 27, 2021, at a large regional health care network. Participants were individuals who received at least 1 of the following International Statistical Classification of Diseases and Related Health Problems, Tenth Revision anaphylaxis codes: T78.2XXA, T80.52XA, T78.2XXD, or E949.9, with documentation of COVID-19 vaccination. Suspected allergy cases were identified and invited for follow-up allergy testing. Exposures: FDA-authorized mRNA COVID-19 vaccines. Main Outcomes and Measures: Allergic reactions were graded using standard definitions, including Brighton criteria. Skin prick testing was conducted to polyethylene glycol (PEG) and polysorbate 80 (P80). Histamine (1 mg/mL) and filtered saline (negative control) were used for internal validation. Basophil activation testing after stimulation for 30 minutes at 37 °C was also conducted. Concentrations of immunoglobulin (Ig) G and IgE antibodies to PEG were obtained to determine possible mechanisms. Results: Of 22 patients (20 [91%] women; mean [SD] age, 40.9 [10.3] years; 15 [68%] with clinical allergy history), 17 (77%) met Brighton anaphylaxis criteria. All reactions fully resolved. Of patients who underwent skin prick tests, 0 of 11 tested positive to PEG, 0 of 11 tested positive to P80, and 1 of 10 (10%) tested positive to the same brand of mRNA vaccine used to vaccinate that individual. Among these same participants, 10 of 11 (91%) had positive basophil activation test results to PEG and 11 of 11 (100%) had positive basophil activation test results to their administered mRNA vaccine. No PEG IgE was detected; instead, PEG IgG was found in tested individuals who had an allergy to the vaccine. Conclusions and Relevance: Based on this case series, women and those with a history of allergic reactions appear at have an elevated risk of mRNA vaccine allergy. Immunological testing suggests non-IgE-mediated immune responses to PEG may be responsible in most individuals.

Empowering patients: simplifying discharge instructions.

Patients who do not have enough information about their discharge plans have decreased treatment compliance, decreased patient safety, increased emergency department (ED) recidivism, and poor satisfaction. This project aimed to develop and implement a method to assess and improve patient understanding of treatment and discharge plan in the ED. The authors developed a questionnaire to assess patient knowledge using Centers for Medicare and Medicaid Services and Joint Commission recommendations, areas of communication deficits reported in other manuscripts, and ED staff and provider input. Responses from patient interviews were then scored against the medical record. Three trained scorers graded all responses, and inter-rater reliability was calculated using the kappa statistic.Baseline observations found that written discharge instructions were long and tedious, and important information was difficult to find. Based on initial patient scores, stakeholder interviews, and fishbone diagrams, the team developed a one-page simplified information page (SIP) targeted to inform patients their most relevant discharge instructions. Next, the SIP was tested on 118 patients to measure its effect on patient understanding. At the baseline study, no patients had complete understanding of their discharge instructions. The areas of lowest scores were medication instructions and indications to return to the ED. Implementation of the SIP resulted in statistically significant changes in score distribution across all questions assessed with the Wilcoxon signed-rank test. Interrater reliability between scorers was high (kappa=0.84). We incorporated the concept of the SIP to the cover page of our standard discharge instructions.Healthcare providers often spend valuable time educating their patients, and it is important to assess the effectiveness of this teaching to identify areas in which we may improve health literacy and patient understanding. This project has shown that a simple, easy-to-read, concise page developed with patient input significantly improved ED discharge instruction knowledge.

Association Between SARS-CoV-2 RNAemia and Post-Acute Sequelae of COVID-19.

Determinants of Post-Acute Sequelae of COVID-19 are not known. Here we show that 75% of patients with viral RNA in blood (RNAemia) at presentation were symptomatic in the post-acute phase. RNAemia at presentation successfully predicted PASC, independent of patient demographics, initial disease severity, and length of symptoms.

Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.

Our understanding of protective versus pathological immune responses to SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), is limited by inadequate profiling of patients at the extremes of the disease severity spectrum. Here, we performed multi-omic single-cell immune profiling of 64 COVID-19 patients across the full range of disease severity, from outpatients with mild disease to fatal cases. Our transcriptomic, epigenomic, and proteomic analyses revealed widespread dysfunction of peripheral innate immunity in severe and fatal COVID-19, including prominent hyperactivation signatures in neutrophils and NK cells. We also identified chromatin accessibility changes at NF-κB binding sites within cytokine gene loci as a potential mechanism for the striking lack of pro-inflammatory cytokine production observed in monocytes in severe and fatal COVID-19. We further demonstrated that emergency myelopoiesis is a prominent feature of fatal COVID-19. Collectively, our results reveal disease severity-associated immune phenotypes in COVID-19 and identify pathogenesis-associated pathways that are potential targets for therapeutic intervention.

SARS-CoV-2 IgG Seropositivity and Acute Asymptomatic Infection Rate among Firefighter First Responders in an Early Outbreak County in California.

Objective: Firefighter first responders and other emergency medical services (EMS) personnel have been among the highest risk healthcare workers for illness during the SARS-CoV-2 pandemic. We sought to determine the rate of seropositivity for SARS-CoV-2 IgG antibodies and of acute asymptomatic infection among firefighter first responders in a single county with early exposure in the pandemic. Methods: We conducted a cross-sectional study of clinically active firefighters cross-trained as paramedics or EMTs in the fire departments of Santa Clara County, California. Firefighters without current symptoms were tested between June and August 2020. Our primary outcomes were rates of SARS-CoV-2 IgG antibody seropositivity and SARS-CoV-2 RT-PCR swab positivity for acute infection. We report cumulative incidence, participant characteristics with frequencies and proportions, and proportion positive and associated relative risk (with 95% confidence intervals). Results: We enrolled 983 out of 1339 eligible participants (response rate: 73.4%). Twenty-five participants (2.54%, 95% CI 1.65-3.73) tested positive for IgG antibodies and 9 (0.92%, 95% CI 0.42-1.73) tested positive for SARS-CoV-2 by RT-PCR. Our cumulative incidence, inclusive of self-reported prior positive PCR tests, was 34 (3.46%, 95% CI 2.41-4.80). Conclusion: In a county with one of the earliest outbreaks in the United States, the seroprevalence among firefighter first responders was lower than that reported by other studies of frontline health care workers, while the cumulative incidence remained higher than that seen in the surrounding community.