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OBJECTIVE: To assess the feasibility of using respiratory frequencies up to 15 Hz during high-frequency oscillatory ventilation (HFO) of adults with acute respiratory distress syndrome (ARDS). DESIGN: Observational study. SETTING: Medical intensive care unit at a tertiary care university hospital. PATIENTS: Thirty adult patients receiving HFO at the discretion of their physicians for management of severe ARDS. INTERVENTIONS: Clinical management algorithm for HFO that minimized delivered tidal volumes by encouraging the use of the highest frequency that allowed acceptable clearance of carbon dioxide. This contrasts with the typical use of HFO in adults, in which frequencies generally do not exceed 6 Hz. MEASUREMENTS AND MAIN RESULTS: Patients were 42 +/- 15 yrs old, weighed 83 +/- 25 kg, and had failed conventional lung-protective ventilation due to refractory hypoxia or respiratory acidosis and high plateau airway pressures. During HFO, 25 of 30 patients maintained acceptable gas exchange at frequencies > 6 Hz; 12 reached maximal frequencies of > or = 10 Hz. Among patients whose maximal frequencies exceeded 6 Hz, mean maximal frequency was 9.9 +/- 2.1 Hz, at a mean oscillation pressure amplitude of 81 +/- 11 cm H2O. At those settings, blood gases were pH 7.31 +/- 0.06, PaCO2 was 58 +/- 21 mm Hg, and PaO2 was 82 +/- 33 mm Hg. Survival to hospital discharge among this severely ill cohort was 37%. CONCLUSIONS: Most adults can maintain adequate gas exchange using HFO frequencies well above 5-6 Hz. Use of higher frequencies should minimize tidal volume and we speculate might thereby reduce ventilator-associated lung injury. [ABSTRACT FROM AUTHOR]

OBJECTIVE: a) Characterize how ventilator and patient variables affect tidal volume during high-frequency oscillatory ventilation; and b) measure tidal volumes in adults with acute respiratory distress syndrome during high-frequency oscillatory ventilation. DESIGN: Observational study. SETTING: Research laboratory and medical intensive care unit. PATIENTS: Test lung and patients with acute respiratory distress syndrome. INTERVENTIONS: Using a previously validated hot wire anemometer placed in series with a Sensormedics 3100B high-frequency ventilator, an endotracheal tube, and a test lung, tidal volume was measured at different combinations of frequency (4, 6, 8, 10, and 12 Hz), pressure amplitude (50, 60, 70, 80, and 90 cm H2O), mean airway pressure (20, 30, and 40 cm H2O), test lung compliance (10, 30, and 50 mL/cm H2O), endotracheal tube internal diameter (6, 7, and 8 mm), bias flow (20, 30, and 40 L/min), and inspiratory/expiratory ratio (1:2 and 1:1). In patients, tidal volume was measured at baseline ventilator settings and at baseline frequency +/-2 Hz and baseline pressure amplitude +/-10 cm H2O. MEASUREMENTS AND MAIN RESULTS: Measured tidal volumes were 23-225 mL during high-frequency oscillatory ventilation of the test lung. A 2-Hz increase in frequency and a 10-cm H2O increase in pressure amplitude caused a 21.3% +/- 4.1% decrease and 21.4% +/- 3.4% increase in tidal volume, respectively. Decreasing endotracheal tube internal diameter from 8 mm to 7 mm and from 7 mm to 6 mm caused a 15.3% +/- 1.7% and 18.9% +/- 2.1% reduction in tidal volume, respectively. Increasing bias flow from 20 L/min to 30 L/min increased tidal volume by 11.2% +/- 3.9%. Further increases in bias flow, changes in compliance, and changes in mean airway pressure had little effect. Tidal volumes measured in acute respiratory distress syndrome patients were 44-210 mL. A 2-Hz increase in frequency was associated with a 23.1% +/- 6.3% decrease in tidal volume. In contrast to the test lung data, a 10-cm H2O increase in pressure amplitude resulted in only a 5.6% +/- 4.5% increase in tidal volume. CONCLUSIONS: Tidal volumes are not uniformly small during high-frequency oscillatory ventilation. The primary determinant of tidal volume in adults with acute respiratory distress syndrome during high-frequency oscillatory ventilation with the Sensormedics 3100B is frequency. Test lung findings suggest that endotracheal tube internal diameter is also an important determinant of tidal volume. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Assess the accuracy of four different methods of measuring tidal volume during simulated high-frequency oscillatory ventilation. DESIGN: In vitro study. SETTING: Research laboratory. SUBJECTS: Three differential pressure pneumotachometers, a modified Pitot tube, an ultrasound flowmeter, and an adult hot wire anemometer. INTERVENTIONS: Each device was placed in series with a Sensormedics 3100B high-frequency ventilator and an 8.0-mm endotracheal tube attached to a 48.9-L plethysmograph. Inspiratory/expiratory ratio was fixed at 1:1 and mean airway pressure at 10 cm H2O. Tidal volumes were calculated at each combination of frequency (f: 3, 4, 6, 8, 10, 12 Hz) and pressure amplitude (DeltaP: 30, 60, 90 cm H2O) by digital integration of the sampled flow signals from each device and compared with those calculated from pressure changes within the plethysmograph. The protocol was repeated after incorporation of frequency-specific calibrations to the flow-measuring algorithm of each device. The hot wire anemometer was further evaluated at Fio2 of 1.0, 37 degrees C, 80% humidity, mean airway pressure of 20 cm H2O, and an inspiratory/expiratory ratio of 1:2. MEASUREMENTS AND MAIN RESULTS: Tidal volumes were 36-305 mL. Bland-Altman analysis demonstrated that each device exhibited systematic bias before frequency-specific adjustment. After frequency-specific adjustment of the flow-measuring algorithm, the two most accurate and precise devices were the Hans Rudolph pneumotachometer, which exhibited a mean error of 0.2% (95% confidence interval, -3.0% to 3.4%), and the hot wire anemometer, which had a mean error of -1.1% (95% confidence interval, -5.5% to 3.3%). The hot wire anemometer remained accurate at Fio2 1.0, 37 degrees C, 80% humidity, mean airway pressure of 20 cm H2O, and an inspiratory/expiratory ratio of 1:2. CONCLUSIONS: Tidal volume can be measured during high-frequency oscillatory ventilation using a variety of techniques. Frequency-specific calibration improves the accuracy and precision of tidal volume measurements. Hot wire anemometry exhibits stable performance characteristics across the range of temperature, humidity, Fio2, and inspiratory/expiratory ratios encountered clinically, has a small deadspace, is unaffected by mean airway pressure, and is therefore suitable for clinical applications. [ABSTRACT FROM AUTHOR]

Use of a volume- and pressure-limited mechanical ventilation strategy improves clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, the extent to which tidal volumes and inspiratory airway pressures should be reduced to optimize clinical outcomes is a controversial topic. This article addresses the question, "Is there a safe upper limit to inspiratory plateau pressure in patients with ALI/ARDS?" We reviewed data from animal models with and without preexisting lung injury, studies of normal human respiratory system mechanics, and the results of five clinical trials of lung-protective mechanical ventilation strategies. We also present an original analysis of data from the largest of the five clinical trials. The available data from each of these assessments do not support the commonly held view that inspiratory plateau pressures of 30 to 35 cm H2O are safe. We could not identify a safe upper limit for plateau pressures in patients with ALI/ARDS. [ABSTRACT FROM AUTHOR]

COVID-19 vaccination averted approximately 68,000 hospitalizations during the 2023-24 respiratory season. In June 2024, CDC and the Advisory Committee on Immunization Practices (ACIP) recommended that all persons aged ≥6 months receive a 2024-2025 COVID-19 vaccine, which targets Omicron JN.1 and JN.1-derived sublineages. Interim effectiveness of 2024-2025 COVID-19 vaccines was estimated against COVID-19-associated emergency department (ED) or urgent care (UC) visits during September 2024-January 2025 among adults aged ≥18 years in one CDC-funded vaccine effectiveness (VE) network, against COVID-19-associated hospitalization in immunocompetent adults aged ≥65 years in two networks, and against COVID-19-associated hospitalization among adults aged ≥65 years with immunocompromising conditions in one network. Among adults aged ≥18 years, VE against COVID-19-associated ED/UC visits was 33% (95% CI = 28%-38%) during the first 7-119 days after vaccination. Among immunocompetent adults aged ≥65 years from two CDC networks, VE estimates against COVID-19-associated hospitalization were 45% (95% CI = 36%-53%) and 46% (95% CI = 26%-60%) during the first 7-119 days after vaccination. Among adults aged ≥65 years with immunocompromising conditions in one network, VE was 40% (95% CI = 21%-54%) during the first 7-119 days after vaccination. These findings demonstrate that vaccination with a 2024-2025 COVID-19 vaccine dose provides additional protection against COVID-19-associated ED/UC encounters and hospitalizations compared with not receiving a 2024-2025 dose and support current CDC and ACIP recommendations that all persons aged ≥6 months receive a 2024-2025 COVID-19 vaccine dose., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. James D. Chappell reports grants from Merck to study respiratory virus epidemiology among hospitalized children in Jordan. Natasha Halasa reports grants from Merck and participation on a CSL-Seqirus advisory board. Akram Khan reports grant or contract support from Dompe Pharmaceuticals, Direct Biologics, 4D Medical, and Vivacell Bio. Adam S. Lauring reports receipt of grant or contract support and consulting fees from Roche. Ithan D. Peltan reports institutional support from Novartis and Bluejay Diagnostics, and grant support from the National Institutes of Health. Ivana A. Vaughn reports institutional support from eMaxHealth, Eli Lily, and Evidera PPD. Malini B. DeSilva reports institutional support from Westat, Inc. Stephanie A. Irving and Allison L. Naleway report institutional support from Westat for VISION funding. Michelle A. Barron reports payment or honorarium as a speaker bureau participant from Innoviva Specialty Therapeutics. Colin Rogerson reports receipt of an infrastructure grant from Indiana University Health to support the development of an Observational Medical Outcomes Partnership-based database at the Regenstrief Institute. Toan C. Ong reports receipt of consulting fees from Regenstrief Institute for serving as a domain expert in patient matching in global health informatics; travel support from Patient-Centered Outcomes Research Institute (PCORI) to attend the 2023 PCORI annual meeting; and travel support from Regenstrief to attend the Open Health Information Exchange 23 meeting in Malawi. Nicola P. Klein reports institutional support from Sanofi Pasteur, Merck, Pfizer, Seqirus, and GSK; unpaid membership on an expert panel for a planned Hepatitis E Phase II vaccine clinical trial among pregnant women in Pakistan; unpaid membership on the Western States COVID-19 Scientific Safety Review Workgroup, Board on Population Health and Pubic Health Practice, National Academies of Science, Engineering, and Medicine, and the National Vaccine Advisory Committee Safety Subcommittee. Tamara Sheffield reports unpaid service as chair of the Utah Adult Immunization Coalition, membership on the CDC Advisory Committee on Immunization Practices Influenza Vaccine Work Group, and membership on the Utah Department of Health and Human Services Scientific Advisory Committee on Vaccines. Ousseny Zerbo reports support from Moderna, Pfizer, and the National Institutes of Health to the Kaiser Foundation Research Institute for studies unrelated to the current work. No other potential conflicts of interest were disclosed.

Background: Understanding similarities and differences between hesitancy for influenza and COVID-19 vaccines could facilitate strategies to improve public receptivity toward vaccination., Methods: We compared hesitancy for COVID-19 vaccines during the first 13 months of availability (January 2021-January 2022) with hesitancy for influenza vaccines in the 15 months prior to COVID-19 vaccine availability (October 2019-December 2020) among adults hospitalized with acute respiratory illness at 21 hospitals in the United States. We interviewed patients regarding vaccination status, willingness to be vaccinated, and perceptions of vaccine safety and efficacy. We used multivariate logistic regression to identify factors associated with vaccine hesitancy., Results: Among 12,292 patients enrolled during the COVID-19 vaccine period, 5485 (44.6 %) were unvaccinated. Patient characteristics associated with not receiving the COVID-19 vaccine included younger age, female sex, higher BMI, lack of health insurance, absence of chronic comorbid medical conditions, no or rare influenza vaccination in prior years, higher CDC social vulnerability index (SVI), a measure of external stresses that may negatively impact health, living in the Midwest or southern US, lack of college or higher education, and not wearing a mask. Among 983 patients enrolled during the influenza vaccination period, 381(37.8 %) were unvaccinated. Characteristics associated with not receiving the influenza vaccine included no or one chronic comorbid medical condition, no or rare influenza vaccination in prior years, being a current smoker, and higher SVI. Discussion with healthcare providers was a reason for vaccination for 27.7 % (167) for influenza and 8.3 % (564) for COVID-19 and to decline vaccination for 0.5 % Ten great public health achievements-United States (2011) (2) for influenza and 2.2 % (118) for COVID-19., Conclusions: We found that higher SVI scores and lack of prior influenza vaccination were associated with hesitancy for both COVID-19 and influenza vaccines. There were regional variations in COVID-19 vaccine acceptance and discussions with HCPs significantly influenced acceptance for both vaccines., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Coronavirus disease 2019 (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 messenger RNA (mRNA) COVID-19 vaccination series, and VTE. Prevalence of VTE was compared between unvaccinated and vaccinated patients with COVID-19. The vaccine effectiveness (VE) in preventing COVID-19 hospitalization with VTE was calculated using a test-negative design. The VE was also stratified by predominant circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant., Results: Among 18 811 patients (median age [interquartile range], 63 [50-73] years; 49% women; 59% non-Hispanic white, 20% non-Hispanic black, and 14% Hispanic; and median of 2 comorbid conditions [interquartile range, 1-3]), 9792 were admitted with COVID-19 (44% vaccinated), and 9019 were test-negative controls (73% vaccinated). Among patients with COVID-19, 601 had VTE diagnosed by hospital day 28, of whom 170 were vaccinated. VTE was more common among unvaccinated than vaccinated patients with COVID-19 (7.8% vs 4.0%; P = .001). The VE against COVID-19 hospitalization with VTE was 84% overall (95% confidence interval, 80%-87%), and VE stratified by predominant circulating variant was 88% (73%-95%) for Alpha, 93% (90%-95%) for Delta, and 68% (58%-76%) for Omicron variants., Conclusions: 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., Competing Interests: Potential conflicts of interest . M. B. S. reports consulting fees from Bristol Myers Squibb, Janssen, Pfizer, CSL Behrin, and Attralus and honoraria from Bristol Myers Squibb, Janssen, and Pfizer, and he has participated on a data and safety monitoring board on behalf of CSL Behring. I. D. P. reports support from Janssen Pharmaceutical and institutional support from Bluejay Diagnostics and Regeneron. A. S. L. reports support from FluLab and Roche Pharmaceuticals. 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) 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.)

Background: Plasma dipeptidyl peptidase-3 (DPP3) and renin levels are associated with organ dysfunction and mortality. However, whether these biomarkers are associated with the subsequent onset of shock in at-risk patients is unknown., Methods: Using plasma samples collected from participants enrolled in the fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines Host Tissue platform trial, we measured DPP3 and renin in 184 subjects hospitalized with acute hypoxemia from COVID-19 without baseline vasopressor requirement. We calculated the odds ratio of development of shock (defined as the initiation of vasopressor therapy) by Day 28 based on Day 0 DPP3 and renin levels., Results: Subjects with DPP3 above the median had a significantly higher incidence of vasopressor initiation within 28 days (28.4 % vs. 16.7 %, p = 0.031) and higher 28-day mortality (25.0 % vs. 6.7 %, p < 0.001). After adjusting for covariables, DPP3 above the median was associated with shorter time to vasopressor initiation, greater 28-day mortality, fewer vasopressor-free days, and greater odds of a hypotensive event over 7 days. Significant associations were not observed for renin., Conclusions: In patients hospitalized with COVID-19 and hypoxemia without baseline hypotension, higher baseline plasma levels of DPP3 but not renin were associated with increased risk of subsequent shock and death., Competing Interests: Declaration of competing interest All authors completed and submitted the ICMJE form for disclosure of potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Rationale: Early identification of intensive care unit (ICU) patients likely to benefit from specialist palliative care could reduce the time such patients spend in the ICU receiving care inconsistent with their goals. Objectives: To evaluate the real-world effects of early screening for palliative care criteria in a medical ICU. Methods: We performed a retrospective cohort study in adults admitted to the ICU using a causal inference approach with instrumental variable analysis. The intervention consisted of screening ICU admissions for palliative care trigger conditions and, if present, offering specialist palliative care consultation, which could be accepted or declined by the ICU. We evaluated specialist palliative care use in pre and postimplementation cohorts from the year before and after screening implementation began (October 2022). In the postimplementation cohort, we compared use of specialist palliative care in those who received early screening versus not. We then estimated the effect of early screening on the primary outcome of days to do-not-resuscitate (DNR) code status or ICU discharge, with death without a DNR order placed at the 99th percentile of the days to DNR or ICU discharge distribution. Secondary outcomes included: DNR order, ICU and hospital lengths of stay, hospice discharge, and mortality metrics. To address unmeasured confounding, we used two-stage least-squares instrumental variables analysis. The instrument, which predicts early screening, comprised weekend versus weekday admission and number of patients meeting palliative care criteria on a patient's ICU Days 1 and 2. Results: Among 1,282 postimplementation admissions, 626 (45%) received early screening, and 398 (28%) received specialty palliative consultation. Early receipt of specialist palliative care was higher in patients who received early screening versus not (17% vs. 1%; P  < 0.001), and overall use of specialty palliative care was higher after versus before screening implementation (28% vs. 15%; P  < 0.001). In the postimplementation cohort, there were no statistically significant effects of early screening on the primary outcome of days to DNR or ICU discharge (15% relative increase; 95% confidence interval, -11% to +48%) or other secondary outcomes. Conclusions: Despite significantly increased specialty palliative care consultation, there was no evidence that early screening for palliative care criteria affected time to DNR/ICU discharge or other secondary outcomes.

Intermediate care (IC) is prevalent nationwide, but little is known about how to best organize this level of care. Using a 99-item cross-sectional survey assessing four domains (hospital and physical IC features, provider and nurse staffing, monitoring, and interventions/services), we describe the organizational heterogeneity of IC within a five-hospital healthcare system. Surveys were completed by nurse managers from 12 (86%) of 14 IC settings. Six IC settings (50%) were embedded within acute care wards, four (33%) were stand-alone units, and two (17%) were embedded within an ICU. All had a nurse-to-patient ratio of 1:3, provided continuous cardiac telemetry, continuous pulse oximetry, high-flow nasal oxygen, and bedside intermittent hemodialysis. Most (> 50%) permitted arterial lines, frequent nursing assessments (every 2 hr), and noninvasive ventilation or mechanical ventilation via a tracheostomy. Vasopressors were less often permitted (< 25% of settings). Models of IC vary greatly within a single healthcare system., Competing Interests: Dr. Case received funding from the National Institutes of Health (NIH) T32 Training Award (T32HL007534) and the NIH F32 Award (F32HS029594). Dr. Hochberg received funding from the NIH K23 Award (K23Hl169743). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2025 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background: In test-negative studies of vaccine effectiveness (VE), including patients with co-circulating, vaccine-preventable, respiratory pathogens in the control group for the pathogen of interest can introduce a downward bias on VE estimates., Methods: A multicenter sentinel surveillance network in the US prospectively enrolled adults hospitalized with acute respiratory illness from September 1, 2022-March 31, 2023. We evaluated bias in estimates of VE against influenza-associated and COVID-19-associated hospitalization based on: inclusion vs exclusion of patients with a co-circulating virus among VE controls; observance of VE against the co-circulating virus (rather than the virus of interest), unadjusted and adjusted for vaccination against the virus of interest; and observance of influenza or COVID-19 against a sham outcome of respiratory syncytial virus (RSV)., Results: Overall VE against influenza-associated hospitalizations was 6 percentage points lower when patients with COVID-19 were included in the control group, and overall VE against COVID-19-associated hospitalizations was 2 percentage points lower when patients with influenza were included in the control group. Analyses of VE against the co-circulating virus and against the sham outcome of RSV showed that downward bias was largely attributable the correlation of vaccination status across pathogens, but also potentially attributable to other sources of residual confounding in VE models., Conclusion: Excluding cases of confounding respiratory pathogens from the control group in VE analysis for a pathogen of interest can reduce downward bias. This real-world analysis demonstrates that such exclusion is a helpful bias mitigation strategy, especially for measuring influenza VE, which included a high proportion of COVID-19 cases among controls., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Michelle Ng Gong reports grants from NHLBI as a HART co-investigator and APS steering committee co-chair, support for travel to the ATS meeting, participating on an advisory board from Novartis, Philips Healthcase, Regeneron, and Radiomater, and participating on the DSMB for Best clinical trials, outside the submitted work. Carlos G. Grijalva reports receiving compensation for participation in an advisory board for Merck, and receiving research support from CDC, NIH, FDA, AHRQ and SyneosHealth, outside the submitted work. Natasha Halasa receives current support from Merck (investigator-initiated grant), past support from Sanofi and Quidel, and served on an advisory board for Seqirus, outside the submitted work. Akram Khan reports receiving research funding from Dompe pharmaceuticals, 4D Medical, Eli Lilly, and Direct Biologics for patient enrollment in studies, outside the submitted work. Adam S. Lauring reports consulting fees and research support from Roche, and research funding from NIAID, NSF, CDC, and Burroughs Wellcome Fund, outside the submitted work. Ithan Peltan reports funding from NIH (R35GM151147), funding from NHLBI and Janssen, and payments to his institution from Regeneron, Bluejay Diagnostics, and Novartis, outside the submitted work. Mayur Ramesh reports participating on an advisory board for AstraZeneca, Moderna, and Pfizer, outside the submitted work. Ivana A Vaughn reports funding from CDC via University of Michigan for US Flu VE Network, funding from eMaxHealth through her institution, and funding from Lilly USA through her institution, outside the submitted work. No other potential conflicts of interest were disclosed., (Published by Elsevier Ltd.)

Importance: Fostamatinib, a spleen tyrosine kinase inhibitor, has been reported to improve outcomes of COVID-19., Objective: To evaluate the efficacy and safety of fostamatinib in adults hospitalized with COVID-19 and hypoxemia., Design, Setting, and Participants: This multicenter, phase 3, placebo-controlled, double-blinded randomized clinical trial was conducted at 41 US sites and 21 international sites between November 17, 2021, and September 27, 2023; the last follow-up visit was December 31, 2023. Participants were adults aged 18 years or older hospitalized with acute SARS-CoV-2 infection and hypoxemia. Data were analyzed between January 10 and March 8, 2024., Interventions: Fostamatinib, 150 mg orally twice daily for 14 days, or placebo., Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome classifying a participant's status at day 28 based on mortality and duration of supplemental oxygen use. An adjusted odds ratio (AOR) greater than 1.0 was considered to indicate superiority of fostamatinib over placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included elevated transaminase values, neutropenia, and hypertension., Results: Of the 400 participants randomized (median age, 67 years [IQR, 58-76 years]; 210 [52.5%] men), 199 received fostamatinib and 201 received placebo. The mean (SD) number of oxygen-free days was 13.4 (12.4) in the fostamatinib group and 14.2 (12.1) in the placebo group (unadjusted mean difference, -1.26 days [95% CI, -3.52 to 1.00 days]; AOR, 0.82 [95% credible interval (CrI), 0.58-1.17]). Mortality at 28 days occurred in 22 of 195 patients (11.3%) in the fostamatinib group and 16 of 197 (8.1%) in the placebo group (AOR, 1.44; 95% CrI, 0.72-2.90). Aspartate aminotransferase elevation occurred more commonly in the fostamatinib group (23 [11.6%]) than in the placebo group (11 [5.5%]; AOR, 2.28; 95% CrI, 1.07-4.84). Other safety outcomes were similar between groups., Conclusions and Relevance: In this randomized clinical trial of adults hospitalized with COVID-19 and hypoxemia, fostamatinib did not increase the number of oxygen-free days compared with placebo. These results do not support the hypothesis that fostamatinib improves outcomes among adults hospitalized with hypoxemia during the Omicron era., Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Background: clinical guidelines recommend initiation of antiviral therapy as soon as possible for patients hospitalized with confirmed or suspected influenza., Methods: A multicenter US observational sentinel surveillance network prospectively enrolled adults (aged ≥18 years) hospitalized with laboratory-confirmed influenza at 24 hospitals during October 1, 2022-July 21, 2023. A multivariable proportional odds model was used to compare peak pulmonary disease severity (no oxygen support, standard supplemental oxygen, high-flow oxygen/non-invasive ventilation, invasive mechanical ventilation, or death) after the day of hospital admission among patients starting oseltamivir treatment on the day of admission (early) versus those who did not (late or not treated), adjusting for baseline (admission day) severity, age, sex, site, and vaccination status. Multivariable logistic regression models were used to evaluate the odds of intensive care unit (ICU) admission, acute kidney replacement therapy or vasopressor use, and in-hospital death., Results: A total of 840 influenza-positive patients were analyzed, including 415 (49%) who started oseltamivir treatment on the day of admission, and 425 (51%) who did not. Compared with late or not treated patients, those treated early had lower peak pulmonary disease severity (proportional aOR: 0.60, 95% CI: 0.49-0.72), and lower odds of intensive care unit admission (aOR: 0.24, 95% CI: 0.13-0.47), acute kidney replacement therapy or vasopressor use (aOR: 0.40, 95% CI: 0.22-0.67), and in-hospital death (aOR: 0.36, 95% CI: 0.18-0.72)., Conclusion: Among adults hospitalized with influenza, treatment with oseltamivir on day of hospital admission was associated reduced risk of disease progression, including pulmonary and extrapulmonary organ failure and death., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

Background: Assessments of COVID-19 vaccine effectiveness are needed to monitor the protection provided by updated vaccines against severe COVID-19. We evaluated the effectiveness of original monovalent and bivalent (ancestral strain and Omicron BA.4/5) COVID-19 vaccination against COVID-19-associated hospitalization and severe in-hospital outcomes., Methods: During September 8, 2022 to August 31, 2023, adults aged ≥ 18 years hospitalized with COVID-19-like illness were enrolled at 26 hospitals in 20 US states. Using a test-negative case-control design, we estimated vaccine effectiveness (VE) with multivariable logistic regression adjusted for age, sex, race/ethnicity, admission date, and geographic region., Results: Among 7028 patients, 2924 (41.6%) were COVID-19 case patients, and 4104 (58.4%) were control patients. Compared to unvaccinated patients, absolute VE against COVID-19-associated hospitalization was 6% (-7%-17%) for original monovalent doses only (median time since last dose [IQR] = 421 days [304-571]), 52% (39%-61%) for a bivalent dose received 7-89 days earlier, and 13% (-10%-31%) for a bivalent dose received 90-179 days earlier. Absolute VE against COVID-19-associated invasive mechanical ventilation or death was 51% (34%-63%) for original monovalent doses only, 61% (35%-77%) for a bivalent dose received 7-89 days earlier, and 50% (11%-71%) for a bivalent dose received 90-179 days earlier., Conclusion: Bivalent vaccination provided protection against COVID-19-associated hospitalization and severe in-hospital outcomes within 3 months of receipt, followed by a decline in protection to a level similar to that remaining from previous original monovalent vaccination by 3-6 months. These results underscore the benefit of remaining up to date with recommended COVID-19 vaccines., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

COVID-19 convalescent plasma (CCP) was one of the first therapies to receive emergency use authorization for management of COVID-19. We assessed the effectiveness of CCP in a propensity-matched analysis, and whether the presence of antibodies in the recipient at the time of treatment or the titer of antibodies in the administered CCP influenced clinical effectiveness. In an inpatient population within a single large health system, a total of 290 CCP patients were matched to 290 controls. While CCP increased titers of anti-SARS-CoV-2 RBD IgG titers post-CCP (p = <0.0001), no differences in 30-day survival were observed between CCP patients and controls in univariate and multivariate analyses. Survival at 30 days was numerically lower in recipients who were seronegative prior to CCP administration, compared to those with low titer and high titer anti-SARS-CoV-2 RBD IgG, respectively, but did not reach statistical significance (56% vs 82% vs 75%, p = 0.16). Patients who received 2 units of high-titer CCP had numerically better survival versus those who received fewer high-titer units, but this was not statistically significant (p = 0.08). CCP did not improve 30-day survival compared to propensity matched controls. Together these data support that CCP therapy provides limited benefit to hospitalized patients with SARS-CoV-2 infection., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Iasella et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Rationale: Prone positioning for ⩾16 hours in moderate-to-severe acute respiratory distress syndrome (ARDS) improves survival. However, the optimal duration of proning is unknown. Objectives: To estimate the effect of extended versus standard proning duration on patients with moderate-to-severe coronavirus disease (COVID-19) ARDS. Methods: Data were extracted from a five-hospital electronic medical record registry. Patients who were proned within 72 hours of mechanical ventilation were categorized as receiving extended (⩾24 h) versus standard (16-24 h) proning based on the first proning session length. We used a target trial emulation design to estimate the effect of extended versus standard proning on the primary outcome of 90-day mortality and secondary outcomes of ventilator liberation and intensive care unit (ICU) discharge. Analytically, we used inverse probability of treatment weighted (IPTW) Cox or Fine-Gray regression models. Results: A total of 314 patients were included; 234 received extended proning, and 80 received standard-duration proning. Patients who received extended proning were older, had greater comorbidity, were more often at an academic hospital, and had shorter time from admission to mechanical ventilation. After IPTW, characteristics were well balanced. Unadjusted 90-day mortality in the extended versus standard proning groups was 39% versus 58%. In doubly robust IPTW analyses, we found no significant effects of extended versus standard proning duration on mortality (hazard ratio [95% confidence interval], 0.95 [0.51-1.77]), ventilator liberation (subdistribution hazard, 1.60 [0.97-2.64], or ICU discharge (subdistribution hazard, 1.31 [0.82-2.10]). Conclusions: Using target trial emulation, we found no significant effect of extended versus standard proning duration on mortality, ventilator liberation, or ICU discharge. However, given the imprecision of estimates, further study is justified.

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.)

Objective: During the COVID-19 pandemic, some centers converted intermediate care units (IMCUs) to COVID-19 ICUs (IMCU/ICUs). In this study, we compared adherence to lung protective ventilation (LPV) and outcomes for patients with COVID-19-related acute respiratory distress syndrome (ARDS) treated in an IMCU/ICU versus preexisting medical ICUs (MICUs)., Design: Retrospective observational study using electronic medical record data., Setting: Two academic medical centers from March 2020 to September 2020 (period 1) and October 2020 to May 2021 (period 2), which capture the first two COVID-19 surges in this health system., Patients: Adults with COVID-19 receiving invasive mechanical ventilation who met ARDS oxygenation criteria (Pao2/Fio2 ≤ 300 mm Hg or Spo2/Fio2 ≤ 315)., Interventions: None., Measurements and Main Results: We defined LPV adherence as the percent of the first 48 hours of mechanical ventilation that met a restrictive definition of LPV of, tidal volume/predicted body weight (Vt/PBW) less than or equal to 6.5 mL/kg and plateau pressure (Pplat) less than or equal to 30 cm H2o. In an expanded definition, we added that if Pplat is greater than 30 cm H2o, Vt/PBW had to be less than 6.0 mL/kg. Using the restricted definition, period 1 adherence was lower among 133 IMCU/ICU versus 199 MICU patients (92% [95% CI, 50-100] vs. 100% [86-100], p = 0.05). Period 2 adherence was similar between groups (100% [75-100] vs. 95% CI [65-100], p = 0.68). A similar pattern was observed using the expanded definition. For the full study period, the adjusted hazard of death at 90 days was lower in IMCU/ICU versus MICU patients (hazard ratio [HR] 0.73 [95% CI, 0.55-0.99]), whereas ventilator liberation by day 28 was similar between groups (adjusted subdistribution HR 1.09 [95% CI, 0.85-1.39])., Conclusions: In patients with COVID-19 ARDS treated in an IMCU/ICU, LPV adherence was similar to, and observed survival better than those treated in preexisting MICUs. With adequate resources, protocols, and staffing, IMCUs provide an effective source of additional ICU capacity for patients with acute respiratory failure., Competing Interests: Dr. Brodie reports receiving research support from and consults for LivaNova. He has been on the medical advisory boards for Xenios, Medtronic, Inspira, and Cellenkos. He is the President-elect of the Extracorporeal Life Support Organization and the Chair of the Board of the International ECMO Network, and he writes for UpToDate. Dr. Hochberg received funding from the National Institutes of Health-National Heart Blood and Lung Institute (K23HL169743). Dr. Case received funding from the NIH-NHBLI (T32HL007534). Dr. Sahetya received funding from the NIH-NHLBI (K23HL155507) and personal consulting fees from Getinge. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Intermediate care (IC) is used for patients who do not require the human and technological support of the intensive care unit (ICU) yet require more care and monitoring than can be provided on general wards. Though prevalent in many countries, there is marked variability in models of organization and staffing, as well as monitoring and interventions provided. In this article, the authors will discuss the historical background of IC, review the impact of IC on ICU and IC patient outcomes, and highlight where future studies can shed light on how to optimize IC organization and outcomes., Competing Interests: Disclosure Dr A.S. Case is funded by an National Institutes of Health (NIH) T32 Training Award (T32HL007534). Dr C.H. Hochberg is funded by an NIH K23 Award (K23Hl169743). Dr D.N. Hager is funded by the Centers for Disease Control and Prevention (CDC) (IVY Network) and NIH (ACTIV-4d) via subcontracts with Vanderbilt University Medical Center., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The intensive care unit (ICU) was born from the postanesthesia care unit (PACU). In today's hospital systems, there remains a lot of overlap in the care missions of each location. The patient populations share many similarities and many of the same care, technology, and care protocols apply to patients in both units. As shown by the COVID-19 pandemic, there is immense value in maintaining protocols, processes, and staffing models for the safe care of ICU patients in the PACU when ICU demands exceed capacity., Competing Interests: Disclosures Drs M.R. Gaylor and K. Tyson have no disclosures. Dr D.N. Hager is funded by the CDC (IVY Network) and NIH (ACTIV-4d) via subcontracts with Vanderbilt University Medical Center., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Malakoplakia is a rare inflammatory disorder believed to result from a defect in macrophage phagocytic function triggering a granulomatous reaction. It can present with genitourinary, gastrointestinal, or cutaneous manifestations in immunocompromised or, less commonly, immunocompetent hosts. We describe a case of renal malakoplakia in a young, otherwise healthy patient presenting with nephromegaly and sepsis following an E. coli urinary tract infection. We discuss diagnosis and management, including antibiotic selection and the decision to pursue nephrectomy. This case highlights the potential for kidney recovery with prolonged antibiotic therapy in conjunction with adjunct immunomodulatory therapies and source control., (© 2024. The Author(s).)

Aims: To elicit experiences of patients, family caregivers, and healthcare professionals in intermediate care units (IMCUs) in an academic medical centre in Baltimore, MD related to the challenges and intricacies of multimorbidity management to inform development of a multimorbidity symptom management toolkit., Design: Experience-based co-design., Methods: Between July and October 2021, patients aged 55 years and older with multimorbidity admitted to IMCUs at an academic medical centre in Baltimore, Maryland, USA were recruited and interviewed in person. Interdisciplinary healthcare professionals working in the IMCU were interviewed virtually. Participants were asked questions about their role in recognizing and treating symptoms, factors affecting the quality of life, symptom burden and trajectory over time, and strategies that have and have not worked for managing symptoms. An inductive thematic analysis approach was used for analysis., Results: Twenty-three interviews were conducted: 9 patients, 2 family caregivers, and 12 healthcare professionals. Patients' mean age was 67.5 (±6.5) years, over half (n = 5) were Black or Hispanic, and the average number of comorbidities was 3.67. Five major themes that affect symptom management emerged: (1) the patient-provider relationship; (2) open and honest communication; (3) accessibility of resources during hospitalization and at discharge; (4) caregiver support, training, and education; and (5) care coordination and follow-up care., Conclusion: Patients, caregivers, and healthcare professionals often have similar goals but different priorities for multimorbidity management. It is imperative to identify shared priorities and target holistic interventions that consider patient and caregiver experiences to improve outcomes., Implications for the Profession And/or Patient Care and Impact: This paper addresses the paucity of research related to the shared experience of disease trajectory and symptom management for people living with multimorbidity. We found that patients, caregivers, and healthcare professionals often have similar goals but different care and communication priorities. Understanding differing priorities will help better design interventions to support symptom management so people with multimorbidity can have the best possible quality of life., Reporting Method: We have adhered to the Consolidated Criteria for Reporting Qualitative Studies (COREQ) guidelines in our reporting., Patient or Public Contribution: This study has been designed and implemented with patient and public involvement throughout the process, including community advisory board engagement in the project proposal phase and interview guide development, and member checking in the data collection and analysis phases. The method we chose, experience-based co-design, emphasizes the importance of engaging members of a community to act as experts in their own life challenges. In the coming phases of the study, the public will be involved in developing and testing a new intervention, informed by these qualitative interviews and co-design events, to support symptom management for people with multimorbidity., (© 2024 The Authors. Journal of Advanced Nursing published by John Wiley & Sons Ltd.)

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.

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: 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.

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.

Acute brain injury (ABI) and neuroinflammation is reported in COVID-19 and acute respiratory distress syndrome (ARDS). It remains unclear if COVID-19 plays an independent role in development of ABI compared to those with non-COVID-19 ARDS. We aimed to evaluate if COVID-19 ARDS is associated with higher risk and specific patterns of ABI compared to non-COVID-19 ARDS. We conducted an age and sex matched case-control autopsy study at a tertiary academic center. Ten patients with COVID-19 ARDS were matched to 20 non-COVID-19 ARDS patients. Baseline demographics were comparable between the two groups including severity of ARDS ( p = 0.3). The frequency of overall ABI (70 vs. 60%), infratentorial ABI (40 vs. 25%), ischemic infarct (40 vs. 25%), intracranial hemorrhage (30 vs. 35%), and hypoxic-ischemic brain injury (30 vs. 35%) was similar between COVID-19 and non-COVID-19 ARDS patients, respectively ( p > 0.05). Intracapillary megakaryocytes were exclusively seen in 30% of COVID-19 patients. Overall, frequency and pattern of ABI in COVID-19 ARDS was comparable to non-COVID-19., Competing Interests: LZ was employed by Inova Health System. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Humayun, Zhang, Zaikos, Kannapadi, Suarez, Hager, Troncoso and Cho.)

Introduction: Sustainable approaches to support care coordination and symptom management needs of critically ill adults living with multimorbidity are needed to combat the challenges and complexity that multimorbidity presents. The study aims to test the feasibility of the Care cOORDInatioN And sympTom managEment (COORDINATE) intervention to improve health outcomes of adults living with multimorbidity., Methods and Analysis: A multicomponent nurse-driven intervention was developed using experience-based co-design and human-centred design. Inclusion criteria include (1) age 55 years and older, (2) admitted to an intermediate care unit, (3) presence of two or more chronic health conditions and (4) signed informed consent. Data collection will occur at baseline (time of recruitment predischarge) and 6 weeks and 3 months following hospital discharge. Outcome of interest from this feasibility study is to evaluate the financial, technical and logistic feasibility of a full-scale study including data collection and protocol adherence. Additionally, Cohen's d effect sizes for the change in outcomes over time will be computed to establish power calculations required for a full-scale study. The protocol was prepared in accordance with Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) checklist., Ethics and Dissemination: The study has been reviewed and approved by the Institutional Review Board of Johns Hopkins Medical Institutions. Given the success of this feasibility study, the potential for the COORDINATE intervention to decrease the symptom burden and improve participant quality of life among critically ill people with multimorbidity will be tested in a full-scale study, and findings will be actively disseminated., Trial Registration Number: NCT05985044., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Rationale: Despite multiple reports of pulse oximeter inaccuracy among hospitalized Black individuals, regulatory testing of pulse oximeters is performed on healthy volunteers., Objective: Evaluate pulse oximeter accuracy among intensive care unit patients with diverse skin pigmentation., Methods: Skin pigmentation was measured using a chromameter in 12 patients and individual typology angle (ITA), a measure of constitutive pigmentation, calculated. Arterial blood gas (ABG) arterial oxygen saturation (SaO 2 ) sampling was precisely matched to pulse oximetry (SpO 2 ) using arterial line waveforms analysis. Error (SpO 2 -SaO 2 ), bias, and average root mean square error (A RMS ) were calculated. Multivariable linear mixed effects models evaluated the association of SpO 2 -SaO 2 with skin pigmentation., Measurements and Main Results: Sampling time was determined for 350 ABGs. Five participants (N=96 ABGs) were darkly pigmented (forehead ITA<-30°), and 7 lighter pigmented (N=254 ABGs). Darkly pigmented individuals had 1.05% bias and 4.15% A RMS compared to 0.34% bias and 1.97% A RMS among lighter pigmented individuals. After adjusting for SaO 2 , pH, heart rate, and mean arterial pressure, SpO 2 -SaO 2 was falsely elevated by 1.00% more among darkly pigmented individuals (95% confidence interval: 0.25-1.76%). SpO 2 significantly overestimated SaO 2 for dark, brown, and tan forehead or forearm pigmentation and brown and tan finger pad pigmentation compared to intermediate/light pigmentation., Conclusions: The pulse oximeter in clinical use at an academic medical center performed worse in darkly pigmented critically ill patients than established criteria for FDA clearance. Pulse oximeter testing in ICU settings is feasible, and could be required by regulators to ensure equivalent device performance by skin pigmentation among patients.

Objectives: Prone positioning for acute respiratory distress syndrome (ARDS) has historically been underused, but was widely adopted for COVID-19-associated ARDS early in the pandemic. Whether this successful implementation has been sustained over the first 3 years of the COVID-19 pandemic is unknown. In this study, we characterized proning use in patients with COVID-19 ARDS from March 2020 to December 2022., Design: Multicenter retrospective observational study., Setting: Five-hospital health system in Maryland, USA., Patients: Adults with COVID-19 supported with invasive mechanical ventilation and with a P ao2 /F io2 ratio of less than or equal to 150 mm Hg while receiving F io2 of greater than or equal to 0.6 within 72 hours of intubation., Interventions: None., Measurements: We extracted demographic, clinical, and positioning data from the electronic medical record. The primary outcome was the initiation of proning within 48 hours of meeting criteria. We compared proning use by year with univariate and multivariate relative risk (RR) regression. Additionally, we evaluated the association of treatment during a COVID-19 surge period and receipt of prone positioning., Main Results: We identified 656 qualifying patients; 341 from 2020, 224 from 2021, and 91 from 2022. More than half (53%) met severe ARDS criteria. Early proning occurred in 56.2% of patients in 2020, 56.7% in 2021, and 27.5% in 2022. This translated to a 51% reduction in use of prone positioning among patients treated in 2022 versus 2020 (RR = 0.49; 95% CI, 0.33-0.72; p < 0.001). This reduction remained significant in adjusted models (adjusted RR = 0.59; 95% CI, 0.42-0.82; p = 0.002). Treatment during COVID-19 surge periods was associated with a 7% increase in proning use (adjusted RR = 1.07; 95% CI, 1.02-1.13; p = 0.01)., Conclusions: The use of prone positioning for COVID-19 ARDS is declining. Interventions to increase and sustain appropriate use of this evidence-based therapy are warranted., Competing Interests: Dr. Hochberg’s institution received funding from the National Heart, Lung, and Blood Institute (NHLBI) (F32HL160039, T32HL007534). Drs. Hochberg and Eakin received funding from the National Institutes of Health. Dr. Eakin’s institution received funding from the NHBLI. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

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.

Background: Prone positioning was widely adopted for use in patients with ARDS from COVID-19. However, proning was also delivered in ways that differed from historical evidence and practice. In implementation research, these changes are referred to as adaptations, and they occur constantly as evidence-based interventions are used in real-world practice. Adaptations can alter the delivered intervention, impacting patient and implementation outcomes., Research Question: How have clinicians adapted prone positioning to COVID-19 ARDS, and what uncertainties remain regarding optimal proning use?, Study Design and Methods: We conducted a qualitative study using semi-structured interviews with ICU clinicians from two hospitals in Baltimore, MD, from February to July 2021. We interviewed physicians (MDs), registered nurses (RNs), respiratory therapists (RTs), advanced practice providers (APPs), and physical therapists (PTs) involved with proning mechanically ventilated patients with COVID-19 ARDS. We used thematic analysis of interviews to classify proning adaptations and clinician uncertainties about best practice for prone positioning., Results: Forty ICU clinicians (12 MDs, 4 APPs, 12 RNs, 7 RTs, and 5 PTs) were interviewed. Clinicians described several adaptations to the practice of prone positioning, including earlier proning initiation, extended duration of proning sessions, and less use of concomitant neuromuscular blockade. Clinicians expressed uncertainty regarding the optimal timing of initiation and duration of prone positioning. This uncertainty was viewed as a driver of practice variation. Although prescribers intended to use less deep sedation and paralysis in proned patients compared with historical evidence and practice, this raised concerns regarding patient comfort and safety amongst RNs and RTs., Interpretation: Prone positioning in patients with COVID-19 ARDS has been adapted from historically described practice. Understanding the impact of these adaptations on patient and implementation outcomes and addressing clinician uncertainties are priority areas for future research to optimize the use of prone positioning.

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: 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.)

As of April 2023, the COVID-19 pandemic has resulted in 1.1 million deaths in the United States, with approximately 75% of deaths occurring among adults aged ≥65 years (1). Data on the durability of protection provided by monovalent mRNA COVID-19 vaccination against critical outcomes of COVID-19 are limited beyond the Omicron BA.1 lineage period (December 26, 2021-March 26, 2022). In this case-control analysis, the effectiveness of 2-4 monovalent mRNA COVID-19 vaccine doses was evaluated against COVID-19-associated invasive mechanical ventilation (IMV) and in-hospital death among immunocompetent adults aged ≥18 years during February 1, 2022-January 31, 2023. Vaccine effectiveness (VE) against IMV and in-hospital death was 62% among adults aged ≥18 years and 69% among those aged ≥65 years. When stratified by time since last dose, VE was 76% at 7-179 days, 54% at 180-364 days, and 56% at ≥365 days. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against IMV and in-hospital death among adults during the Omicron variant period. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical COVID-19-associated outcomes., Competing Interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Jonathan D. Casey reports grants from the National Institutes of Health (NIH) and the U.S. Department of Defense (DoD), and 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 (DSMB) member for a study at UCLA, outside the submitted work. Abhijit Duggal reports grants from NIH/National Heart, Lung, and Blood Institute (NHLBI), and consulting fees from Alung Technologies, outside the submitted work. David J. Douin reports a grant from NIH/National Institute of General Medical Sciences, outside the submitted work. Matthew C. Exline reports grants from NIH and Regeneron, honoria for speaking at the American Society for Parenteral and Enteral Nutrition conference from Abbott Labs, and payment for testimony as a medical legal expert witness, outside the submitted work. D. Clark Files reports receiving a grant from NIH and participating on the Medpace DSMB, outside the submitted work. Manjusha Gaglani reports having served as co-chair of the Infectious Diseases and Immunization Committee for the Texas Pediatric Society, outside the submitted work. Kevin W. Gibbs reports grants from NIH and DoD, as well as support for travel to the 2022 Military Health System Research Symposium from DoD, outside the submitted work. Adit A. Ginde reports receiving grants from NIH, DoD, AbbVie, and Faron Pharmaceuticals, outside the submitted work. Michelle N. Gong reports grants from NHLBI, the Agency for Healthcare Research and Quality (AHRQ), speaking at medicine grand rounds at Yale and Westchester Medical College, travel support from the American Thoracic Society (ATS) and serving on the ATS board, DSMB membership fees from Regeneron and the Replenish Trial, and participating on the scientific advisory panel for Endpoint, outside the submitted work. Carlos G. Grijalva reports grants from NIH, AHRQ, the Food and Drug Administration (FDA), Campbell Alliance/Syneos Health; receipt of consulting fees from and participation on a DSMB for Merck, outside the submitted work. David N. Hager reports receiving grants from NIH, outside the submitted work. Natasha Halasa reports receiving grants from Sanofi and Quidel, 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 S. Lauring reports receiving grants from FluLab, NIH/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. Emily T. Martin reports grants from Merck and NIH, outside the submitted work. Tresa McNeal reports 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. Arnold S. Monto reports a grant from NIH/NIAID, support for travel from the International Society for Influenza and other Respiratory Diseases, and participation on an advisory board for FDA, 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. Jay S. Steingrub reports a grant from NHLBI, outside the submitted work. Jennifer G. Wilson reports grants from NHLBI, outside the submitted work. No other potential conflicts of interest were disclosed.

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

Background: The COVID-19 pandemic was associated with historically low influenza circulation during the 2020-2021 season, followed by an increase in influenza circulation during the 2021-2022 US season. The 2a.2 subgroup of the influenza A(H3N2) 3C.2a1b subclade that predominated was antigenically different from the vaccine strain., Methods: To understand the effectiveness of the 2021-2022 vaccine against hospitalized influenza illness, a multistate sentinel surveillance network enrolled adults aged ≥18 years hospitalized with acute respiratory illness and tested for influenza by a molecular assay. Using the test-negative design, vaccine effectiveness (VE) was measured by comparing the odds of current-season influenza vaccination in influenza-positive case-patients and influenza-negative, SARS-CoV-2-negative controls, adjusting for confounders. A separate analysis was performed to illustrate bias introduced by including SARS-CoV-2-positive controls., Results: A total of 2334 patients, including 295 influenza cases (47% vaccinated), 1175 influenza- and SARS-CoV-2-negative controls (53% vaccinated), and 864 influenza-negative and SARS-CoV-2-positive controls (49% vaccinated), were analyzed. Influenza VE was 26% (95% CI: -14% to 52%) among adults aged 18-64 years, -3% (-54% to 31%) among adults aged ≥65 years, and 50% (15-71%) among adults aged 18-64 years without immunocompromising conditions. Estimated VE decreased with inclusion of SARS-CoV-2-positive controls., Conclusions: During a season where influenza A(H3N2) was antigenically different from the vaccine virus, vaccination was associated with a reduced risk of influenza hospitalization in younger immunocompetent adults. However, vaccination did not provide protection in adults ≥65 years of age. Improvements in vaccines, antivirals, and prevention strategies are warranted., Competing Interests: Potential conflicts of interest. M. G. reports grants from the Centers for Disease Control and Prevention (CDC), CDC-Abt Associates, CDC-Westat, and Janssen, and a leadership position as co-chair of the Infection Diseases and Immunizations Committee. J. S. S. reports a grant from the National Institutes of Health (NIH). A. D. reports grants from the NIH-PETAL Network, ACTIV-3b, ACTIV-4d, and GRAIL and consulting fees from Alung Technologies. M. E. P. reports a grant from the US Department of Defense and support for speaking at the 2022 North American Congress of Clinical Toxicology. I. D. P. reports grants from NIH, Janssen, Regeneron, and Asahi Kasei Pharma. D. N. H. reports grants from NIH (ACTIV-4d and Host Tissue-Nectar Trial). M. N. G. reports a grant from the National Heart, Lung, and Blood Institute (NHLBI); consulting fees for scientific advisory from Endpoint; support for attending an ATS Board of Executives Meeting; and participation in a Regeneron Data Safety and Monitoring Board (DSMB) for a monoclonal antibody trial. M. C. E. reports grants from NIH, Regeneron Pharmaceuticals, and payment from Abbott Labs for attending/lecture at the ASPEN Annual Meeting and on an Abbott webinar on nutrition in patients with COVID019. A. A. G. reports grants from NIH, Department of Defense, AbbVie, and Faron Pharmaceuticals. N. M. M. reports grants from the US CDC. E. T. M. reports grants from NIH and Merck and payment for lectures from the Michigan Infectious Diseases Society. K. W. G. reports grants from the Department of Defense and NIH support for ACTIV-4HT and Department of Defence support for Military Health System Research Symposium 2022 travel. J. H. K. is supported by grant 1K23AI137321-01A1 from the National Institute of Allergy and Infectious Diseases. N. H. reports grants from Sanofi and Quidel. A. S. L. reports grants from the US CDC, National Institute of Allergy and Infectious Diseases, and Burroughs Wellcome Fund; consulting fees from Sanofi and Roche; and membership on the American Society of Virology governing council (unpaid). C. J. L. reports grants from NIH, Department of Defense, CDC, bioMerieux, Entegrion Inc, Endpoint Health, Astra Zeneca, and AbbVie; patents for risk stratification in sepsis and septic shock issued to the Cincinnati Children's Hospital Medical Center; participation on DSMBs for clinical trials for Study Principal Investigators unrelated to the current work; and stock options in Bioscape Digital unrelated to the current work. C. G. G. reports grants from NIH, CDC, the Food and Drug Administration, the Agency for Healthcare Research and Quality, Sanofi, and Syneos Health and consulting fees from Pfizer, Merck, and Sanofi. 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 2022.)