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Background: Research in critical care extends from the bench to the bedside, involving multiple departments, specialties, and funding organizations. Because of this diversity, it has been difficult for all stakeholders to collectively identify challenges and establish priorities.Objective: To define a comprehensive agenda for critical care research using input from a broad range of stakeholders to serve as a blueprint for future initiatives.Methods: The Critical Care Societies Collaborative (CCSC), consisting of the leadership of the American Association of Critical-Care Nurses (AACN), the American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Society of Critical Care Medicine (SCCM), joined the US Critical Illness and Injury Trials Group (USCIITG) in forming a task force to define a comprehensive critical care research agenda. This group of 25 identified experts was divided into subgroups to address basic, translational, clinical, implementation, and educational research. The subgroups met via conference calls, and the entire task force met in person for a 2-day session. The result was a detailed discussion of the research priorities that served as the basis for this report.Results: The task force identified challenges, specific priority areas, and recommendations for process improvements to support critical care research. Additionally, four overarching themes emerged: 1) the traditional "silo-ed" approach to critical care research is counterproductive and should be modified; 2) an approach that more effectively links areas of research (ie, basic and translational research, or clinical research and implementation) should be embraced; 3) future approaches to human research should account for disease complexity and patient heterogeneity; and 4) an enhanced infrastructure for critical care research is essential for future success.Conclusions: This document contains the themes/recommendations developed by a large, multiprofessional cross section of critical care scientists, clinicians, and educators. It provides a unique framework for future research in critical care medicine. [ABSTRACT FROM AUTHOR]

Study Objective: We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. Methods: We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. Results: There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). Conclusion: In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: Since 2003, the Society of Chest Pain Centers (SCPC) has provided hospital accreditation for acute coronary syndrome care processes. Our objective is to evaluate the association between SCPC accreditation and adherence to the American College of Cardiology/American Heart Association (ACC/AHA) evidence-based guidelines for non-ST-segment elevation myocardial infarction (NSTEMI). The secondary objective is to describe the clinical outcomes and the association with accreditation. METHODS: We conducted a secondary analysis of data from patients with NSTEMI enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative in 2005. The analysis explored differences between SCPC-accredited and nonaccredited hospitals in evidence-based therapy given within the first 24 hours (including aspirin, beta-blocker, glycoprotein IIb/IIIa inhibitors, heparin, and ECG within 10 minutes). RESULTS: Of 33,238 patients treated at 21 accredited hospitals and 323 nonaccredited hospitals, those at SCPC-accredited centers (n=3,059) were more likely to receive aspirin (98.1% versus 95.8%; odds ratio [OR] 1.73; 95% confidence interval [CI] 1.06 to 2.83) and beta-blockers (93.4% versus 90.6%; OR 1.68; 95% CI 1.04 to 2.70) within 24 hours than patients at non-SCPC-accredited centers (n=30,179). No difference was observed in obtaining a timely ECG (40.4% versus 35.2%; OR 1.28; 95% CI 0.98 to 1.67), administering a glycoprotein IIb/IIIa inhibitor (OR 1.30; 95% CI 0.93 to 1.80), or administering heparin (OR 1.12; 95% CI 0.74 to 1.70). Also, there was no significant difference in risk-adjusted mortality for patients treated at SCPC hospitals versus nonaccredited hospitals (3.4% versus 3.5%; adjusted OR 1.17; 95% CI 0.88 to 1.55). CONCLUSION: SCPC-accredited hospitals had higher NSTEMI ACC/AHA evidence-based guideline adherence in the first 24 hours of care on 2 of the 5 measures. No difference in outcomes was observed. Further studies are needed to better understand the association between SCPC accreditation and improved care for patients with acute coronary syndrome. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: Although regionalized care for ST-segment elevation myocardial infarction (STEMI) has improved the use of timely reperfusion therapy, its effect on patient outcomes has been difficult to assess. Our objective is to explore temporal trends in STEMI mortality with the implementation of a statewide STEMI regionalization program (Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments [RACE]). METHODS: We compared trends in inpatient mortality among STEMI patients treated at North Carolina (NC) hospitals participating in the RACE program, relative to those not participating, using state inpatient claims data. Using Medicare claims data, we compared trends in 30-day mortality among Medicare beneficiaries in NC with those nationally. Logistic models with random effects were used to evaluate the association of the program with mortality. RESULTS: From 2005 to 2007, inpatient mortality for 6,565 STEMI patients treated at NC hospitals participating in RACE decreased from 11.6% to 10.1% (risk difference -1.5%; 95% confidence interval [CI] -3.0% to 0.04%), whereas inpatient mortality among 5,850 STEMI patients treated at NC nonparticipating hospitals decreased from 10.2% to 8.6% (risk difference -1.6%; 95% CI -3.1% to 0.10%); (adjusted odds ratio 1.28; 95% CI 0.88 to 1.85 for temporal differences between groups). During the same period, 30-day STEMI mortality among Medicare beneficiaries decreased from 22.7% to 21.4% in NC (risk difference -1.28%; 95% CI -3.60% to 1.03%) and from 22.3% to 21.6% nationally (risk difference -0.71%, 95% CI -1.13% to -0.29%; adjusted odds ratio 0.99, 95% CI 0.85 to 1.15 for temporal differences between regions). CONCLUSION: The initiation of a statewide STEMI collaborative care model was associated with a reduction in mortality rates according to claims data, yet these changes were similar to those seen nationally. Further study is needed to evaluate regionalized systems of STEMI care and to determine the role of claims data to evaluate population-based STEMI outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUNDPatients hospitalized for COVID-19 exhibit diverse clinical outcomes, with outcomes for some individuals diverging over time even though their initial disease severity appears similar to that of other patients. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity.METHODSWe performed deep immunophenotyping and conducted longitudinal multiomics modeling, integrating 10 assays for 1,152 Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) study participants and identifying several immune cascades that were significant drivers of differential clinical outcomes.RESULTSIncreasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, formation of neutrophil extracellular traps, and T cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma Igs and B cells and dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to failure of viral clearance in patients with fatal illness.CONCLUSIONOur longitudinal multiomics profiling study revealed temporal coordination across diverse omics that potentially explain the disease progression, providing insights that can inform the targeted development of therapies for patients hospitalized with COVID-19, especially those who are critically ill.TRIAL REGISTRATIONClinicalTrials.gov NCT04378777.FUNDINGNIH (5R01AI135803-03, 5U19AI118608-04, 5U19AI128910-04, 4U19AI090023-11, 4U19AI118610-06, R01AI145835-01A1S1, 5U19AI062629-17, 5U19AI057229-17, 5U19AI125357-05, 5U19AI128913-03, 3U19AI077439-13, 5U54AI142766-03, 5R01AI104870-07, 3U19AI089992-09, 3U19AI128913-03, and 5T32DA018926-18); NIAID, NIH (3U19AI1289130, U19AI128913-04S1, and R01AI122220); and National Science Foundation (DMS2310836).

Age is a major risk factor for severe coronavirus disease 2019 (COVID-19), yet the mechanisms behind this relationship have remained incompletely understood. To address this, we evaluated the impact of aging on host immune response in the blood and the upper airway, as well as the nasal microbiome in a prospective, multicenter cohort of 1031 vaccine-naïve patients hospitalized for COVID-19 between 18 and 96 years old. We performed mass cytometry, serum protein profiling, anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody assays, and blood and nasal transcriptomics. We found that older age correlated with increased SARS-CoV-2 viral abundance upon hospital admission, delayed viral clearance, and increased type I interferon gene expression in both the blood and upper airway. We also observed age-dependent up-regulation of innate immune signaling pathways and down-regulation of adaptive immune signaling pathways. Older adults had lower naïve T and B cell populations and higher monocyte populations. Over time, older adults demonstrated a sustained induction of pro-inflammatory genes and serum chemokines compared with younger individuals, suggesting an age-dependent impairment in inflammation resolution. Transcriptional and protein biomarkers of disease severity differed with age, with the oldest adults exhibiting greater expression of pro-inflammatory genes and proteins in severe disease. Together, our study finds that aging is associated with impaired viral clearance, dysregulated immune signaling, and persistent and potentially pathologic activation of pro-inflammatory genes and proteins.

The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease., (© 2024. The Author(s).)

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC., (© 2024. The Author(s).)

Introduction: Cognitive activity and awareness during cardiac arrest (CA) are reported but ill understood. This first of a kind study examined consciousness and its underlying electrocortical biomarkers during cardiopulmonary resuscitation (CPR)., Methods: In a prospective 25-site in-hospital study, we incorporated a) independent audiovisual testing of awareness, including explicit and implicit learning using a computer and headphones, with b) continuous real-time electroencephalography(EEG) and cerebral oxygenation(rSO 2 ) monitoring into CPR during in-hospital CA (IHCA). Survivors underwent interviews to examine for recall of awareness and cognitive experiences. A complementary cross-sectional community CA study provided added insights regarding survivors' experiences., Results: Of 567 IHCA, 53(9.3%) survived, 28 of these (52.8%) completed interviews, and 11(39.3%) reported CA memories/perceptions suggestive of consciousness. Four categories of experiences emerged: 1) emergence from coma during CPR (CPR-induced consciousness [CPRIC]) 2/28(7.1%), or 2) in the post-resuscitation period 2/28(7.1%), 3) dream-like experiences 3/28(10.7%), 4) transcendent recalled experience of death (RED) 6/28(21.4%). In the cross-sectional arm, 126 community CA survivors' experiences reinforced these categories and identified another: delusions (misattribution of medical events). Low survival limited the ability to examine for implicit learning. Nobody identified the visual image, 1/28(3.5%) identified the auditory stimulus. Despite marked cerebral ischemia (Mean rSO 2  = 43%) normal EEG activity (delta, theta and alpha) consistent with consciousness emerged as long as 35-60 minutes into CPR., Conclusions: Consciousness. awareness and cognitive processes may occur during CA. The emergence of normal EEG may reflect a resumption of a network-level of cognitive activity, and a biomarker of consciousness, lucidity and RED (authentic "near-death" experiences)., 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 © 2023. Published by Elsevier B.V.)

The IMPACC cohort, composed of >1,000 hospitalized COVID-19 participants, contains five illness trajectory groups (TGs) during acute infection (first 28 days), ranging from milder (TG1-3) to more severe disease course (TG4) and death (TG5). Here, we report deep immunophenotyping, profiling of >15,000 longitudinal blood and nasal samples from 540 participants of the IMPACC cohort, using 14 distinct assays. These unbiased analyses identify cellular and molecular signatures present within 72 h of hospital admission that distinguish moderate from severe and fatal COVID-19 disease. Importantly, cellular and molecular states also distinguish participants with more severe disease that recover or stabilize within 28 days from those that progress to fatal outcomes (TG4 vs. TG5). Furthermore, our longitudinal design reveals that these biologic states display distinct temporal patterns associated with clinical outcomes. Characterizing host immune responses in relation to heterogeneity in disease course may inform clinical prognosis and opportunities for intervention., Competing Interests: Declaration of interests The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines, which list F.K. as co-inventor. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2. F.K. has consulted for Merck and Pfizer (before 2020) and is currently consulting for Pfizer, Seqirus, Third Rock Ventures, Merck, and Avimex. The Krammer laboratory is also collaborating with Pfizer on animal models of SARS-CoV-2. Viviana Simon is a co-inventor on a patent filed relating to SARS-CoV-2 serological assays (the “Serology Assays”). O.L. is a named inventor on patents held by Boston Children’s Hospital relating to vaccine adjuvants and human in vitro platforms that model vaccine action. His laboratory has received research support from GlaxoSmithKline (GSK). C.B.C. serves as a consultant to bioMerieux and is funded for a grant from the Bill & Melinda Gates Foundation. J.A.O. is a consultant at Knocean, Inc. J.L.-S. serves as a scientific advisor of Precion, Inc. S.R.H., G.M., and K.W. are employees of Metabolon, Inc. V.S.-M. is a current employee of MyOwnMed. N.R. reports contracts with Lilly and Sanofi for COVID-19 clinical trials and serves as a consultant for ICON EMMES for consulting on safety for COVID19 clinical trials. A. Rahman is a current employee of Immunai, Inc. S.H.K. is a consultant related to ImmPort data repository for Peraton. N.D.G. is a consultant for Tempus Labs and the National Basketball Association. Akiko Iwasaki is a consultant for 4BIO, Blue Willow Biologics, Revelar Biotherapeutics, RIGImmune, Xanadu Bio, and Paratus Sciences. M. Kraft receives research funds paid to her institution from NIH and ALA and from Sanofi and Astra-Zeneca for work in asthma; serves as a consultant for Astra-Zeneca, Sanofi, Chiesi, and GSK for severe asthma; and is a co-founder and CMO for RaeSedo, Inc., a company created to develop peptidomimetics for treatment of inflammatory lung disease. E. Melamed received research funding from Babson Diagnostics and honorarium from Multiple Sclerosis Association of America and has served on the advisory boards of Genentech, Horizon, Teva, and Viela Bio., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

One-third of women with asthma have deterioration of their asthma during pregnancy, and one-fourth of pregnant women with asthma will experience severe exacerbations necessitating emergency department (ED) visits or hospitalizations. Early recognition of acute severe asthma, including life-threatening status asthmaticus, and aggressive medical interventions with β2-agonists, anticholinergic agents, and systemic corticosteroids are necessary to treat maternal airway bronchoconstriction, support maternal and fetal oxygenation, and avoid adverse fetal outcomes. This review describes management of acute severe asthma in pregnancy, including status asthmaticus, in the ED and intensive care unit., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Better understanding of the association between characteristics of patients hospitalized with coronavirus disease 2019 (COVID-19) and outcome is needed to further improve upon patient management., Methods: Immunophenotyping Assessment in a COVID-19 Cohort (IMPACC) is a prospective, observational study of 1164 patients from 20 hospitals across the United States. Disease severity was assessed using a 7-point ordinal scale based on degree of respiratory illness. Patients were prospectively surveyed for 1 year after discharge for post-acute sequalae of COVID-19 (PASC) through quarterly surveys. Demographics, comorbidities, radiographic findings, clinical laboratory values, SARS-CoV-2 PCR and serology were captured over a 28-day period. Multivariable logistic regression was performed., Findings: The median age was 59 years (interquartile range [IQR] 20); 711 (61%) were men; overall mortality was 14%, and 228 (20%) required invasive mechanical ventilation. Unsupervised clustering of ordinal score over time revealed distinct disease course trajectories. Risk factors associated with prolonged hospitalization or death by day 28 included age ≥ 65 years (odds ratio [OR], 2.01; 95% CI 1.28-3.17), Hispanic ethnicity (OR, 1.71; 95% CI 1.13-2.57), elevated baseline creatinine (OR 2.80; 95% CI 1.63- 4.80) or troponin (OR 1.89; 95% 1.03-3.47), baseline lymphopenia (OR 2.19; 95% CI 1.61-2.97), presence of infiltrate by chest imaging (OR 3.16; 95% CI 1.96-5.10), and high SARS-CoV2 viral load (OR 1.53; 95% CI 1.17-2.00). Fatal cases had the lowest ratio of SARS-CoV-2 antibody to viral load levels compared to other trajectories over time (p=0.001). 589 survivors (51%) completed at least one survey at follow-up with 305 (52%) having at least one symptom consistent with PASC, most commonly dyspnea (56% among symptomatic patients). Female sex was the only associated risk factor for PASC., Interpretation: Integration of PCR cycle threshold, and antibody values with demographics, comorbidities, and laboratory/radiographic findings identified risk factors for 28-day outcome severity, though only female sex was associated with PASC. Longitudinal clinical phenotyping offers important insights, and provides a framework for immunophenotyping for acute and long COVID-19., Funding: NIH., Competing Interests: Declaration of interests J.S reports funds paid to institution by the National Institute of Health - National Institute of Allergy and Infectious Diseases for the completion of this manuscript. C.S.C reports funds from NHLBI, has grants/contracts from Bayer, Roche-Genentech, Quantum Leap Healthcare Collaborative and received consulting fees from Vasomune, Gen1e Life Sciences, Cellenkos, Janssen. C.B.C reports funds paid to institution from the National Institute of Health - National Institute of Allergy and Infectious Diseases for the completion of this manuscript. C.B.C also reports a grant paid to institution by the Bill & Melinda Gates Foundation for Covid-19 work. C.B.C is a consultant for bioMerieux on clinical biomarkers. He reports his participation on a data safety monitoring board or advisory board for the Convalescent plasma Covid-19 study for the National Heart, Lung and Blood Institute (NHLBI). CBC is also President, Board of Directors for the National Foundation of Emergency Medicine (NFEM), a non-profit supporting emergency medicine research and researchers. M.K reports funds paid to institution for grants or contracts from the National Institute of Health. L.B reports grant awarded to institution from the National Institute of Health - National Institute of Allergy and Infectious Diseases. A.C.S reports funds paid to institution by the National Institute of Health for the completion of this manuscript (NIH U19 AI089992 – NIH K24 AG042489). F.KR has received funds from the National Institute of Allergy and Infectious Diseases Collaborative Influenza Vaccine Innovation Centers (CIVIC) contract 75N93019C00051, the National Institute of Health - Centers of Excellence for influenza Research and Response, (CEIRR), 75N93021C00014, the JPB Foundation and the Open Philanthropy Project (research grant 2020-215611, 5384), the National Cancer Institute, National Institutes of Health, under Contract No. 75N91019D00024, Task Order No. 75N91020F00003 and Research funding from Pfizer for development of animal models for SARS-CoV-2. F.KR receives royalties from Avimex, and receives consulting fees from Pfizer, Seqirus, Avimex and Third Rock Ventures. F.KR has received several payments or honoraria for academic lectures over the past two years. F. KR is listed as a co-inventor on patents filed for applications relating to SARS-CoV-2 serological assays (the “Serology Assays”) and NDV-based SARS-CoV-2 vaccines. H.vB reports receipt of the following grants paid to institution: National Institute of Health Centers of Excellence for influenza Research and Response, (CEIRR - 75N93021C00014), and National Institute of Health (Dengue Human Immunology Project Consortium - Mount Sinai IMPACC COVID-19 Cores - U19 AI118610 S1). D. E reports funds paid to institution for grants or contracts from the National Institute of Health. D.E is a statistician on the Data Safety Monitoring Board for the COLSTAT Trial. D.E is on the board of Directors for the Society for Clinical Trials. V.S is listed as a co-inventor on a patent filed relating to SARS-CoV-2 serological assays (the “Serology Assays”). R.M reports a grant from the National Institute of Health for the completion of this manuscript (AI 089992). R. M served as a Counselor for the Society of Leukocyte Biology from 2018 to 2021. S.K is a personal consultant related to ImmPort data repository for Peraton. O.L reports funds paid to institution by the National Institute of Health - National Institute of Allergy and Infectious Diseases for the completion of this manuscript (1-U19-AI118608-01A1). O.L received payments in the past 36 months from Midsized Bank Coalition of America (MBCA) and Moody's Analytics for presentations regarding the coronavirus pandemic. D.J.E reports funds paid to institution for grants or contracts from the National Institute of Health. K.C.N reports having received grants paid to institution from the following institutes in the past 36 months: National Institute of Allergy and Infectious Diseases (NIAID), National Heart, Lung, and Blood Institute (NHLBI), National Institute of Environmental Health Sciences (NIEHS), and Food Allergy Research & Education (FARE). K.C.N receives consulting fees from Excellergy, Eli Lilly, Red Tree Ventures, and Phylaxis. K.C.N has one Licensee: Alladapt and Before Brands (Application number: US15/048,609) for Mixed allergen composition and methods for using the same. K.C.N has two patents issued: Granulocyte-based methods for detecting and monitoring immune system disorders (Application number: US12/686,121), and Methods and Assays for Detecting and Quantifying Pure Subpopulations of White Blood Cells in Immune System Disorders (Application number: US12/610,94). K.C.N is the director of the World Allergy Organization Center of Excellence for Stanford and a co-founder of Seed Health, IgGenix, ClostraBio, and ImmuneID. K.C.N is also a co-founder of Before Brands, Alladapt, and Latitude and an advisor for Cour Pharma. K.C.N is a member of the national scientific committee for the Immune Tolerance Network (ITN) and the National Institutes of Health (NIH) clinical research centers. C.L.H reports a grant awarded to institution by the National Institute of Health and the American Lung Association. C.L.H also reports having received consulting fees from the National Institute of Health. C.L.H has received payment for medical grand rounds at institution and support for attending meetings and/or travel from Critical care trialists, critical care reviews and multiple universities. C.L.H is on the data safety monitoring board of QuantumHealth for iSPY COVID and is on the board of directors for the American Thoracic Society. W.M reports a grant from the National Institute of Health – National Institute of Allergy and Infectious Diseases for the completion of this manuscript (NIH NIAID R01AI14583). J.P.M reports funds paid to institution for grants or contracts from the National Institute of Health for the completion of this manuscript (NIH Grant # 3U19AI062629-17S2). M.A.A reports a grant from the National Institute of Health - National Institute of Allergy and Infectious Diseases for the completion of this manuscript (5U54AI142766-03). L.E reports grant awarded to institution from the National Institute of Health (NIH R01AI104870-S1). E.M reports funds paid to institution for grants or contracts from the National Institute of Health for the completion of this manuscript (NIH R01 AI104870S1). E.M also reports having received the following grants paid to institution in the past 36 months: the Babson Diagnostics Grant, the Austin Public Health Grant, and K08 26-1616-11. E.M received payments for lectures for the MS Association of America. E. M received payments for the participation in the advisory boards of Genentech, Horizon, Teva and Viela Bio. G.M receives consulting fees from Gilead. B.PE reports a grant from the National Institute of Health - National Institute of Allergy and Infectious Diseases for the completion of this manuscript. E.F.R reports funds paid to institution by the National Institute of Health - National Institute of Allergy and Infectious Diseases for the completion of this manuscript (NIAID U19AI12891303). M.C.A reports funds received from the National Institute of Health for the completion of this manuscript (NIH – R01AI32774) and funding by the National Institute of Allergy and Infectious Diseases for travel to present data related to this study. P.M.B is a federal employee serving as project scientist for this project but has no role in funding decisions or oversight for relevant grants. N.R reports funds paid to institution by the National Institute of Health - National Institute of Allergy and Infectious Diseases for the completion of this manuscript. N.R reports contracts with Lilly and Sanofi for conduct of Covid-19 clinical trials. N.R receives consulting fees from ICON EMMES for consulting on safety for Covid-19 clinical trials. N.R is an associate editor for Clinical infectious diseases. The remaining authors declare that they have no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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

Objectives: Host gene expression signatures discriminate bacterial and viral infection but have not been translated to a clinical test platform. This study enrolled an independent cohort of patients to describe and validate a first-in-class host response bacterial/viral test., Design: Subjects were recruited from 2006 to 2016. Enrollment blood samples were collected in an RNA preservative and banked for later testing. The reference standard was an expert panel clinical adjudication, which was blinded to gene expression and procalcitonin results., Setting: Four U.S. emergency departments., Patients: Six-hundred twenty-three subjects with acute respiratory illness or suspected sepsis., Interventions: Forty-five-transcript signature measured on the BioFire FilmArray System (BioFire Diagnostics, Salt Lake City, UT) in ~45 minutes., Measurements and Main Results: Host response bacterial/viral test performance characteristics were evaluated in 623 participants (mean age 46 yr; 45% male) with bacterial infection, viral infection, coinfection, or noninfectious illness. Performance of the host response bacterial/viral test was compared with procalcitonin. The test provided independent probabilities of bacterial and viral infection in ~45 minutes. In the 213-subject training cohort, the host response bacterial/viral test had an area under the curve for bacterial infection of 0.90 (95% CI, 0.84-0.94) and 0.92 (95% CI, 0.87-0.95) for viral infection. Independent validation in 209 subjects revealed similar performance with an area under the curve of 0.85 (95% CI, 0.78-0.90) for bacterial infection and 0.91 (95% CI, 0.85-0.94) for viral infection. The test had 80.1% (95% CI, 73.7-85.4%) average weighted accuracy for bacterial infection and 86.8% (95% CI, 81.8-90.8%) for viral infection in this validation cohort. This was significantly better than 68.7% (95% CI, 62.4-75.4%) observed for procalcitonin (p < 0.001). An additional cohort of 201 subjects with indeterminate phenotypes (coinfection or microbiology-negative infections) revealed similar performance., Conclusions: The host response bacterial/viral measured using the BioFire System rapidly and accurately discriminated bacterial and viral infection better than procalcitonin, which can help support more appropriate antibiotic use., Competing Interests: Dr. Tsalik received in-kind support from BioFire Diagnostics by way of consumables and test instruments; received funding from Predigen, Inc.. BioFire, Inc. provided in-kind support for test development reagents used in this study. Drs. Tsalik, Henao, McClain, Ginsburg, Burke, and Woods disclosed filing for a patent pertaining to the signatures discussed in this study (WO 2017/004390 A1). Dr. Montgomery was an employee of BioFire Diagnostics, LLC. Dr. Nawrocki disclosed he has shares in BioMérieux. Dr. Lydon was supported by the Eugene A. Stead Scholarship from Duke University School of Medicine and the Infectious Diseases Society of America Medical Scholars Program. Drs. Tsalik, Ginsburg, and Woods disclosed that they are cofounders of Predigen, Inc. Drs. Tsalik, Ko, Petzold, Cairns, Kingsmore, Fowler, Ginsburg, Burke, and Woods received support for article research from the National Institutes of Health (NIH). Drs. Nawrocki and Hemmert received funding from BioFire Diagnostics, LLC.; and disclosed that they are employees of BioFire Diagnostics, LLC. Dr. Cairns is a consultant for BioMérieux, Inc. Dr. Ko’s institution received funding from the Antibiotic Resistance Leadership Group; disclosed the off-label product use of diagnostic tests. Dr. Petzold received support for article research from the Defense Advanced Research Projects Agency (DARPA) (NIH National Institute of Allergy and Infectious Diseases (NIAID) U01AI066569 and UM1AI104681 U.S. DARPA contract—N66001-09-C2082). Dr. Cairns’ institution received funding from the NIH (NIAID) and the DARPA; and received funding from BioMérieux. Dr. Kingsmore’s institution received funding from the NIH. Dr. Fowler received funding from the NIH, MedImmune, Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, Basilea, and Janssen; received funding from Basilea, Affinergy, Janssen, Basilea, Integrated Biotherapeutics; C3J, Armata, Valanbio; Akagera, Aridis, Novartis, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Destiny, UpToDate; Stock options Valanbio; a patent for sepsis diagnosis (US9850539B2). Dr. McClain disclosed he has patents pending on diagnostic signatures for respiratory infections. Dr. Crisp was an employee of BioFire Diagnostics and is currently an employee of BioMérieux, Inc. Dr. Ginsburg’s institution received funding from DARPA; received support for article research from the Bill & Melinda Gates Foundation. Dr. Burke is a consultant for and holds equity in Predigen, Inc. Dr. Burke’s institution received funding from the NIH; received funding from Predigen, Inc.; disclosed he is a coinventor on patents pending on Molecular Methods to Diagnose and Treat Respiratory Infections. Dr. Hemmert disclosed the off-label product use of BioFire FilmArray System. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Masking, which is known to decrease the transmission of respiratory viruses, was not widely practiced in the United States until the coronavirus disease 2019 (COVID-19) pandemic. This provides a natural experiment to determine whether the percentage of community masking was associated with decreases in emergency department (ED) visits due to non-COVID viral illnesses (NCVIs) and related respiratory conditions., Methods: In this observational study of ED encounters in a 11-hospital system in Maryland during 2019-2020, year-on-year ratios for all complaints were calculated to account for "lockdowns" and the global drop in ED visits due to the pandemic. Encounters for specific complaints were identified using the International Classification of Diseases, version 10. Encounters with a positive COVID test were excluded. Linear regression was used to determine the association of publicly available masking data with ED visits for NCVI and exacerbations of asthma and chronic obstructive pulmonary disease (COPD), after adjusting for patient age, sex, and medical history., Results: There were 285,967 and 252,598 ED visits across the hospital system in 2019 and 2020, respectively. There was a trend toward an association between the year-on-year ratio for all ED visits and the Maryland stay-at-home order (parameter estimate = -0.0804, P = .10). A 10% percent increase in the prevalence of community masking was associated with a 17.0%, 8.8%, and 9.4% decrease in ED visits for NCVI and exacerbations of asthma exacerbations and chronic obstructive pulmonary disease, respectively (P < .001 for all)., Conclusions: Increasing the prevalence of masking is associated with a decrease in ED visits for viral illnesses and exacerbations of asthma and COPD. These findings may be valuable for future public health responses, particularly in future pandemics with respiratory transmission or in severe influenza seasons., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Emergency medicine is acuity-based and focuses on time-sensitive treatments for life-threatening diseases. Prolonged time in the emergency department, however, is associated with higher mortality in critically ill patients. Thus, we explored management after an acuity-based intervention, which we call perpetuity, as a potential mechanism for increased risk. To explore this concept, we evaluated the impact of each hour above a lung-protective tidal volume on risk of mortality., Methods: This cohort analysis includes all critically ill, non-trauma, adult patients admitted to two academic EDs between 1 November 2013 and 30 April 2017. Cox models with time-varying covariates were developed with time in perpetuity as a time-varying covariate, defined as hours above 8 mL/kg ideal body weight, adjusted for covariates. The primary outcome was the time to in-hospital death., Results: Our analysis included 2025 patients, 321 (16%) of whom had at least 1 h of perpetuity time. A partial likelihood-ratio test comparing models with and without hours in perpetuity was statistically significant (χ 2 (3) = 13.83, p = 0.0031). There was an interaction between age and perpetuity (Relative risk (RR) 0.9995; 95% Confidence interval (CI 95 ): 0.9991-0.9998). For example, for each hour above 8 mL/kg ideal body weight, a 20-year-old with 90% oxygen saturation has a relative risk of death of 1.02, but a 40-year-old with 90% oxygen saturation has a relative risk of 1.01., Conclusions: Perpetuity, illustrated through the lens of mechanical ventilation, may represent a target for improving outcomes in critically ill patients, starting in the emergency department. Research is needed to evaluate the types of patients and interventions in which perpetuity plays a role.

Objectives: The objectives of this study were to: 1) determine the association between vasopressor dosing intensity during the first 6 hours and first 24 hours after the onset of septic shock and 30-day in-hospital mortality; 2) determine whether the effect of vasopressor dosing intensity varies by fluid resuscitation volume; and 3) determine whether the effect of vasopressor dosing intensity varies by dosing titration pattern., Design: Multicenter prospective cohort study between September 2017 and February 2018. Vasopressor dosing intensity was defined as the total vasopressor dose infused across all vasopressors in norepinephrine equivalents., Setting: Thirty-three hospital sites in the United States (n = 32) and Jordan (n = 1)., Patients: Consecutive adults requiring admission to the ICU with septic shock treated with greater than or equal to 1 vasopressor within 24 hours of shock onset., Interventions: None., Measurements and Main Results: Out of 1,639 patients screened, 616 were included. Norepinephrine (93%) was the most common vasopressor. Patients received a median of 3,400 mL (interquartile range, 1,851-5,338 mL) during the 24 hours after shock diagnosis. The median vasopressor dosing intensity during the first 24 hours of shock onset was 8.5 μg/min norepinephrine equivalents (3.4-18.1 μg/min norepinephrine equivalents). In the first 6 hours, increasing vasopressor dosing intensity was associated with increased odds ratio of 30-day in-hospital mortality, with the strength of association dependent on concomitant fluid administration. Over the entire 24 hour period, every 10 μg/min increase in vasopressor dosing intensity was associated with an increased risk of 30-day mortality (adjusted odds ratio, 1.33; 95% CI, 1.16-1.53), and this association did not vary with the amount of fluid administration. Compared to an early high/late low vasopressor dosing strategy, an early low/late high or sustained high vasopressor dosing strategy was associated with higher mortality., Conclusions: Increasing vasopressor dosing intensity during the first 24 hours after septic shock was associated with increased mortality. This association varied with the amount of early fluid administration and the timing of vasopressor titration.

Objectives: To characterize the association between the use of physiologic assessment (central venous pressure, pulmonary artery occlusion pressure, stroke volume variation, pulse pressure variation, passive leg raise test, and critical care ultrasound) with fluid and vasopressor administration 24 hours after shock onset and with in-hospital mortality., Design: Multicenter prospective cohort study between September 2017 and February 2018., Settings: Thirty-four hospitals in the United States and Jordan., Patients: Consecutive adult patients requiring admission to the ICU with systolic blood pressure less than or equal to 90 mm Hg, mean arterial blood pressure less than or equal to 65 mm Hg, or need for vasopressor., Interventions: None., Measurement and Main Results: Of 1,639 patients enrolled, 39% had physiologic assessments. Use of physiologic assessment was not associated with cumulative fluid administered within 24 hours of shock onset, after accounting for baseline characteristics, etiology and location of shock, ICU types, Acute Physiology and Chronic Health Evaluation III, and hospital (beta coefficient, 0.04; 95% CI, -0.07 to 0.15). In multivariate analysis, the use of physiologic assessment was associated with a higher likelihood of vasopressor use (adjusted odds ratio, 1.98; 95% CI, 1.45-2.71) and higher 24-hour cumulative vasopressor dosing as norepinephrine equivalent (beta coefficient, 0.37; 95% CI, 0.19-0.55). The use of vasopressor was associated with increased odds of in-hospital mortality (adjusted odds ratio, 1.88; 95% CI, 1.27-2.78). In-hospital mortality was not associated with the use of physiologic assessment (adjusted odds ratio, 0.86; 95% CI, 0.63-1.18)., Conclusions: The use of physiologic assessment in the 24 hours after shock onset is associated with increased use of vasopressor but not with fluid administration.

Objective: Medical errors in the emergency department (ED) occur frequently. Yet, common adverse event detection methods, such as voluntary reporting, miss 90% of adverse events. Our objective was to demonstrate the use of patient-reported data in the ED to assess patient safety, including medical errors., Methods: Analysis of patient-reported survey data collected over a 1-year period in a large, academic emergency department. All patients who provided a valid e-mail or cell phone number received a brief electronic survey within 24 hours of their ED encounter by e-mail or text message with Web link. Patients were asked about ED safety-related processes., Results: From Aug 2012 to July 2013, we sent 52,693 surveys and received 7103 responses (e-mail response rate 25.8%), including 2836 free-text comments (44% of respondents). Approximately 242 (8.5%) of 2836 comments were classified as potential safety issues, including 12 adverse events, 40 near-misses, 23 errors with minimal risk of harm, and 167 general safety issues (eg, gaps in care transitions). Of the 40 near misses, 35 (75.0%) of 40 were preventable. Of the 52 adverse events or near misses, 5 (9.6%) were also identified via an existing patient occurrence reporting system., Conclusions: A patient-reported approach to assess ED-patient safety yields important, complementary, and potentially actionable safety information.

Background: Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases., Methods: Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin., Findings: 151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85-0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02)., Interpretation: The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases., (Copyright © 2019. Published by Elsevier B.V.)

Outcomes data on point-of-care ultrasound (POCUS) in critically ill patients are lacking. This study examines the association between POCUS in the emergency department and outcomes in critically ill patients., Design: Retrospective cohort study of critically ill emergency department patients in two academic emergency departments. All emergency department patients admitted to the intensive care unit or that die in the emergency department were entered prospectively into a registry., Setting: Two academic emergency departments., Patients: All adult (> 18 years old) non-trauma patients with hemodynamic instability [shock index (heart rate/systolic blood pressure) > 0.6] between November 1, 2013-October 31, 2016, were included., Interventions: Cohorts were assigned as follows: no POCUS (cohort 1), POCUS prior to a key intervention (cohort 2), and POCUS after a key intervention (cohort 3). A key intervention was either a fluid bolus or vasoactive drug initiation., Measurements and Main Results: Multivariable logistic regression was used to evaluate the association between POCUS use and the primary outcome of in-hospital mortality. We conducted several sensitivity analyses including propensity score matching and inverse-probability-weighted regression-adjustment along with multiple imputation to account for non-random assignment of POCUS as well as bias due to missing data. Of the 7,734 eligible patients, 2,293 patients were excluded. The remaining 5,441 patients were included in the analysis: 4165 in Cohort 1, 614 in Cohort 2, and 662 in Cohort 3. Mortality was 22%, 29%, and 26%, respectively ( p < 0.001). POCUS prior to an intervention was associated with an adjusted odds ratio for death of 1.41 (95% CI, 1.12-1.76) compared to no POCUS. The sensitivity analyses showed an absolute increased mortality of +0.05 (95% CI, 0.02-0.09) for cohort 2 compared to 1., Conclusions: POCUS use prior to interventions appears to be associated with care delays and increased in-hospital mortality compared to critically ill patients with no POCUS. Further explorations of the impact of POCUS in the emergency department appear warranted., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Today it is not uncommon to discover that a candidate for a faculty position has a partner or spouse who is also an academician, adding complexity to the recruitment process. Here, the authors address two practical obstacles to the recruitment of faculty who have an academic partner: dual recruitment and conflict of interest. The authors have found that tandem recruitment works best when suitable positions for both spouses are first identified so that recruitment can proceed synchronously. This approach decreases misperceptions of favoritism toward either's candidacy. Managing conflict of interest, generated by the appointment of one spouse in a supervisory position over the other, requires a proactive, transparent, well-designed plan. After canvassing human resource policies and conducting interviews with national academic leaders, the authors have developed an administrative structure that places "key" decisions (hiring and retention; promotion and tenure; salary, bonuses, and benefits; performance evaluations; and disciplinary matters) regarding the supervised spouse in the jurisdiction of an alternative administrator or committee. The authors also offer suggestions both for mitigating misperceptions of bias in day-to-day decisions and for the support and mentoring of the supervised partner or spouse.

Background: Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of severe influenza., Methods: In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ≤20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480., Findings: Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96-3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 [95% CI 0·02-1·65], p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days [IQR 4-16] vs 11 days [5-25], p=0·13) and days on mechanical ventilation (median 0 days [IQR 0-6] vs 3 days [0-14], p=0·14). Fewer plasma plus standard care participants had serious adverse events compared with standard care alone recipients (nine [20%] of 46 vs 20 [38%] of 52, p=0·041), the most frequent of which were acute respiratory distress syndrome (one [2%] vs two [4%] patients) and stroke (one [2%] vs two [4%] patients)., Interpretation: Although there was no significant effect of plasma treatment on the primary endpoint, the treatment seemed safe and well tolerated. A phase 3 randomised trial is now underway to further assess this intervention., Funding: National Institute of Allergy and Infectious Diseases, US National Institutes of Health., (Copyright © 2017 Elsevier Ltd. All rights reserved.)