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Objective: The objective of this study is to evaluate the diagnostic performance of the BinaxNow Influenza A&B rapid antigen test (RAT) in emergency department (ED) patients.Methods: We prospectively enrolled a systematic sample of ED patients older than 6 months with acute respiratory symptoms or nonlocalizing fever during 3 consecutive influenza seasons (2008-2011). Nasal and throat swabs collected by research personnel were tested for influenza by real-time reverse transcription-polymerase chain reaction (RT-PCR). Clinicians independently ordered RATs during clinical care; these specimens were collected by clinical staff and tested for influenza using the BinaxNow RAT. Patients with both a research RT-PCR and clinical RAT were included in the study. Rapid antigen test diagnostic performance was evaluated using RT-PCR as a criterion standard, with preplanned, stratified analysis for subject age, duration of symptoms, influenza subtype, and polymerase chain reaction cycle threshold, which provides a semiquantitative estimate of viral load.Results: Of 561 subjects enrolled, 131 (23.4%) had a positive RT-PCR, and 37 (6.6%) had a positive RAT. Overall, RAT performance included sensitivity of 24.4% (95% confidence interval [CI], 17.5%-32.9%), specificity of 98.8% (95% CI, 97.1%-99.6%), positive predictive value of 86.5% (95% CI, 70.4%-94.9%), negative predictive value of 81.1% (95% CI, 77.4%-84.3%). Rapid antigen test sensitivities were low for all categories of subject age, symptom duration, influenza subtype, and cycle threshold.Conclusion: The BinaxNow RAT demonstrated high specificity and poor sensitivity in ED patients selected by treating clinicians for influenza testing. A negative RAT is a poor predictor for the absence of influenza in the ED and should not be used as a criterion to withhold antiviral medications. [ABSTRACT FROM AUTHOR]

Objectives: To address the need for interactive visualization tools and databases in characterizing multimorbidity patterns across different populations, we developed the Phenome-wide Multi-Institutional Multimorbidity Explorer (PheMIME). This tool leverages three large-scale EHR systems to facilitate efficient analysis and visualization of disease multimorbidity, aiming to reveal both robust and novel disease associations that are consistent across different systems and to provide insight for enhancing personalized healthcare strategies., Materials and Methods: PheMIME integrates summary statistics from phenome-wide analyses of disease multimorbidities, utilizing data from Vanderbilt University Medical Center, Mass General Brigham, and the UK Biobank. It offers interactive and multifaceted visualizations for exploring multimorbidity. Incorporating an enhanced version of associationSubgraphs, PheMIME also enables dynamic analysis and inference of disease clusters, promoting the discovery of complex multimorbidity patterns. A case study on schizophrenia demonstrates its capability for generating interactive visualizations of multimorbidity networks within and across multiple systems. Additionally, PheMIME supports diverse multimorbidity-based discoveries, detailed further in online case studies., Results: The PheMIME is accessible at https://prod.tbilab.org/PheMIME/. A comprehensive tutorial and multiple case studies for demonstration are available at https://prod.tbilab.org/PheMIME_supplementary_materials/. The source code can be downloaded from https://github.com/tbilab/PheMIME., Discussion: PheMIME represents a significant advancement in medical informatics, offering an efficient solution for accessing, analyzing, and interpreting the complex and noisy real-world patient data in electronic health records., Conclusion: PheMIME provides an extensive multimorbidity knowledge base that consolidates data from three EHR systems, and it is a novel interactive tool designed to analyze and visualize multimorbidities across multiple EHR datasets. It stands out as the first of its kind to offer extensive multimorbidity knowledge integration with substantial support for efficient online analysis and interactive visualization., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Because 20-30% of patients with sepsis deteriorate to critical illness, biomarkers that provide accurate early prognosis may identify which patients need more intensive treatment versus safe early discharge. The objective was to test the performance of sVEGFR2, suPAR and PCT, alone or combined with clinical signs and symptoms, for the prediction of clinical deterioration. This prospective observational study enrolled patients with suspected infection who met SIRS criteria without organ dysfunction (delta SOFA <2 from baseline) from 16 emergency departments. The primary endpoint was clinical deterioration (increased SOFA score ≥2 points, new or increased organ support, or death) within 72 hours of enrollment. Diagnosis and classification of infection status were adjudicated. 724 patients were enrolled, (54% men, median age 55 [38-70] y-o). Infection origin was abdominopelvic (21%), skin and soft tissues (17%), urinary (16%) and pulmonary (15%). 176 (24%) patients deteriorated, with a 28-day mortality of 1.4%. They had lower sVEGFR2 level (6.17 [5.00-7.40] vs 6.52 [5.40-7.84], p=0.024), higher circulating suPAR (5.25 [3.86-7.50] vs 4.18 [3.16-5.68], p<0.001) and higher PCT level (0.32 [0.08-1.80] vs 0.18 [0.05-0.98], p=0.004). suPAR demonstrated superior performance (AUC=0.65 [0.60-0.70]), compared to other biomarkers (PCT, AUC=0.57 [0.52-0.62] and sVEGFR2, AUC=0.58 [0.53-0.64]). Maximum accuracy was achieved from the combination of clinical information, sVEGFR2 and suPAR, yielding an AUC of 0.74 [0.69-0.78] and NPV 0.90 [0.88-0.94]. sVEGFR2 and suPAR were insufficiently accurate to rule out clinical deterioration. Panels of biomarkers will likely be needed to capture the heterogeneous mechanistic pathways involved in sepsis-related organ failure., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: COVID-19 is a strong risk factor for venous thromboembolism (VTE). Few studies have evaluated the effectiveness of COVID-19 vaccination in preventing hospitalization for COVID-19 with VTE., Methods: Adults hospitalized at 21 sites between March 2021 and October 2022 with symptoms of acute respiratory illness were assessed for COVID-19, completion of the original monovalent mRNA COVID-19 vaccination series, and VTE. Prevalence of VTE was compared between unvaccinated and vaccinated patients with COVID-19. Vaccine effectiveness in preventing COVID-19 hospitalization with VTE was calculated using a test negative design. Vaccine effectiveness was also stratified by predominant circulating SARS-CoV-2 variant., Results: Among 18,811 patients (median age 63 [IQR:50-73], 49% women, 59% non-Hispanic White, 20% non-Hispanic Black, 14% Hispanic, and median of 2 comorbid conditions [IQR:1-3]), 9,792 were admitted with COVID-19 (44% vaccinated) and 9,019 were test-negative controls (73% vaccinated). Among patients with COVID-19, 601 were diagnosed with VTE by hospital day 28, of whom 170 were vaccinated. VTE was more common among unvaccinated than vaccinated COVID-19 patients (7.8% versus 4.0%; p=0.001). Vaccine effectiveness against COVID-19 hospitalization with VTE was 84% (95% CI: 80-87%) overall. Vaccine effectiveness stratified by predominant circulating variant was 88% (73-95%) for alpha, 93% (90-95%) for delta, and 68% (58-76%) for omicron variants., Conclusions and Relevance: Vaccination with the original monovalent mRNA series was associated with a decrease in COVID-19 hospitalization with VTE, though data detailing prior history of VTE and use of anticoagulation were not available. These findings will inform risk-benefit considerations for those considering vaccination., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Understanding the pneumococcal serotypes causing community-acquired pneumonia (CAP) is essential for evaluating the impact of pneumococcal vaccines., Methods: We conducted a prospective surveillance study of adults aged ≥18 years hospitalized with CAP at 3 hospitals in Tennessee and Georgia between 1 September 2018 and 31 October 2022. We assessed for pneumococcal etiology with cultures, the BinaxNOW urinary antigen detection test, and serotype-specific urinary antigen detection assays that detect 30 pneumococcal serotypes contained in the investigational pneumococcal conjugate vaccine V116, as well as licensed vaccines PCV15 and PCV20 (except serotype 15B). The distribution of pneumococcal serotypes was calculated based on serotype-specific urinary antigen detection results., Results: Among 2917 hospitalized adults enrolled with CAP, 352 (12.1%) patients had Streptococcus pneumoniae detected, including 51 (1.7%) patients with invasive pneumococcal pneumonia. The 8 most commonly detected serotypes were: 3, 22F, 19A, 35B, 9N, 19F, 23A, and 11A. Among 2917 adults with CAP, 272 (9.3%) had a serotype detected that is contained in V116, compared to 196 (6.7%) patients with a serotype contained in PCV20 (P < .001), and 168 (5.8%) patients with a serotype contained in PCV15 (P < .001). A serotype contained in V116 but not PCV15 or PCV20 was detected in 120 (4.1%) patients, representing 38.0% of serotype detections., Conclusions: Approximately 12% of adults hospitalized with CAP had S. pneumoniae detected, and approximately one-third of the detected pneumococcal serotypes were not contained in PCV15 or PCV20. Development of new pneumococcal vaccines with expanded serotype coverage has the potential to prevent a substantial burden of disease., Competing Interests: Potential conflicts of interest . This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. Additionally, the following authors made the following disclosures. K. D. J. reports being an employee and shareholder with stock options of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. C. G. G. reports consulting fees from Merck & Co., Inc and research funding outside the submitted work from NIH, CDC, AHRQ, FDA, and Campbell Alliance/Syneos Health. C. A. R. reports research funding outside the submitted work from BioFire, GSK, MedImmune, Micron, Merck, Novavx, PaxVax, Regeneron, Pfizer, Sanofi-Pasteur, Janssen, Moderna, NIH, and CDC, reports royalties from Meissa Vaccines, and reports 2 planned patents for RSV vaccines. I. Y. reports research funding outside the submitted work from Merck, and consulting fees from Sanofi Pasteur and Merck. T. W. reports being an employee and shareholder with stock options of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. C. R. reports being an employee and shareholder with stock options of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc. N. R. reports research funding outside the submitted work from Merck, Sanofi, Pfizer, Vaccine Company, Immorna, Quidel and Lilly, reports consulting fees from Krog, reports honoraria from Virology Education and Medscape, reports support for attending a meeting from Sanofi and Moderna, reports participation in advisory boards for Moderna, Sanofi, Seqirus, Pfizer, EMMES, ICON, and Micron, and reports leadership roles with ARLG, TMRC, CDC-Pertussis challenge, and Clinical Infectious Diseases. The other authors reported no conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Rationale: For critically ill adults receiving invasive mechanical ventilation, the ventilator mode determines how breaths are delivered. Whether the choice of ventilator mode affects outcomes for critically ill patients is unknown. To compare the effects of three common ventilator modes (volume control, pressure control, and adaptive pressure control) on death and duration of mechanical ventilation., Methods: We conducted a pragmatic, cluster-randomized, crossover trial among adults receiving invasive mechanical ventilation in a medical ICU between November 1, 2022 and July 31, 2023. Each month, patients in the participating unit were assigned to receive volume control, pressure control, or adaptive pressure control during continuous mandatory ventilation. The primary outcome was ventilator-free days through 28 days., Results: Among 566 patients included in the primary analysis, the median number of ventilator-free days was 23 [IQR, 0-26] in the volume control group, 22 [0-26] in the pressure control group, and 24 [0-26] in the adaptive pressure control group (P=0.60). The median tidal volume was similar in the three groups, but the percentage of breaths larger than 8mL/kg of predicted body weight differed between volume control (median, 4.0%; IQR, 0.0-14.1), pressure control (10.6%; 0.0-31.5), and adaptive pressure control (4.7%; 0.0-19.2). Incidences of hypoxemia, acidemia, and barotrauma were similar in the three groups., Conclusions: Among critically ill adults receiving invasive mechanical ventilation, the use of volume control, pressure control, or adaptive pressure control did not affect the number of ventilator-free days, however, confidence intervals included differences that may be clinically meaningful.

Study Objective: To examine the association between the neuromuscular blocking agent received (succinylcholine versus rocuronium) and the incidences of successful intubation on the first attempt and severe complications during tracheal intubation of critically ill adults in an emergency department (ED) or ICU., Methods: We performed a secondary analysis of data from 2 multicenter randomized trials in critically ill adults undergoing tracheal intubation in an ED or ICU. Using a generalized linear mixed-effects model with prespecified baseline covariates, we examined the association between the neuromuscular blocking agent received (succinylcholine versus rocuronium) and the incidences of successful intubation on the first attempt (primary outcome) and severe complications during tracheal intubation (secondary outcome)., Results: Among the 2,440 patients in the trial data sets, 2,339 (95.9%) were included in the current analysis; 475 patients (20.3%) received succinylcholine and 1,864 patients (79.7%) received rocuronium. Successful intubation on the first attempt occurred in 375 patients (78.9%) who received succinylcholine and 1,510 patients (81.0%) who received rocuronium (an adjusted odds ratio of 0.87; 95% CI 0.65 to 1.15). Severe complications occurred in 67 patients (14.1%) who received succinylcholine and 456 patients (24.5%) who received rocuronium (adjusted odds ratio, 0.88; 95% CI 0.62 to 1.26)., Conclusion: Among critically ill adults undergoing tracheal intubation, the incidences of successful intubation on the first attempt and severe complications were not significantly different between patients who received succinylcholine and patients who received rocuronium., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of the study was to assess patients' attitudes regarding participation in a randomized trial of antibiotics versus placebo for acute diverticulitis., Background: Despite evidence that antibiotics may not be necessary to treat acute uncomplicated diverticulitis, they remain the mainstay of treatment in the United States. A randomized trial in the United States evaluating antibiotic effectiveness could accelerate the implementation of antibiotic-free treatment, but providers maintain concerns that patients may be unwilling to participate., Methods: This mixed-methods study conducted semi-structured interviews of patients presenting to a quaternary care emergency department with acute diverticulitis and a web-based survey of a larger cohort. The interviews assessed patients' experiences with diverticulitis and perceptions of participation in a trial comparing antibiotics versus placebo. The survey quantified patients' willingness to participate in such a study and the relative importance of factors influencing the process., Results: Thirteen patients completed an interview. Reasons to participate included a desire to help others or contribute to scientific knowledge. Doubts about the efficacy of observation as a treatment method were the main barrier to participation. In a survey of 218 subjects, 62% of respondents reported willingness to participate in a randomized clinical trial. "What my doctor thinks," followed by "What I have experienced in the past" were the most important decision-making factors., Conclusion: Patients with acute uncomplicated diverticulitis maintain complex and varying perceptions of antibiotic use. Most surveyed patients would be willing to participate in a trial of antibiotics versus placebo. Our findings support the trial's feasibility and may facilitate an informed approach to recruitment and consent., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

In absence of a "gold standard", a standardized clinical adjudication process was developed for a registrational trial of a transcriptomic host response (HR) test. Two physicians independently reviewed clinical data to adjudicate presence and source of bacterial and viral infections in emergency department patients. Discordant cases were resolved by a third physician. Agreement among 955 cases was 74.1% (708/955) for bacterial, 75.6% (722/955) for viral infections, and 71.2% (680/955) overall. Most discordances were minor (85.2%; 409/480) versus moderate (11.7%; 56/480) or complete (3.3%; 16/480). Concordance levels were lowest for bacterial skin and soft tissue infections (8.2%) and for viral respiratory tract infections (4.5%). This robust adjudication process can be used to evaluate HR tests and other diagnostics by regulatory agencies and for educating clinicians, laboratorians, and clinical researchers. Clinicaltrials.gov NCT04094818. SUMMARY: Without a gold standard for evaluating host response tests, clinical adjudication is a robust reference standard that is essential to determine the true infection status in diagnostic registrational clinical studies., Competing Interests: Declaration of competing interest NNW and OL: The authors are employees and stock option holders of Inflammatix, Inc. CH: The author is a consultant of Inflammatix, Inc. JC: The author has no conflicts of interest to disclose. LM: The author has received honoraria from Inflammatix, Inc. and Thermofisher and was a consultant to Cytovale. She is an advisor for Roche, Biomerieux, and Talis Biomedical. JH: The author has served as a consultant to Beckman Coulter on the use of Artificial Intelligence tools in the practice of emergency medicine. EBH: The author has no conflicts of interest to disclose. EM: The author has no conflicts of interest to disclose. RR: The author has received research funding through his University from Inflammatix, Inc. and has served as a paid scientific expert advisor to Inflammatix, Inc. DS: The author has no conflicts of interest to disclose. RH: The author has no conflicts of interest to disclose. EAM: The author has received research funding from Inflammatix, Inc. WHS: The author has received research funding from Inflammatix, Inc. HAS: The author has no conflicts of interest to disclose. JSS: The author has no conflicts of interest to disclose. HCSK: The author has no conflicts of interest to disclose. AW: The author has served as a consultant to Inflammatix, Inc. DWW: The author has no conflicts of interest to disclose. NIS: The author has received research funding from Inflammatix, Inc, and Luminos; and served as a consultant for Diagnostic Robotics and Prenosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages., Methods: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression., Results: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations., Conclusions: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Among critically ill adults undergoing tracheal intubation, hypoxemia increases the risk of cardiac arrest and death. The effect of preoxygenation with noninvasive ventilation, as compared with preoxygenation with an oxygen mask, on the incidence of hypoxemia during tracheal intubation is uncertain., Methods: In a multicenter, randomized trial conducted at 24 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults (age, ≥18 years) undergoing tracheal intubation to receive preoxygenation with either noninvasive ventilation or an oxygen mask. The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation., Results: Among the 1301 patients enrolled, hypoxemia occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (difference, -9.4 percentage points; 95% confidence interval [CI], -13.2 to -5.6; P<0.001). Cardiac arrest occurred in 1 patient (0.2%) in the noninvasive-ventilation group and in 7 patients (1.1%) in the oxygen-mask group (difference, -0.9 percentage points; 95% CI, -1.8 to -0.1). Aspiration occurred in 6 patients (0.9%) in the noninvasive-ventilation group and in 9 patients (1.4%) in the oxygen-mask group (difference, -0.4 percentage points; 95% CI, -1.6 to 0.7)., Conclusions: Among critically ill adults undergoing tracheal intubation, preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask. (Funded by the U.S. Department of Defense; PREOXI ClinicalTrials.gov number, NCT05267652.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: Electronic health records (EHR) are increasingly used for studying multimorbidities. However, concerns about accuracy, completeness, and EHRs being primarily designed for billing and administrative purposes raise questions about the consistency and reproducibility of EHR-based multimorbidity research., Methods: Utilizing phecodes to represent the disease phenome, we analyzed pairwise comorbidity strengths using a dual logistic regression approach and constructed multimorbidity as an undirected weighted graph. We assessed the consistency of the multimorbidity networks within and between two major EHR systems at local (nodes and edges), meso (neighboring patterns), and global (network statistics) scales. We present case studies to identify disease clusters and uncover clinically interpretable disease relationships. We provide an interactive web tool and a knowledge base combining data from multiple sources for online multimorbidity analysis., Findings: Analyzing data from 500,000 patients across Vanderbilt University Medical Center and Mass General Brigham health systems, we observed a strong correlation in disease frequencies (Kendall's τ = 0.643) and comorbidity strengths (Pearson ρ = 0.79). Consistent network statistics across EHRs suggest similar structures of multimorbidity networks at various scales. Comorbidity strengths and similarities of multimorbidity connection patterns align with the disease genetic correlations. Graph-theoretic analyses revealed a consistent core-periphery structure, implying efficient network clustering through threshold graph construction. Using hydronephrosis as a case study, we demonstrated the network's ability to uncover clinically relevant disease relationships and provide novel insights., Interpretation: Our findings demonstrate the robustness of large-scale EHR data for studying phenome-wide multimorbidities. The alignment of multimorbidity patterns with genetic data suggests the potential utility for uncovering shared biology of diseases. The consistent core-periphery structure offers analytical insights to discover complex disease interactions. This work also sets the stage for advanced disease modeling, with implications for precision medicine., Funding: VUMC Biostatistics Development Award, the National Institutes of Health, and the VA CSRD., Competing Interests: JWS is a member of the Scientific Advisory Board of Sensorium Therapeutics (with equity) and has received grant support from Biogen, Inc. He is the principal investigator of a collaborative study of the genetics of depression and bipolar disorder sponsored by 23andMe, for which 23andMe provides analysis time as in-kind support but no payments. DMR has served on advisory boards for Illumina and Alkermes and has received research funds unrelated to this work from PTC Therapeutics. All other authors declare no competing interests.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into numerous lineages with unique spike mutations and caused multiple epidemics domestically and globally. Although COVID-19 vaccines are available, new variants with the capacity for immune evasion continue to emerge. To understand and characterize the evolution of circulating SARS-CoV-2 variants in the U.S., the Centers for Disease Control and Prevention (CDC) initiated the National SARS-CoV-2 Strain Surveillance (NS3) program and has received thousands of SARS-CoV-2 clinical specimens from across the nation as part of a genotype to phenotype characterization process. Focus reduction neutralization with various antisera was used to antigenically characterize 143 SARS-CoV-2 Delta, Mu and Omicron subvariants from selected clinical specimens received between May 2021 and February 2023, representing a total of 59 unique spike protein sequences. BA.4/5 subvariants BU.1, BQ.1.1, CR.1.1, CQ.2 and BA.4/5 + D420N + K444T; BA.2.75 subvariants BM.4.1.1, BA.2.75.2, CV.1; and recombinant Omicron variants XBF, XBB.1, XBB.1.5 showed the greatest escape from neutralizing antibodies when analyzed against post third-dose original monovalent vaccinee sera. Post fourth-dose bivalent vaccinee sera provided better protection against those subvariants, but substantial reductions in neutralization titers were still observed, especially among BA.4/5 subvariants with both an N-terminal domain (NTD) deletion and receptor binding domain (RBD) substitutions K444M + N460K and recombinant Omicron variants. This analysis demonstrated a framework for long-term systematic genotype to antigenic characterization of circulating and emerging SARS-CoV-2 variants in the U.S., which is critical to assessing their potential impact on the effectiveness of current vaccines and antigen recommendations for future updates.

Objectives: Sepsis is one of the most common, costly, and misdiagnosed conditions in U.S. emergency departments (EDs). ED providers often treat on nonspecific signs, subjective suspicion, or presumption of infection, resulting in over- and undertreatment. An increased understanding of host response has opened a new direction for sepsis diagnostics. The IntelliSep test is a U.S. Food and Drug Administration-cleared cellular host response diagnostic that could help distinguish sepsis in ED settings. Our objective was to evaluate the potential of the cellular host response test to expedite appropriate care for patients who present with signs of infection., Methods: We performed a pooled analysis of five adult (≥18 years) cohorts enrolled at seven geographically diverse U.S. sites in separate studies. Structured blinded adjudication was used to classify presence or absence of sepsis, and only patients with high confidence in the adjudicated label were included (n = 1002), defined as patients for whom there was consensus in the determination of sepsis per the Sepsis-3 and severe sepsis per the Sepsis-2 definitions between both the independent adjudication panel and the site-level physician., Results: Among patients with signs or suspicion of infection, the test achieved similar or better performance compared to other indicators in identifying patients at high risk for sepsis (specificity > 83%) and significantly superior performance in identifying those at low risk (sensitivity > 92%; 0% sepsis-associated mortality). The test also stratified severity of illness, as shown by 30-day in-hospital mortality (p < 0.001), hospital length of stay (p < 0.01), and use of hospital resources (p < 0.001)., Conclusions: Our data suggest that the cellular host response test provides clinically actionable results for patients at both high and low risk for sepsis and provides a rapid, objective means for risk stratification of patients with signs of infection. If integrated into standard of care, the test may help improve outcomes and reduce unnecessary antibiotic use., (© 2024 Cytovale, Inc. and The Authors. Academic Emergency Medicine published by Wiley Periodicals LLC on behalf of Society for Academic Emergency Medicine.)

Background: Influenza circulation during the 2022-2023 season in the United States largely returned to pre-coronavirus disease 2019 (COVID-19)-pandemic patterns and levels. Influenza A(H3N2) viruses were detected most frequently this season, predominately clade 3C.2a1b.2a, a close antigenic match to the vaccine strain., Methods: To understand effectiveness of the 2022-2023 influenza vaccine against influenza-associated hospitalization, organ failure, and death, a multicenter sentinel surveillance network in the United States prospectively enrolled adults hospitalized with acute respiratory illness between 1 October 2022, and 28 February 2023. Using the test-negative design, vaccine effectiveness (VE) estimates against influenza-associated hospitalization, organ failures, and death were measured by comparing the odds of current-season influenza vaccination in influenza-positive case-patients and influenza-negative, SARS-CoV-2-negative control-patients., Results: A total of 3707 patients, including 714 influenza cases (33% vaccinated) and 2993 influenza- and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative controls (49% vaccinated) were analyzed. VE against influenza-associated hospitalization was 37% (95% confidence interval [CI]: 27%-46%) and varied by age (18-64 years: 47% [30%-60%]; ≥65 years: 28% [10%-43%]), and virus (A[H3N2]: 29% [6%-46%], A[H1N1]: 47% [23%-64%]). VE against more severe influenza-associated outcomes included: 41% (29%-50%) against influenza with hypoxemia treated with supplemental oxygen; 65% (56%-72%) against influenza with respiratory, cardiovascular, or renal failure treated with organ support; and 66% (40%-81%) against influenza with respiratory failure treated with invasive mechanical ventilation., Conclusions: During an early 2022-2023 influenza season with a well-matched influenza vaccine, vaccination was associated with reduced risk of influenza-associated hospitalization and organ failure., Competing Interests: Potential conflicts of interest. S. B. reports participating as the DSMB chair for Hamilton Ventilators, outside the submitted work. J. C. reports receiving funding from the National Institutes of Health (NIH) and Department of Defense (DoD), and a travel grant from Fisher-Paykel, outside the submitted work. S. C. reports consulting for PureTech Health in 2021–2022 and Kiniksa Pharmaceuticals in 2022, outside the submitted work. A. D. reports participating on an advisory board for ALung Technologies and being a principal investigator (PI) for the PETAL Network, outside the submitted work. C. G. G. reports consulting fees from Merck and received research support from Campbell Alliance/Syneos Health, NIH, CDC, Food and Drug Administration (FDA), and AHRQ, outside the submitted work. M. N. G. reports receiving grant funding from NIH and AHRQ for research, honorarium for giving Medicine grand rounds at Yale and Washington Healthcare, fees for DSMB for Palm trial and Regeneron trials on monoclonal antibodies, and fees for serving on scientific advisory board for Philips Healthcare on monitoring, outside the submitted work. R. G. reports consulting for Gilead Sciences, Eli Lily, GSK, Janssen, and AbbVie, being on an advisory board for Gilead Sciences, Eli Lily, GlaxoSmithKline (GSK), and AstraZeneca, speaker bureau for Pfizer and AbbVie, and gift-in-kind to institution from Gilead Sciences, outside the submitted work. N. H. reports prior grant support from Sanofi and Quidel, and current funding from Merck, outside the submitted work. A. L. reports being a consultant for Roche on a clinical trial of baloxavir, outside the submitted work. Christopher Mallow reports medical legal consulting, outside the submitted work. I. P. reports receiving grants from NHLBI, NIGMS, and Janssen Pharmaceuticals and institutional support from Regeneron, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Importance: Among critically ill adults, randomized trials have not found oxygenation targets to affect outcomes overall. Whether the effects of oxygenation targets differ based on an individual's characteristics is unknown., Objective: To determine whether an individual's characteristics modify the effect of lower vs higher peripheral oxygenation-saturation (Spo2) targets on mortality., Design, Setting, and Participants: A machine learning model to predict the effect of treatment with a lower vs higher Spo2 target on mortality for individual patients was derived in the Pragmatic Investigation of Optimal Oxygen Targets (PILOT) trial and externally validated in the Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) trial. Critically ill adults received invasive mechanical ventilation in an intensive care unit (ICU) in the United States between July 2018 and August 2021 for PILOT (n = 1682) and in 21 ICUs in Australia and New Zealand between September 2015 and May 2018 for ICU-ROX (n = 965)., Exposures: Randomization to a lower vs higher Spo2 target group., Main Outcome and Measure: 28-Day mortality., Results: In the ICU-ROX validation cohort, the predicted effect of treatment with a lower vs higher Spo2 target for individual patients ranged from a 27.2% absolute reduction to a 34.4% absolute increase in 28-day mortality. For example, patients predicted to benefit from a lower Spo2 target had a higher prevalence of acute brain injury, whereas patients predicted to benefit from a higher Spo2 target had a higher prevalence of sepsis and abnormally elevated vital signs. Patients predicted to benefit from a lower Spo2 target experienced lower mortality when randomized to the lower Spo2 group, whereas patients predicted to benefit from a higher Spo2 target experienced lower mortality when randomized to the higher Spo2 group (likelihood ratio test for effect modification P = .02). The use of a Spo2 target predicted to be best for each patient, instead of the randomized Spo2 target, would have reduced the absolute overall mortality by 6.4% (95% CI, 1.9%-10.9%)., Conclusion and Relevance: Oxygenation targets that are individualized using machine learning analyses of randomized trials may reduce mortality for critically ill adults. A prospective trial evaluating the use of individualized oxygenation targets is needed.

Importance: On June 21, 2023, the Centers for Disease Control and Prevention recommended the first respiratory syncytial virus (RSV) vaccines for adults aged 60 years and older using shared clinical decision-making. Understanding the severity of RSV disease in adults can help guide this clinical decision-making., Objective: To describe disease severity among adults hospitalized with RSV and compare it with the severity of COVID-19 and influenza disease by vaccination status., Design, Setting, and Participants: In this cohort study, adults aged 18 years and older admitted to the hospital with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 US states from February 1, 2022, to May 31, 2023. Clinical data during each patient's hospitalization were collected using standardized forms. Data were analyzed from August to October 2023., Exposures: RSV, SARS-CoV-2, or influenza infection., Main Outcomes and Measures: Using multivariable logistic regression, severity of RSV disease was compared with COVID-19 and influenza severity, by COVID-19 and influenza vaccination status, for a range of clinical outcomes, including the composite of invasive mechanical ventilation (IMV) and in-hospital death., Results: Of 7998 adults (median [IQR] age, 67 [54-78] years; 4047 [50.6%] female) included, 484 (6.1%) were hospitalized with RSV, 6422 (80.3%) were hospitalized with COVID-19, and 1092 (13.7%) were hospitalized with influenza. Among patients with RSV, 58 (12.0%) experienced IMV or death, compared with 201 of 1422 unvaccinated patients with COVID-19 (14.1%) and 458 of 5000 vaccinated patients with COVID-19 (9.2%), as well as 72 of 699 unvaccinated patients with influenza (10.3%) and 20 of 393 vaccinated patients with influenza (5.1%). In adjusted analyses, the odds of IMV or in-hospital death were not significantly different among patients hospitalized with RSV and unvaccinated patients hospitalized with COVID-19 (adjusted odds ratio [aOR], 0.82; 95% CI, 0.59-1.13; P = .22) or influenza (aOR, 1.20; 95% CI, 0.82-1.76; P = .35); however, the odds of IMV or death were significantly higher among patients hospitalized with RSV compared with vaccinated patients hospitalized with COVID-19 (aOR, 1.38; 95% CI, 1.02-1.86; P = .03) or influenza disease (aOR, 2.81; 95% CI, 1.62-4.86; P < .001)., Conclusions and Relevance: Among adults hospitalized in this US cohort during the 16 months before the first RSV vaccine recommendations, RSV disease was less common but similar in severity compared with COVID-19 or influenza disease among unvaccinated patients and more severe than COVID-19 or influenza disease among vaccinated patients for the most serious outcomes of IMV or death.

Rationale: Among mechanically ventilated critically ill adults, the PILOT (Pragmatic Investigation of Optimal Oxygen Targets) trial demonstrated no difference in ventilator-free days among lower, intermediate, and higher oxygen-saturation targets. The effects on long-term cognition and related outcomes are unknown. Objectives: To compare the effects of lower (90% [range, 88-92%]), intermediate (94% [range, 92-96%]), and higher (98% [range, 96-100%]) oxygen-saturation targets on long-term outcomes. Methods: Twelve months after enrollment in the PILOT trial, blinded neuropsychological raters conducted assessments of cognition, disability, employment status, and quality of life. The primary outcome was global cognition as measured using the Telephone Montreal Cognitive Assessment. In a subset of patients, an expanded neuropsychological battery measured executive function, attention, immediate and delayed memory, verbal fluency, and abstraction. Measurements and Main Results: A total of 501 patients completed follow-up, including 142 in the lower, 186 in the intermediate, and 173 in the higher oxygen target groups. Median (interquartile range) peripheral oxygen saturation values in the lower, intermediate, and higher target groups were 94% (91-96%), 95% (93-97%), and 97% (95-99%), respectively. Telephone Montreal Cognitive Assessment score did not differ between lower and intermediate (adjusted odds ratio [OR], 1.36 [95% confidence interval (CI), 0.92-2.00]), intermediate and higher (adjusted OR, 0.90 [95% CI, 0.62-1.29]), or higher and lower (adjusted OR, 1.22 [95% CI, 0.83-1.79]) target groups. There was also no difference in individual cognitive domains, disability, employment, or quality of life. Conclusions: Among mechanically ventilated critically ill adults who completed follow-up at 12 months, oxygen-saturation targets were not associated with cognition or related outcomes.

Background: Prolonged SARS-CoV-2 infections in people who are immunocompromised might predict or source the emergence of highly mutated variants. The types of immunosuppression placing patients at highest risk for prolonged infection have not been systematically investigated. We aimed to assess risk factors for prolonged SARS-CoV-2 infection and associated intrahost evolution., Methods: In this multicentre, prospective analysis, participants were enrolled at five US medical centres. Eligible patients were aged 18 years or older, were SARS-CoV-2-positive in the previous 14 days, and had a moderately or severely immunocompromising condition or treatment. Nasal specimens were tested by real-time RT-PCR every 2-4 weeks until negative in consecutive specimens. Positive specimens underwent viral culture and whole genome sequencing. A Cox proportional hazards model was used to assess factors associated with duration of infection., Findings: From April 11, 2022, to Oct 1, 2022, 156 patients began the enrolment process, of whom 150 were enrolled and included in the analyses. Participants had B-cell malignancy or anti-B-cell therapy (n=18), solid organ transplantation or haematopoietic stem-cell transplantation (HSCT; n=59), AIDS (n=5), non-B-cell malignancy (n=23), and autoimmune or autoinflammatory conditions (n=45). 38 (25%) participants were real-time RT-PCR-positive and 12 (8%) were culture-positive 21 days or longer after initial SARS-CoV-2 detection or illness onset. Compared with the group with autoimmune or autoinflammatory conditions, patients with B-cell dysfunction (adjusted hazard ratio 0·32 [95% CI 0·15-0·64]), solid organ transplantation or HSCT (0·60 [0·38-0·94]), and AIDS (0·28 [0·08-1·00]) had longer duration of infection, defined as time to last positive real-time RT-PCR test. There was no significant difference in the non-B-cell malignancy group (0·58 [0·31-1·09]). Consensus de novo spike mutations were identified in five individuals who were real-time RT-PCR-positive longer than 56 days; 14 (61%) of 23 were in the receptor-binding domain. Mutations shared by multiple individuals were rare (<5%) in global circulation., Interpretation: In this cohort, prolonged replication-competent omicron SARS-CoV-2 infections were uncommon. Within-host evolutionary rates were similar across patients, but individuals with infections lasting longer than 56 days accumulated spike mutations, which were distinct from those seen globally. Populations at high risk should be targeted for repeated testing and treatment and monitored for the emergence of antiviral resistance., Funding: US Centers for Disease Control and Prevention., Competing Interests: Declaration of interests JDC reports receiving grants from the National Institutes of Health (NIH) and the Department of Defense, outside the submitted work. CGG reports grants from NIH, the Centers for Disease Control and Prevention (CDC), the Agency for Healthcare Research and Quality, the US Food and Drug Administration, and Campbell Alliance/Syneos Health, and consulting fees and participating on a data safety monitoring board for Merck, outside the submitted work. AEF reports a K08 award from NIH and participating on the Hennepin Health Research Institute Board of Directors, outside the submitted work. NH reports grants from Sanofi, Quidel, and Merck, outside the submitted work. ASL reports receiving grants from CDC, National Institute of Allergy and Infectious Diseases, Burroughs Wellcome Fund, and Flu Lab, and consulting fees from Roche, outside the submitted work. ETM reports receiving a grant from Merck, outside the submitted work. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: For every critically ill adult receiving invasive mechanical ventilation, clinicians must select a mode of ventilation. The mode of ventilation determines whether the ventilator directly controls the tidal volume or the inspiratory pressure. Newer hybrid modes allow clinicians to set a target tidal volume; the ventilator controls and adjusts the inspiratory pressure. A strategy of low tidal volumes and low plateau pressure improves outcomes, but the optimal mode to achieve these targets is not known., Research Question: Can a cluster-randomized trial design be used to assess whether the mode of mandatory ventilation affects the number of days alive and free of invasive mechanical ventilation among critically ill adults?, Study Design and Methods: The Mode of Ventilation During Critical Illness (MODE) trial is a cluster-randomized, multiple-crossover pilot trial being conducted in the medical ICU at an academic center. The MODE trial compares the use of volume control, pressure control, and adaptive pressure control. The study ICU is assigned to a single-ventilator mode (volume control vs pressure control vs adaptive pressure control) for continuous mandatory ventilation during each 1-month study block. The assigned mode switches every month in a randomly generated sequence. The primary outcome is ventilator-free days to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of mechanical ventilation to 28 days after enrollment. Enrollment began November 1, 2022, and will end on July 31, 2023., Results: This manuscript describes the protocol and statistical analysis plan for the MODE trial of ventilator modes comparing volume control, pressure control, and adaptive pressure control., Interpretation: Prespecifying the full statistical analysis plan prior to completion of enrollment increases rigor, reproducibility, and transparency of the trial results., Clinical Trial Registration: The trial was registered with clinicaltrials.gov on October 3, 2022, before initiation of patient enrollment on November 1, 2022 (ClinicalTrials.gov identifier: NCT05563779).

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. However, few estimates of updated vaccine effectiveness (VE) against medically attended illness are available. This analysis evaluated VE of an updated COVID-19 vaccine dose against COVID-19-associated emergency department (ED) or urgent care (UC) encounters and hospitalization among immunocompetent adults aged ≥18 years during September 2023-January 2024 using a test-negative, case-control design with data from two CDC VE networks. VE against COVID-19-associated ED/UC encounters was 51% (95% CI = 47%-54%) during the first 7-59 days after an updated dose and 39% (95% CI = 33%-45%) during the 60-119 days after an updated dose. VE estimates against COVID-19-associated hospitalization from two CDC VE networks were 52% (95% CI = 47%-57%) and 43% (95% CI = 27%-56%), with a median interval from updated dose of 42 and 47 days, respectively. Updated COVID-19 vaccine provided increased protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults. These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Steven Y. Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals, and participation on the data safety monitoring board for an unrelated, local study at Ronald Reagan UCLA Medical Center, outside the submitted work. Manjusha Gaglani reports serving as the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics co-chair of the ID and Immunization Committee, outside the submitted work. Adit A. Ginde reports support from Biomeme and Seastar, outside the submitted work. Carlos G. Grijalva reports other funding from Merck, contracts from Syneos Health and the Food and Drug Administration, and grants from National Institutes of Health (NIH) and Agency for Health Care Research and Quality, outside the submitted work. Akram Khan reports grant funding from 4DMedical, Dompe Pharmaceuticals, Ely Lilly, and Roche Pharmaceuticals, outside the submitted work. Adam S. Lauring reports research support from the National Institute of Allergy and Infectious Diseases, Michigan Department of Health and Human Services, Burroughs Wellcome Fund, Flu Lab, and consulting fees from Roche, outside the submitted work. Christopher Mallow reports medical legal consulting, outside the submitted work. Emily T. Martin reports research funding from Merck, outside the submitted work. Ithan D. Peltan reports grant support from NIH, Intermountain Research and Medical Foundation, and Janssen Pharmaceuticals, and funding to his institution from Bluejay Diagnostics and Regeneron, outside the submitted work. Karthik Natarajan reports institutional support from NIH, Office of the Director, the National Center for Advancing Translational Sciences, and the National Heart, Lung, and Blood Institute. Brian E. Dixon reports Institutional support from NIH, National Library of Medicine in the form of a T15 training grant in biomedical informatics, salary support from the U.S. Department of Veterans Affairs, royalties from Elsevier, Inc. for a book on health information technology and from Springer Nature for a book on health information technology. Nicola P. Klein reports support from GSK, Merck, Pfizer, Sanofi Pasteur, and Seqirus for work unrelated to this report. No other potential conflicts of interest were disclosed.

In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Emmanuel B. Walter reports institutional support from Pfizer, Moderna, Seqiris, Clinetic, and Najit Technologies Inc., consulting fees from ILiAD Biotechnologies, payment from the College of Diplomates of the American Board of Pediatric Dentistry, travel support from the American Academy of Pediatrics, and paid compensation for participation on the Vaxcyte Scientific Advisory Board. Yuwei Zhu reports participation on a Vanderbilt University Medical Center Data Safety Monitoring Board. Sara Y. Tartof reports institutional support from Pfizer and Genentech. Samantha M. Olson reports travel support from the Gates Foundation. Nicola P. Klein reports institutional support from Sanofi Pasteur, Merck, Pfizer, Seqirus, and GlaxoSmithKline; membership on an expert panel for a planned hepatitis E Phase II vaccine clinical trial among pregnant women in Pakistan; membership in Western States COVID-19 Scientific Safety Review Workgroup, Board on Population Health and Public Health Practice, National Academies of Science, Engineering and Medicine, and National Vaccine Advisory Committee Safety Subcommittee. Manjusha Gaglani reports receipt of honorarium for educational webinar presentation on respiratory viruses from the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics, and serving as co-chair of the Infectious Diseases and Immunization Committee and Chair of the Texas Respiratory Syncytial Virus Taskforce, Texas Pediatric Society. Kevin W. Gibbs reports grants or contracts from the Department of Defense and the National Institutes of Health (NIH) and service as chair of the Vanderbilt University Medical Center Data Safety Monitoring Board. Adit A. Ginde reports institutional support from the NIH, the Department of Defense, AbbVie, and Faron Pharmaceuticals, consulting fees (paid to institution) from Biomeme and Seastar, and participation on data safety monitoring boards for the NIH and Emory University. Richard K. Zimmerman reports institutional support from the NIH and Sanofi Pasteur, and honorarium from Clinical Educational Alliance. Mary A. Staat reports institutional support from NIH, Pfizer, and Merck and royalties for Up-to-Date chapter on International Adoption. Stacey House reports institutional support from Seegene, Inc., Abbot, Healgen, Roche, CorDx, Hologic, Cepheid, Janssen, and Wondfo Biotech. Geoffrey A. Weinberg reports institutional support from the New York State Department of Health AIDS Institute, consulting fees from Inhalon Biopharma for participation on a Scientific Advisory Board, and honoraria from Merck & Company for textbook chapters. Marian G. Michaels reports institutional support from the National Institute on Allergy and Infectious Diseases and complimentary meeting attendance for presentation at the American Transplant Congress on respiratory viruses. Emily T. Martin reports receipt of grants or contracts from Merck. Natasha B. Halasa reports receipt of grants from Sanofi, Quidell, and Merck. Elie A. Saade reports institutional support from Protein Sciences Corporation, consulting fees, honoraria, and travel support from Johnson & Johnson and participation on a Johnson & Johnson Data Safety Monitoring Board. No other potential conflicts of interest were disclosed.

Objectives: Epinephrine can be a life-saving treatment for patients with anaphylaxis. Potential cardiovascular side effects of epinephrine may contribute to clinician hesitancy to use it. However, the frequency of cardiotoxicity resulting from epinephrine treatment for anaphylaxis is not well described. We sought to describe the frequency of cardiotoxicity following intramuscular (IM) administration of epinephrine in adult emergency department (ED) patients with anaphylaxis., Methods: We conducted a retrospective observational study at a single, quaternary care academic ED in Tennessee. We identified consecutive ED visits with the diagnosis of anaphylaxis from 2017 to 2021 who received at least one intramuscular (IM) dose of epinephrine in the ED. Analysis was primarily descriptive. The primary outcome was cardiotoxicity, the occurrence of any of the following after epinephrine administration: ischemic electrocardiogram changes, systolic blood pressure >200 mmHg, or cardiac arrest ≤4 h; elevated troponin ≤12 h; or percutaneous coronary intervention or depressed ejection fraction ≤72 h., Results: Among 338 included patients, 16 (4.7%; 95%CI: 2.8-7.6%) experienced cardiotoxicity. Cardiotoxic events included eight (2.4%) ischemic electrocardiogram changes, six (1.8%) episodes of elevated troponin, five (1.5%) atrial arrhythmias, one (0.3%) ventricular arrythmia, and one (0.3%) depressed ejection fraction. Patients with cardiotoxicity were significantly older, had more comorbidities, and were more likely to have received multiple doses of epinephrine or an epinephrine infusion compared with a single IM dose of epinephrine., Conclusions: Among 338 consecutive adult ED patients who received IM epinephrine for anaphylaxis during a recent 4-year period, cardiotoxic side effects were observed in approximately 5% of patients., Competing Interests: None., (© 2024 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Background: Influenza is a substantial cause of annual morbidity and mortality; however, correctly identifying those patients at increased risk for severe disease is often challenging. Several severity indices have been developed; however, these scores have not been validated for use in patients with influenza. We evaluated the discrimination of three clinical disease severity scores in predicting severe influenza-associated outcomes., Methods: We used data from the Influenza Hospitalization Surveillance Network to assess outcomes of patients hospitalized with influenza in the United States during the 2017-2018 influenza season. We computed patient scores at admission for three widely used disease severity scores: CURB-65, Quick Sepsis-Related Organ Failure Assessment (qSOFA), and the Pneumonia Severity Index (PSI). We then grouped patients with severe outcomes into four severity tiers, ranging from ICU admission to death, and calculated receiver operating characteristic (ROC) curves for each severity index in predicting these tiers of severe outcomes., Results: Among 8252 patients included in this study, we found that all tested severity scores had higher discrimination for more severe outcomes, including death, and poorer discrimination for less severe outcomes, such as ICU admission. We observed the highest discrimination for PSI against in-hospital mortality, at 0.78., Conclusions: We observed low to moderate discrimination of all three scores in predicting severe outcomes among adults hospitalized with influenza. Given the substantial annual burden of influenza disease in the United States, identifying a prediction index for severe outcomes in adults requiring hospitalization with influenza would be beneficial for patient triage and clinical decision-making., Competing Interests: E.J.A. has consulted for Pfizer, Sanofi Pasteur, GSK, Janssen, and Medscape, and his institution receives funds to conduct clinical research unrelated to this manuscript from MedImmune, Regeneron, PaxVax, Pfizer, GSK, Merck, Sanofi‐Pasteur, Janssen, and Micron. He also serves on a safety monitoring board for Kentucky BioProcessing, Inc., and Sanofi Pasteur. His institution has also received funding from NIH to conduct clinical trials of Moderna and Janssen COVID‐19 vaccines. E.J.A. is currently an employee of Moderna. All other authors declare no conflicts of interest., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Potentially septic patients have a huge clinical and economic impact on hospitals and often present to the emergency department (ED) with undifferentiated symptoms. The triage of these patients is complex and has historically relied heavily upon provider judgment. This study aims to evaluate the consistency of provider judgment and the potential of a new host response sepsis test to aid in the triage process. A modified Delphi study involving 26 participants from multiple specialties was conducted to evaluate provider agreement about sepsis risk and to test proposed actions based on the results of a sepsis test. The participants considered case vignettes of potentially septic patients designed to represent diagnostic dilemmas. Provider assessment of sepsis risk in these cases ranged from 10% to 90% and agreement was poor. Agreement about clinical actions to take in response to testing improved when participants considered their own hypothetical borderline cases. New host response testing for sepsis may have the potential to improve sepsis diagnosis and care and should be applied in a protocolized fashion to ensure consistency of results.

Diuresis to achieve decongestion is a central aim of therapy in patients hospitalized for acute decompensated heart failure (ADHF). While multiple clinical trials have investigated initial diuretic strategies for a designated period of time, there is a paucity of evidence to guide diuretic titration strategies continued until decongestion is achieved. The use of urine chemistries (urine sodium and creatinine) in a natriuretic response prediction equation accurately estimates natriuresis in response to diuretic dosing, but a randomized clinical trial is needed to compare a urine chemistry-guided diuresis strategy with a strategy of usual care. The urinE chemiStry guided aCute heArt faiLure treATmEnt (ESCALATE) trial is designed to test the hypothesis that protocolized diuretic therapy guided by spot urine chemistry through completion of intravenous diuresis will be superior to usual care and improve outcomes over the 14 days following randomization. ESCALATE will randomize and obtain complete data on 450 patients with acute heart failure to a diuretic strategy guided by urine chemistry or a usual care strategy. Key inclusion criteria include an objective measure of hypervolemia with at least 10 pounds of estimated excess volume, and key exclusion criteria include significant valvular stenosis, hypotension, and a chronic need for dialysis. Our primary outcome is days of benefit over the 14 days after randomization. Days of benefit combines patient symptoms captured by global clinical status with clinical state quantifying the need for hospitalization and intravenous diuresis. CLINICAL TRIAL REGISTRATION: NCT04481919., Competing Interests: Disclosures ZC receives research funding from AstraZeneca and Cumberland Pharmaceuticals and consulting fees from Roche and Translational Catalyst. JHH receives research funding from the NIA, Boehringer Ingelheim and Merck. JL receives research funding from AstraZeneca, Volumetrix, Sensible Medical, NIH and consulting fees from AstraZeneca, Abbott, Alleviant, Boehringer Ingelheim, Boston Scienrific, CVRx, Edwards Lifesciences, Medtronic, Merck, Vascular Dynamics, VWave, WHiteswell. CJL reports research grants and contracts to institution from NIH, CDC, DoD, AbbVie, Entegrion, Endpoint Health, bioMerieux, and patents for risk stratification in septic shock unrelated to the current work. JOW receives research funding from Bristol Myers Squibb. EDS receives personal fees as an Associate Editor for the Clinical Journal of the American Society of Nephrology and royalties as an author for UptoDate. JT reports grants and/or personal fees from 3ive labs, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Astra Zeneca, Novartis, Cardionomic, MagentaMed, Reprieve inc., FIRE1, W.L. Gore, Sanofi, Sequana Medical, Otsuka, Abbott, Merck, Windtree Therapeutics, Lexicon pharmaceuticals, Precardia, Relypsa, Regeneron, BD, Edwards life sciences, and Lilly. In addition, JMT has a patent Treatment of diuretic resistance issued to Yale and Corvidia Therapeutics Inc, a patent Methods for measuring renalase issued to Yale, and a patent Treatment of diuretic resistance pending with Reprieve inc. SPC reports consulting with Boehringer Ingelheim, Reprieve Cardiovascular, Aboott and research support from PCORI, NIH, DOD, and Beckman Coulter., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Importance: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial., Objective: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction., Design, Setting, and Participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022., Interventions: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam., Main Outcomes and Measures: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days., Results: There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95])., Conclusions and Relevance: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction., Trial Registration: ClinicalTrials.gov Identifier: NCT05094154.

On June 21, 2023, CDC's Advisory Committee on Immunization Practices recommended respiratory syncytial virus (RSV) vaccination for adults aged ≥60 years, offered to individual adults using shared clinical decision-making. Informed use of these vaccines requires an understanding of RSV disease severity. To characterize RSV-associated severity, 5,784 adults aged ≥60 years hospitalized with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 U.S. states during February 1, 2022-May 31, 2023. Multivariable logistic regression was used to compare RSV disease severity with COVID-19 and influenza severity on the basis of the following outcomes: 1) standard flow (<30 L/minute) oxygen therapy, 2) high-flow nasal cannula (HFNC) or noninvasive ventilation (NIV), 3) intensive care unit (ICU) admission, and 4) invasive mechanical ventilation (IMV) or death. Overall, 304 (5.3%) enrolled adults were hospitalized with RSV, 4,734 (81.8%) with COVID-19 and 746 (12.9%) with influenza. Patients hospitalized with RSV were more likely to receive standard flow oxygen, HFNC or NIV, and ICU admission than were those hospitalized with COVID-19 or influenza. Patients hospitalized with RSV were more likely to receive IMV or die compared with patients hospitalized with influenza (adjusted odds ratio = 2.08; 95% CI = 1.33-3.26). Among hospitalized older adults, RSV was less common, but was associated with more severe disease than COVID-19 or influenza. High disease severity in older adults hospitalized with RSV is important to consider in shared clinical decision-making regarding RSV vaccination., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Samuel M. Brown reports that ReddyPort pays royalties on his invention of an airway device, outside the submitted work. Jonathan D. Casey reports a travel grant from Fisher and Paykel, outside the submitted work. Steven Y. Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals and participation as a data safety monitoring board member for a study at University of California, Los Angeles outside the submitted work. James D. Chappell reports participating as a coinvestigator for a Merck investigator studies program, where he supported surveillance of respiratory syncytial virus infection among hospitalized children in Jordan, outside the submitted work. Manjusha Gaglani reports grants from Abt Associates and Westat, having served as cochair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society (TPS), and receiving an honorarium for serving as a TPS Project Firstline webinar speaker panelist for Respiratory Virus Review: Clinical Considerations and IPC Guidance, outside the submitted work. Adit A. Ginde reports receiving grants from the National Institutes of Health (NIH), U.S. Department of Defense, AbbVie, and Faron Pharmaceuticals outside the submitted work. Michelle N. Gong reports a grant from NIH outside the submitted work. Carlos G. Grijalva reports grants from NIH, the Agency for Healthcare Research and Quality, Food and Drug Administration, and Syneos Health, and receipt of compensation for participation in an advisory board for Merck outside the submitted work. Natasha Halasa reports receiving grants from Sanofi, Merck, and Quidel outside the submitted work. Akram Khan reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GSK outside the submitted work. Adam S. Lauring reports receiving grants from FluLab, NIH/National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund and fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. Emily T. Martin reports a grant from Merck outside the submitted work. Christopher Mallow reports medical legal consulting outside the submitted work. Ithan D. Peltan reports grants from NIH and Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron outside the submitted work. Mayur Ramesh reports participating in a nonbranded speaker program supported by AstraZeneca and serving on an advisory board for Moderna outside the submitted work. No other potential conflicts of interest were disclosed.

Study Objective: To compare the effect of the use of a video laryngoscope versus a direct laryngoscope on each step of emergency intubation: laryngoscopy (step 1) and intubation of the trachea (step 2)., Methods: In a secondary observational analysis of data from 2 multicenter, randomized trials that enrolled critically ill adults undergoing tracheal intubation but did not control for laryngoscope type (video laryngoscope vs direct laryngoscope), we fit mixed-effects logistic regression models examining the 1) the association between laryngoscope type (video laryngoscope vs direct laryngoscope) and the Cormack-Lehane grade of view and 2) the interaction between grade of view, laryngoscope type (video laryngoscope vs direct laryngoscope), and the incidence of successful intubation on the first attempt., Results: We analyzed 1,786 patients: 467 (26.2%) in the direct laryngoscope group and 1,319 (73.9%) in the video laryngoscope group. The use of a video laryngoscope was associated with an improved grade of view as compared with a direct laryngoscope (adjusted odds ratio for increasingly favorable grade of view 3.14, 95% confidence interval [CI] 2.47 to 3.99). Successful intubation on the first attempt occurred in 83.2% of patients in the video laryngoscope group and 72.2% of patients in the direct laryngoscope group (absolute difference 11.1%, 95% CI 6.5% to 15.6%). Video laryngoscope use modified the association between grade of view and successful intubation on the first attempt such that intubation on the first attempt was similar between video laryngoscope and direct laryngoscope at a grade 1 view and higher for video laryngoscope than direct laryngoscope at grade 2 to 4 views (P<.001 for interaction term)., Conclusions: Among critically ill adults undergoing tracheal intubation, the use of a video laryngoscope was associated both with a better view of the vocal cords and with a higher probability of successfully intubating the trachea when the view of the vocal cords was incomplete in this observational analysis. However, a multicenter, randomized trial directly comparing the effect of a video laryngoscope with a direct laryngoscope on the grade of view, success, and complications is needed., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Successful intubation on the first attempt has historically been defined as successful placement of an endotracheal tube (ETT) using a single laryngoscope insertion. More recent studies have defined successful placement of an ETT using a single laryngoscope insertion followed by a single ETT insertion. We sought to estimate the prevalence of first-attempt success using these 2 definitions and estimate their associations with the duration of intubation and serious complications., Methods: We performed a secondary analysis of data from 2 multicenter randomized trials of critically ill adults being intubated in the emergency department or ICU. We calculated the percent difference in successful intubations on the first attempt, median difference in the duration of intubation, and percent difference in the development of serious complications by definition., Results: The study population included 1,863 patients. Successful intubation on the first attempt decreased by 4.9% (95% confidence interval 2.5% to 7.3%) when defined as 1 laryngoscope insertion followed by 1 ETT insertion (81.2%) compared with when defined as only 1 laryngoscope insertion (86.0%). When successful intubation with 1 laryngoscope and 1 ETT insertion was compared with 1 laryngoscope and multiple ETT insertions, the median duration of intubation decreased by 35.0 seconds (95% confidence interval 8.9 to 61.1 seconds)., Conclusion: Defining successful intubation on the first attempt as placement of an ETT in the trachea using 1 laryngoscope and 1 ETT insertion identifies attempts with the shortest apneic time., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: We sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months., Methods: This was a multi-center prospective cohort study in adult hospitalized patients with acute COVID-19. The following in-hospital factors were assessed: delirium; frequency of in-person and virtual visits by friends and family; and hydroxychloroquine, corticosteroid, and remdesivir administration. Twelve-month global cognition was characterized by the MOCA-Blind. Twelve-month PTSD and depression were characterized using the PTSD Checklist for the DSM-V and Hospital Anxiety Depression Scale, respectively., Findings: Two hundred three patients completed the 12-month follow-up assessments. Remdesivir use was associated with significantly higher cognition at 12 months based on the MOCA-Blind (adjusted odds ratio [aOR] = 1.98, 95% CI: 1.06, 3.70). Delirium was associated with worsening 12-month PTSD (aOR = 3.44, 95% CI: 1.89, 6.28) and depression (aOR = 2.18, 95% CI: 1.23, 3.84) symptoms. Multiple virtual visits per day during hospitalization was associated with lower 12-month depression symptoms compared to those with less than daily virtual visits (aOR = 0.40, 95% CI: 0.19, 0.85)., Conclusion: Potentially modifiable factors associated with better long-term outcomes included remdesivir use (associated with better cognitive function), avoidance of delirium (associated with less PTSD and depression symptoms), and increased virtual interactions with friends and family (associated with less depression symptoms)., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Importance: Spanish-speaking participants are underrepresented in clinical trials, limiting study generalizability and contributing to ongoing health inequity. The Comparison of Outcomes of Antibiotic Drugs and Appendectomy (CODA) trial intentionally included Spanish-speaking participants., Objective: To describe trial participation and compare clinical and patient-reported outcomes among Spanish-speaking and English-speaking participants with acute appendicitis randomized to antibiotics., Design, Setting, and Participants: This study is a secondary analysis of the CODA trial, a pragmatic randomized trial comparing antibiotic therapy with appendectomy in adult patients with imaging-confirmed appendicitis enrolled at 25 centers across the US from May 1, 2016, to February 28, 2020. The trial was conducted in English and Spanish. All 776 participants randomized to antibiotics are included in this analysis. The data were analyzed from November 15, 2021, through August 24, 2022., Intervention: Randomization to a 10-day course of antibiotics or appendectomy., Main Outcomes and Measures: Trial participation, European Quality of Life-5 Dimensions (EQ-5D) questionnaire scores (higher scores indicating a better health status), rate of appendectomy, treatment satisfaction, decisional regret, and days of work missed. Outcomes are also reported for a subset of participants that were recruited from the 5 sites with a large proportion of Spanish-speaking participants., Results: Among eligible patients 476 of 1050 Spanish speakers (45%) and 1076 of 3982 of English speakers (27%) consented, comprising the 1552 participants who underwent 1:1 randomization (mean age, 38.0 years; 976 male [63%]). Of the 776 participants randomized to antibiotics, 238 were Spanish speaking (31%). Among Spanish speakers randomized to antibiotics, the rate of appendectomy was 22% (95% CI, 17%-28%) at 30 days and 45% (95% CI, 38%-52%) at 1 year, while in English speakers, these rates were 20% (95% CI, 16%-23%) at 30 days and 42% (95% CI 38%-47%) at 1 year. Mean EQ-5D scores were 0.93 (95% CI, 0.92-0.95) among Spanish speakers and 0.92 (95% CI, 0.91-0.93) among English speakers. Symptom resolution at 30 days was reported by 68% (95% CI, 61%-74%) of Spanish speakers and 69% (95% CI, 64%-73%) of English speakers. Spanish speakers missed 6.69 (95% CI, 5.51-7.87) days of work on average, while English speakers missed 3.76 (95% CI, 3.20-4.32) days. Presentation to the emergency department or urgent care, hospitalization, treatment dissatisfaction, and decisional regret were low for both groups., Conclusions and Relevance: A high proportion of Spanish speakers participated in the CODA trial. Clinical and most patient-reported outcomes were similar for English- and Spanish-speaking participants treated with antibiotics. Spanish speakers reported more days of missed work., Trial Registration: ClinicalTrials.gov Identifier: NCT02800785.

Background: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure., Methods: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761., Findings: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10)., Interpretation: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy., Funding: National Institutes of Health., Competing Interests: Declaration of interests SMB reports funding from the National Institutes of Health during the conduct of the study and chairing a Data and Safety Monitoring Board (DSMB) for Hamilton Ventilators, outside of the study. CEB reports funding from the National Institutes of Health (NIH) for the Aviptadil study, during the conduct of the study. BG reports grants from the NIH, during the conduct of the study. SS reports a grant from the NIH, during the conduct of the study. ANP reports grants from the Wellcome Trust, the National Institute for Health and Care Research, UK Research and Innovation (UKRI), and the Bill & Melinda Gates Foundation, and consulting fees from the Bill & Melinda Gates Foundation, outside of the submitted work. IDP reports funding from NIH and the National Institute of General Medical Sciences, during the conduct of the study, a grant from Janssen for a study of influenza patient reported outcomes, and a contract with Regeneron for a COVID-19 therapy trial, outside of the submitted work. JRB reports a grant from the NIH, during the conduct of the study, grants from the NIH, Quantum Leap Healthcare Collaborative, and Sedana Medical, consulting fees from Sedana Medical, Biomarck, and Global Blood Therapeutics, and compensation from Hamilton Medical for participation as a medical monitor, outside of the submitted work. ESHa reports study materials from NeuroRx and Gilead through a National Heart, Lung, and Blood Institute (NHLBI) subcontract, during the conduct of the study, subcontracts with Bristol Meyers Squibb (BMS), Allergan, Gilead, and Janssen for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-1) clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the Therapeutics for Inpatients with COVID-19 (TICO) clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR) clinical trial, outside of the submitted work. EAM reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. MAGB reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. KSM reports grants and contracts from NIH, NHLBI, and the Society for Critical Care Medicine, participation as a steering committee member for Roivant-Kinevant Sciences, and employment as a clinical research physician at Chiesi USA, outside of submitted work. JM reports receiving study materials and funding from the Albert Einstein College of Medicine for the study protocol, during the conduct of the study. CH reports funding from the National Institute of Allergy and Infectious Diseases (NIAID) in the form of per-patient payments for A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients with Acute Respiratory Distress Syndrome Associated with COVID-19, during the conduct of the study. AK reports grants from Eli Lilly, AstraZeneca, 4D Medical, United Therapeutics, Regeneron Pharmaceuticals, and Dompe Pharmaceuticals and consulting fees from Dompe Pharmaceuticals for clinical trial design, outside of the submitted work. AD reports grants from NHLBI Prevention and Early Treatment of Acute Lung Injury network and the US Centers for Disease Control and Prevention (CDC) and data safety monitoring board (DSMB) or advisory board participation for Alung Technologies, outside of the submitted work. SD reports a grant from Chest Sonosite Ultrasound to study the incidence of deep vein thrombosis in patients with COVID-19, during the conduct of the study. AJG reports payment from Sound Pharmaceuticals for participation as a medical monitor for a COVID therapeutic trial, outside of the submitted work. USS reports consulting fees from Shionogi, Paratek, and ViiV Healthcare for participation on advisory boards and speaking fees from Shionogi and Paratek, outside of the submitted work. NJJ reports grants from the CDC, the US Department of Defense (DOD), and NIH and participation on a DSMB for the Legacy Health System, outside of the submitted work. MAM reports grants from NIH and NIAID, during the conduct of the study. NRA reports funding from NIH, during the conduct of the study. JDC reports grants from NIH and DOD, outside of the submitted work. DDM reports funding from the Danish National Research Foundation (DNRF126), during the conduct of study. AAG reports funding from NIH, during the conduct of the study, grants or contracts from NIH, DOD, CDC, Faron Pharmaceuticals, and Abbvie, and participation on a DSMB or advisory board for NIH, outside of the submitted work. WHS reports funding from NIH and NIAID, during the conduct of the study. CFO reports contracts with NIH and NHLBI, outside of the submitted work. BTT reports a grant from NHLBI, consulting fees from Bayer, Genetec, and Novartis, and participation on a DSMB or advisory board for Aperion, outside of the submitted work. During a portion of this research, BTT had a financial interest in Direct Biologics, a developer and manufacturer of regenerative biologic products, including an investigational treatment of COVID-19-associated ARDS. BTT's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies, and had no relationship to the agents studied. VK reports subcontracts with University of Minnesota, NIAID, and NIH for the TICO and Therapeutics for Severely Ill Inpatients with COVID-19 platform trials, outside of the submitted work. AGB reports a grant from University of Minnesota, during the conduct of the study, grants from the Medical Reserve Corps and UKRI, payment from NIAID for participation on a COVID-19 Vaccines DSMB, and participation on the WHO Trial Data and Safety Monitoring Committee, outside of the submitted work. JDN reports grants from NIAID, NIH, and Leidos Biomedical, outside of the submitted work. HCL reports employment from NIAID, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Understanding the changing epidemiology of adults hospitalized with coronavirus disease 2019 (COVID-19) informs research priorities and public health policies., Methods: Among adults (≥18 years) hospitalized with laboratory-confirmed, acute COVID-19 between 11 March 2021, and 31 August 2022 at 21 hospitals in 18 states, those hospitalized during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron-predominant period (BA.1, BA.2, BA.4/BA.5) were compared to those from earlier Alpha- and Delta-predominant periods. Demographic characteristics, biomarkers within 24 hours of admission, and outcomes, including oxygen support and death, were assessed., Results: Among 9825 patients, median (interquartile range [IQR]) age was 60 years (47-72), 47% were women, and 21% non-Hispanic Black. From the Alpha-predominant period (Mar-Jul 2021; N = 1312) to the Omicron BA.4/BA.5 sublineage-predominant period (Jun-Aug 2022; N = 1307): the percentage of patients who had ≥4 categories of underlying medical conditions increased from 11% to 21%; those vaccinated with at least a primary COVID-19 vaccine series increased from 7% to 67%; those ≥75 years old increased from 11% to 33%; those who did not receive any supplemental oxygen increased from 18% to 42%. Median (IQR) highest C-reactive protein and D-dimer concentration decreased from 42.0 mg/L (9.9-122.0) to 11.5 mg/L (2.7-42.8) and 3.1 mcg/mL (0.8-640.0) to 1.0 mcg/mL (0.5-2.2), respectively. In-hospital death peaked at 12% in the Delta-predominant period and declined to 4% during the BA.4/BA.5-predominant period., Conclusions: Compared to adults hospitalized during early COVID-19 variant periods, those hospitalized during Omicron-variant COVID-19 were older, had multiple co-morbidities, were more likely to be vaccinated, and less likely to experience severe respiratory disease, systemic inflammation, coagulopathy, and death., Competing Interests: Potential conflicts of interest. J. C. reports grants from the National Institutes of Health (NIH) and Department of Defense (DoD), outside the submitted work. J. C. reports receiving grants from the NIH, DoD, outside the submitted work. A. D, reports grants from the NIH and National Heart, Lung, and Blood Institute (NHLBI) for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) platform and Prevention and Early Treatment of Acute Lung Injury (PETAL) network respectively, as well as consulting fees for Alung Technologies, outside the submitted work. S. C. reports receiving consulting fees from PureTech Health and Kiniksa Pharmaceuticals and participating as a Data and Safety Monitoring Board (DSMB) member for a neuromodulation study at University of California, Los Angeles, outside the submitted work. M. E. reports grants from NIH and Regeneron, personal funds for speaking at the ASPEN conference for Abbott Labs, and payment for testimony from Medical Legal Expert Witness, outside the submitted work. M. G. reports receiving grants from CDC, CDC-Abt Associates, CDC-Westat, and Janssen, and served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. K. G. reports grants from NIH and DoD, outside the submitted work. A. G. reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. M. N. G. reports grants from NHLBI, CDC, Agency for Healthcare Research and Quality (AHRQ), speaking at medicine grand rounds at New York Medical College, travel support for the American Thoracic Society (ATS) executive meeting and serving as ATS Chair Critical Care Assembly, DSMB membership fees from Regeneron, and participating on the scientific advisory panel for Endpoint, outside the submitted work. D. H. reports receiving grants from NHLBI, outside the submitted work. A. K. reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. J. K. reports a grant from NIH, outside the submitted work A. L. reports receiving grants from CDC, National Institute of Allergy and Infectious Diseases (NIAID), and Burroughs Wellcome Fund, Michigan Department of Health and Human Services, Flu Lab, and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. E. M. reports grants from Flu Lab, Merck, and NIH outside the submitted work. T. N. reports receiving a grant from CDC, receiving a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure, and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. I. D, P. reports grants from NIH/NHLBI, Janssen Pharmaceuticals and institutional support from Regeneron, outside the submitted work. J. S. reports a grant from NHLBI, outside the submitted work. W. B. S, reports grants from NIH/NHLBI, outside the submitted work. J. W. reports a grant from NIH/NHLBI, payment for the American College of Emergency Physicians speaker honorarium and participating on the American Board of Internal Medicine Critical Care Exam Committee, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomic and subgenomic RNA levels are frequently used as a correlate of infectiousness. The impact of host factors and SARS-CoV-2 lineage on RNA viral load is unclear., Methods: Total nucleocapsid (N) and subgenomic N (sgN) RNA levels were measured by quantitative reverse transcription polymerase chain reaction (RT-qPCR) in specimens from 3204 individuals hospitalized with coronavirus disease 2019 (COVID-19) at 21 hospitals. RT-qPCR cycle threshold (Ct) values were used to estimate RNA viral load. The impact of time of sampling, SARS-CoV-2 variant, age, comorbidities, vaccination, and immune status on N and sgN Ct values were evaluated using multiple linear regression., Results: Mean Ct values at presentation for N were 24.14 (SD 4.53) for non-variants of concern, 25.15 (SD 4.33) for Alpha, 25.31 (SD 4.50) for Delta, and 26.26 (SD 4.42) for Omicron. N and sgN RNA levels varied with time since symptom onset and infecting variant but not with age, comorbidity, immune status, or vaccination. When normalized to total N RNA, sgN levels were similar across all variants., Conclusions: RNA viral loads were similar among hospitalized adults, irrespective of infecting variant and known risk factors for severe COVID-19. Total N and subgenomic RNA N viral loads were highly correlated, suggesting that subgenomic RNA measurements add little information for the purposes of estimating infectivity., Competing Interests: Potential conflicts of interest. J. Ca. reports grants from National Institutes of Health (NIH) and Department of Defense (DoD), outside the submitted work. J. Ch. reports grants from the NIH, DoD, and Dolly Parton COVID-19 Research Fund, outside the submitted work. D. D. reports a grant from NIH, outside the submitted work. A. D. reports grants from the NIH and National Heart, Lung, and Blood Institute (NHLBI) for the ACTIV platform and PETAL network, respectively; and consulting fees for Alung Technologies, outside the submitted work. M. E. reports grants from NIH and Regeneron; personal funds for speaking at the ASPEN conference for Abbott Labs; and payment for testimony from Medical Legal Expert Witness, outside the submitted work. A. F. reports grants from NIH, outside the submitted work. M. G. reports grants from CDC, CDC-Abt Associates, and CDC-Westat; and served as cochair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. K. G. reports grants from NIH and DoD; and support for MHSRS 2022 travel from the DoD, outside the submitted work. A. G. reports grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. M. N. G. reports grants from NHLBI, CDC, and Agency for Healthcare Research and Quality; speaking at medicine grand rounds at New York Medical College; travel support for the American Thoracic Society (ATS) executive meeting and serving as ATS Chair Critical Care Assembly; data and safety monitoring board (DSMB) membership fees from Regeneron; and participating on the scientific advisory panel for Endpoint, outside the submitted work. C. G. reports grants from NIH, CDC, AHRQ, FDA, and Campbell Alliance/Syneos Health; and consulting fees from and participating on a DSMB for Merck, outside the submitted work. D. H. reports grants from NHLBI, outside the submitted work. N. H. reports grants from Sandofi and Quidel; and a Genentech educational grant to give a lecture, outside the submitted work. A. K. reports grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. A. L. reports grants from CDC, National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund; and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir, respectively, outside the submitted work. E. M. reports grants from Flu Lab, Merck, and NIH outside the submitted work. T. M. reports a grant from CDC; a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure; and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. I. D. P. reports grants from NIH and Janssen Pharmaceuticals; and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. W. B. S. reports grants and support for meetings/travel from the NIH/NHLBI, outside the submitted work. J. W. reports payment for the American College of Emergency Physicians speaker honorarium and participating on the American Board of Internal Medicine Critical Care Exam Committee, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Whether video laryngoscopy as compared with direct laryngoscopy increases the likelihood of successful tracheal intubation on the first attempt among critically ill adults is uncertain., Methods: In a multicenter, randomized trial conducted at 17 emergency departments and intensive care units (ICUs), we randomly assigned critically ill adults undergoing tracheal intubation to the video-laryngoscope group or the direct-laryngoscope group. The primary outcome was successful intubation on the first attempt. The secondary outcome was the occurrence of severe complications during intubation; severe complications were defined as severe hypoxemia, severe hypotension, new or increased vasopressor use, cardiac arrest, or death., Results: The trial was stopped for efficacy at the time of the single preplanned interim analysis. Among 1417 patients who were included in the final analysis (91.5% of whom underwent intubation that was performed by an emergency medicine resident or a critical care fellow), successful intubation on the first attempt occurred in 600 of the 705 patients (85.1%) in the video-laryngoscope group and in 504 of the 712 patients (70.8%) in the direct-laryngoscope group (absolute risk difference, 14.3 percentage points; 95% confidence interval [CI], 9.9 to 18.7; P<0.001). A total of 151 patients (21.4%) in the video-laryngoscope group and 149 patients (20.9%) in the direct-laryngoscope group had a severe complication during intubation (absolute risk difference, 0.5 percentage points; 95% CI, -3.9 to 4.9). Safety outcomes, including esophageal intubation, injury to the teeth, and aspiration, were similar in the two groups., Conclusions: Among critically ill adults undergoing tracheal intubation in an emergency department or ICU, the use of a video laryngoscope resulted in a higher incidence of successful intubation on the first attempt than the use of a direct laryngoscope. (Funded by the U.S. Department of Defense; DEVICE ClinicalTrials.gov number, NCT05239195.)., (Copyright © 2023 Massachusetts Medical Society.)

Hypotension affects approximately 40% of critically ill patients undergoing emergency intubation and is associated with an increased risk of death. The objective of this study was to examine the association between prophylactic vasopressor administration and the incidence of peri-intubation hypotension and other clinical outcomes., Design: A secondary analysis of two multicenter randomized clinical trials. The clinical effect of prophylactic vasopressor administration was estimated using a one-to-one propensity-matched cohort of patients with and without prophylactic vasopressors., Setting: Seven emergency departments and 17 ICUs across the United States., Patients: One thousand seven hundred ninety-eight critically ill patients who underwent emergency intubation at the study sites between February 1, 2019, and May 24, 2021., Interventions: None., Measurements and Main Results: The primary outcome was peri-intubation hypotension defined as a systolic blood pressure less than 90 mm Hg occurring between induction and 2 minutes after tracheal intubation. A total of 187 patients (10%) received prophylactic vasopressors prior to intubation. Compared with patients who did not receive prophylactic vasopressors, those who did were older, had higher Acute Physiology and Chronic Health Evaluation II scores, were more likely to have a diagnosis of sepsis, had lower pre-induction systolic blood pressures, and were more likely to be on continuous vasopressor infusions prior to intubation. In our propensity-matched cohort, prophylactic vasopressor administration was not associated with reduced risk of peri-intubation hypotension (41% vs 32%; p = 0.08) or change in systolic blood pressure from baseline (-12 vs -11 mm Hg; p = 0.66)., Conclusions: The administration of prophylactic vasopressors was not associated with a lower incidence of peri-intubation hypotension in our propensity-matched analysis. To address potential residual confounding, randomized clinical trials should examine the effect of prophylactic vasopressor administration on peri-intubation outcomes., Competing Interests: Dr. Fuchita received a departmental seed grant from the University of Colorado, Department of Anesthesiology, for biostatistical support. Dr. Casey was supported in part by the National Institutes of Health (NIH) (K23HL153584). Dr. Semler was supported in part by the NIH (K23HL143053). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target., Methods: We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo. All participants received remdesivir. The primary outcome was time-to-resolution of illness, defined as improvement on the 8-point NIH-Ordinal COVID-19 Scale to category ≤3. Secondary endpoints were safety and exploratory endpoints were pro-inflammatory and antiviral mediators in serum on days 0-5 & 7. The trial was stopped after 40 patients were randomized and treated due to slow enrollment., Findings: 40 participants were randomized and treated with IC14 (n = 20) or placebo (n = 20). The median time-to-recovery was 6 days (95% CI, 5-11) in the IC14 group vs. 5 days (95% CI, 4-10) in the Placebo group (recovery rate ratio: 0.77 (95% CI, 0.40, 1.48) (log-rank p = 0.435). The number of adverse events was similar in each group, and no IC14-attributable secondary infections occurred. In repeated-measures mixed-effects analyses, IC14 treatment increased serum sCD14 concentrations, an expected pharmacodynamic effect. Pre-planned, exploratory analyses suggested that IC14 treatment decreased the trajectories of circulating MIP-1β and TNF-α., Interpretation: IC14 treatment did not improve time-to-resolution of illness in hypoxemic patients with COVID-19 in this small trial. Results of exploratory analyses suggested IC14 had biologic effects that warrant future clinical investigation., Funding: National Institute of Allergy and Infectious Diseases., Competing Interests: Declaration of interests TRM reported: 1) receiving fees from Novartis Pharmaceuticals for the topic of COVID-19 related ARDS, 2) receiving fees from Quantum Leap Healthcare Collaborative as a member of the clinical safety monitoring committee for another trial in COVID, 3) providing unpaid consulting for Implicit Bioscience Ltd for use of the IC14 anti-CD14 monoclonal antibody in ARDS and COVID-19 illness. JGD reported receiving a fee from RMEI: Medical Education for the topic of severe COVID-19 management outside the submitted work. No other disclosures were reported., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Accurate determination of COVID-19 vaccination status is necessary to produce reliable COVID-19 vaccine effectiveness (VE) estimates. Data comparing differences in COVID-19 VE by vaccination sources (i.e., immunization information systems [IIS], electronic medical records [EMR], and self-report) are limited. We compared the number of mRNA COVID-19 vaccine doses identified by each of these sources to assess agreement as well as differences in VE estimates using vaccination data from each individual source and vaccination data adjudicated from all sources combined., Methods: Adults aged ≥18 years who were hospitalized with COVID-like illness at 21 hospitals in 18 U.S. states participating in the IVY Network during February 1-August 31, 2022, were enrolled. Numbers of COVID-19 vaccine doses identified by IIS, EMR, and self-report were compared in kappa agreement analyses. Effectiveness of mRNA COVID-19 vaccines against COVID-19-associated hospitalization was estimated using multivariable logistic regression models to compare the odds of COVID-19 vaccination between SARS-CoV-2-positive case-patients and SARS-CoV-2-negative control-patients. VE was estimated using each source of vaccination data separately and all sources combined., Results: A total of 4499 patients were included. Patients with ≥1 mRNA COVID-19 vaccine dose were identified most frequently by self-report (n = 3570, 79 %), followed by IIS (n = 3272, 73 %) and EMR (n = 3057, 68 %). Agreement was highest between IIS and self-report for 4 doses with a kappa of 0.77 (95 % CI = 0.73-0.81). VE point estimates of 3 doses against COVID-19 hospitalization were substantially lower when using vaccination data from EMR only (VE = 31 %, 95 % CI = 16 %-43 %) than when using all sources combined (VE = 53 %, 95 % CI = 41 %-62%)., Conclusion: Vaccination data from EMR only may substantially underestimate COVID-19 VE., Competing Interests: Declaration of Competing Interest All authors have completed and submitted the International Committee of Medical Journal Editors (ICJME) disclosure form. Funding for this work was provided to all participating sites by the United States Centers for Disease Control and Prevention. The authors declare the following financial interests/personal relationships, which may be considered as potential competing interests: Samuel Brown reports institutional funds from Janssen for influenza research. Jonathan Casey reports a travel grant from Fischer and Paykel, outside the submitted work. Steven Chang reports consulting fees from PureTech Health and Kiniksa Pharmaceuticals and participating as a DSMB member for a study at UCLA, outside the submitted work. Manjusha Gaglani reports grants from CDC, CDC-Abt Associates, CDC-Westat, and Janssen, and served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. Kevin Gibbs reports grants from NIH and DoD, as well as support for MHSRS 2022 travel from the DoD, outside the submitted work. Adit Ginde reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NHLBI, CDC, AHRQ, speaking at medicine grand rounds at New York Medical College, travel support for the ATS executive meeting and serving as ATS Chair Critical Care Assembly, DSMB membership fees from Regeneron, and participating on the scientific advisory panel for Endpoint, outside the submitted work. Carlos Grijalva reports grants from NIH, CDC, AHRQ, FDA, Campbell Alliance/Syneos Health; receiving consulting fees from and participating on a DSMB for Merck, outside the submitted work. David Hager reports receiving grants from NIH, outside the submitted work. Akram Khan reports receiving grants from United Therapeutics, Johnson & Johnson, 4D Medical, Eli Lily, Dompe Pharmaceuticals, and GlaxoSmithKline; and serves on the guidelines committee for Chest, outside the submitted work. Adam Lauring reports receiving grants from CDC, FluLab, NIAID, and Burroughs Wellcome Fund, and consulting fees from Sanofi and Roche for consulting on oseltamivir and baloxavir respectively, outside the submitted work. Emily Martin reports grants from Merck and NIH, outside the submitted work. Tresa McNeal reports receiving a grant from CDC, receiving a one-time payment for participating as a virtual webinar panelist for Clinical Updates in Heart Failure, and being a Practice Management Committee member for Society of Hospital Medicine, outside the submitted work. Ithan D. Peltan reports grants from NIH, Janssen Pharmaceuticals and institutional support from Asahi Kasei Pharma and Regeneron, outside the submitted work. Jennifer Wilson reports grants from NHLBI, outside the submitted work. No other potential conflicts of interest were disclosed., (Published by Elsevier Ltd.)

Rationale: A recent randomized trial found that using a bougie did not increase the incidence of successful intubation on first attempt in critically ill adults. The average effect of treatment in a trial population, however, may differ from effects for individuals. Objective: We hypothesized that application of a machine learning model to data from a clinical trial could estimate the effect of treatment (bougie vs. stylet) for individual patients based on their baseline characteristics ("individualized treatment effects"). Methods: This was a secondary analysis of the BOUGIE (Bougie or Stylet in Patients Undergoing Intubation Emergently) trial. A causal forest algorithm was used to model differences in outcome probabilities by randomized group assignment (bougie vs. stylet) for each patient in the first half of the trial (training cohort). This model was used to predict individualized treatment effects for each patient in the second half (validation cohort). Measurements and Main Results: Of 1,102 patients in the BOUGIE trial, 558 (50.6%) were the training cohort, and 544 (49.4%) were the validation cohort. In the validation cohort, individualized treatment effects predicted by the model significantly modified the effect of trial group assignment on the primary outcome ( P value for interaction = 0.02; adjusted qini coefficient, 2.46). The most important model variables were difficult airway characteristics, body mass index, and Acute Physiology and Chronic Health Evaluation II score. Conclusions: In this hypothesis-generating secondary analysis of a randomized trial with no average treatment effect and no treatment effect in any prespecified subgroups, a causal forest machine learning algorithm identified patients who appeared to benefit from the use of a bougie over a stylet and from the use of a stylet over a bougie using complex interactions between baseline patient and operator characteristics.

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., Competing Interests: This study was funded by Cytovale, Inc. Expert panelists were compensated for their time for participation. C.K.K. has received funding personally from Cytovale for consulting, H.B.N. has received funding personally from Cytovale for consulting, R.C.J. has received funding personally from Cytovale for consulting, L.S.M. has received funding personally from Cytovale for consulting, N.A.L. has stock options for Cytovale and Inflammatix, H.R.O. reports no conflict of interest, M.A.P. has received funding personally from Cytovale and Opticyte for consulting. M.A.P. reports grant money to Hennepin County Medical Center to conduct research conceived and sponsored by Endpoint Health, T.W.R.’s institution has received grant funding from the National Institutes of Health, Centers for Disease Control and Prevention, and the US Department of Defense, and Endpoint Health, Inc. for investigator‐initiated research. T.W.R. has received funding personally from Cumberland Pharmaceuticals, Inc. and Cytovale, Inc. for consulting and from Sanofi, Inc. for DSMB membership, W.H.S. has received funding personally from Cytovale for consulting, R.E.R. has received funding personally from Cytovale for consulting for serving on an expert advisory committee and providing oversight in formulating, writing and editing this study. R.E.R. previously served on paid expert advisory panels for Abbott, Roche, Cepheid, MeMed, and Inflammatix; R.E.R.’s institution received support from the National Institutes of Health and Biomedical Advanced Research and Development Authority/US Department of Health and Human Services for research in infectious disease diagnostics in emergency settings., (© 2023 The Authors. JACEP Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)