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Objectives: The optimal approach for resuscitation in septic shock remains unclear despite multiple randomized controlled trials (RCTs). Our objective was to investigate whether previously uncharacterized variation across individuals in their response to resuscitation strategies may contribute to conflicting average treatment effects in prior RCTs., Design: We randomly split study sites from the Australian Resuscitation of Sepsis Evaluation (ARISE) and Protocolized Care for Early Septic Shock (ProCESS) trials into derivation and validation cohorts. We trained machine learning models to predict individual absolute risk differences (iARDs) in 90-day mortality in derivation cohorts and tested for heterogeneity of treatment effect (HTE) in validation cohorts and swapped these cohorts in sensitivity analyses. We fit the best-performing model in a combined dataset to explore roles of patient characteristics and individual components of early goal-directed therapy (EGDT) to determine treatment responses., Setting: Eighty-one sites in Australia, New Zealand, Hong Kong, Finland, Republic of Ireland, and the United States., Patients: Adult patients presenting to the emergency department with severe sepsis or septic shock., Interventions: EGDT vs. usual care., Measurements and Main Results: A local-linear random forest model performed best in predicting iARDs. In the validation cohort, HTE was confirmed, evidenced by an interaction between iARD prediction and treatment (p < 0.001). When patients were grouped based on predicted iARDs, treatment response increased from the lowest to the highest quintiles (absolute risk difference [95% CI], -8% [-19% to 4%] and relative risk reduction, 1.34 [0.89-2.01] in quintile 1 suggesting harm from EGDT, and 12% [1-23%] and 0.64 [0.42-0.96] in quintile 5 suggesting benefit). Sensitivity analyses showed similar findings. Pre-intervention albumin contributed the most to HTE. Analyses of individual EGDT components were inconclusive., Conclusions: Treatment response to EGDT varied across patients in two multicenter RCTs with large benefits for some patients while others were harmed. Patient characteristics, including albumin, were most important in identifying HTE., Competing Interests: Drs. Shah’s, Talisa’s, Chang’s, Tang’s, Cooper’s, Angus’s, and Yende’s institutions received funding from the National Institutes of Health (NIH; GM141081). Dr. Shah’s institution received funding from the NIH (K23GM122069, R21HL168070). Dr. Shah, Dr. Talisa, Dr. Chang, Dr. Triantafyllou, Dr. Tang, Mr. Kennedy, Dr. Cooper, Dr. Yealy, Dr. Seymour, Dr. Angus, and Dr. Yende received support for article research from the NIH. Dr. Talisa disclosed the study was supported by the NIH (UL1TR001857; S10OD028483). Dr. Triantafyllou, Mr. Kennedy, Dr. Cooper, and Dr. Seymour’s institutions received funding from the NIH (R01HL164835). Dr. Mayr’s institution received funding from the NIH (K23GM132688); he disclosed government work; and he received personal fees from Baxter for serving on a racial disparities advisory board outside the submitted work. Dr. Higgins’ institution received funding from the National Health and Medical Research Council (NHMRC) (GNT2008447); she received support for article research from the NHMRC. Mr. Mouncey’s institution received funding from the National Institute for Health and Care Research Health Technology Assessment program; he received support for article research from the National Institute for Health and Care Research. Mr. Kennedy’s and Dr. Seymour’s institutions received funding from the NIH (R21GM144851). Mr. Kennedy’s, Dr. Cooper’s, and Dr. Seymour’s institution received funding from the National Institute for General Medical Sciences (R35GM119519). Dr. Yealy’s institution received funding from the NIH. Dr. Seymour received funding from Beckman Coulter and Octapharma. Dr. Angus received funding from AM-Pharma and Abionyx. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Importance: Neurological manifestations during acute SARS-CoV-2-related multisystem inflammatory syndrome in children (MIS-C) are common in hospitalized patients younger than 18 years and may increase risk of new neurocognitive or functional morbidity., Objective: To assess the association of severe neurological manifestations during a SARS-CoV-2-related hospital admission with new neurocognitive or functional morbidities at discharge., Design, Setting, and Participants: This prospective cohort study from 46 centers in 10 countries included patients younger than 18 years who were hospitalized for acute SARS-CoV-2 or MIS-C between January 2, 2020, and July 31, 2021., Exposure: Severe neurological manifestations, which included acute encephalopathy, seizures or status epilepticus, meningitis or encephalitis, sympathetic storming or dysautonomia, cardiac arrest, coma, delirium, and stroke., Main Outcomes and Measures: The primary outcome was new neurocognitive (based on the Pediatric Cerebral Performance Category scale) and/or functional (based on the Functional Status Scale) morbidity at hospital discharge. Multivariable logistic regression analyses were performed to examine the association of severe neurological manifestations with new morbidity in each SARS-CoV-2-related condition., Results: Overall, 3568 patients younger than 18 years (median age, 8 years [IQR, 1-14 years]; 54.3% male) were included in this study. Most (2980 [83.5%]) had acute SARS-CoV-2; the remainder (588 [16.5%]) had MIS-C. Among the patients with acute SARS-CoV-2, 536 (18.0%) had a severe neurological manifestation during hospitalization, as did 146 patients with MIS-C (24.8%). Among survivors with acute SARS-CoV-2, those with severe neurological manifestations were more likely to have new neurocognitive or functional morbidity at hospital discharge compared with those without severe neurological manifestations (27.7% [n = 142] vs 14.6% [n = 356]; P < .001). For survivors with MIS-C, 28.0% (n = 39) with severe neurological manifestations had new neurocognitive and/or functional morbidity at hospital discharge compared with 15.5% (n = 68) of those without severe neurological manifestations (P = .002). When adjusting for risk factors in those with severe neurological manifestations, both patients with acute SARS-CoV-2 (odds ratio, 1.85 [95% CI, 1.27-2.70]; P = .001) and those with MIS-C (odds ratio, 2.18 [95% CI, 1.22-3.89]; P = .009) had higher odds of having new neurocognitive and/or functional morbidity at hospital discharge., Conclusions and Relevance: The results of this study suggest that children and adolescents with acute SARS-CoV-2 or MIS-C and severe neurological manifestations may be at high risk for long-term impairment and may benefit from screening and early intervention to assist recovery.

Allocating patients to treatment arms during a trial based on the observed responses accumulated up to the decision point, and sequential adaptation of this allocation, could minimize the expected number of failures or maximize total benefits to patients. In this study, we developed a Bayesian response-adaptive randomization (RAR) design targeting the endpoint of organ support-free days (OSFD) for patients admitted to the intensive care units. The OSFD is a mixture of mortality and morbidity assessed by the number of days of free of organ support within a predetermined post-randomization time-window. In the past, researchers treated OSFD as an ordinal outcome variable where the lowest category is death. We propose a novel RAR design for a composite endpoint of mortality and morbidity, for example, OSFD, by using a Bayesian mixture model with a Markov chain Monte Carlo sampling to estimate the posterior probability distribution of OSFD and determine treatment allocation ratios at each interim. Simulations were conducted to compare the performance of our proposed design under various randomization rules and different alpha spending functions. The results show that our RAR design using Bayesian inference allocated more patients to the better performing arm(s) compared to other existing adaptive rules while assuring adequate power and type I error rate control across a range of plausible clinical scenarios., (© 2024 John Wiley & Sons Ltd.)

Objective: To determine the association of nirmatrelvir/ritonavir (NMV/r) with hospitalization or death within 30 days as compared with untreated controls previously uninfected and nonhospitalized., Methods: We used a matched cohort design using inverse probability of treatment weight (IPTW). Individuals prescribed NMV/r within 3 days of COVID-19 diagnosis were compared with IPTW-based untreated controls. Variables for IPTW included age, race, sex, body mass index, geographic location, vaccination status, and multiple comorbidities. Additional analyses were conducted on NMV/r-treated and propensity score-matched untreated controls., Results: Among 7615 individuals prescribed NMV/r and 62 077 controls identified between 1 January 2022 and 25 February 2023, the risk of hospitalization/death was lower among NMV/r-treated persons vs untreated controls (243 vs 3468 events; absolute risk difference [ARD], -2.36 [95% CI, -2.57 to -2.14]). The difference was significant for those >60 and ≤60 years old (ARD, -3.86 [95% CI, -4.19 to -3.54] vs -0.27 [95% CI, -0.51 to -0.03]) and for persons asymptomatic and symptomatic (ARD, -7.09 [95% CI, -7.62 to -6.55] vs -1.46 [95% CI, -1.66 to -1.25]). Significant benefit was observed among individuals unvaccinated and vaccinated, with or without a booster dose., Conclusions: NMV/r is associated with a significant reduction in 30-day hospitalization or death among individuals previously uninfected and nonhospitalized., Competing Interests: Potential conflicts of interest. A. A. B. has received investigator-initiated grant funding from Gilead Sciences and Merck & Co (to the Veterans Health Foundation of Pittsburgh), which is unrelated to the work presented here. 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: Clinical benefit of molnupiravir (MPV) in coronavirus disease 2019 (COVID-19)-infected subpopulations is unclear., Methods: We used a matched cohort study design to determine the rate of hospitalization or death within 30 days of COVID-19 diagnosis among MPV treated and untreated controls. Participants were nonhospitalized, previously uninfected Veterans with a first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between 1 January and 31 August 2022, who were prescribed MPV within 3 days of COVID-19 diagnosis, and matched individuals who were not prescribed MPV., Results: Among 1459 matched pairs, the incidence of hospitalization/death was not different among MPV treated versus untreated controls (48 vs 44 cases; absolute risk difference [ARD], 0.27; 95% confidence interval [CI], -.94 to 1.49). No benefit was observed among those >60 or ≤60 years old (ARD, 0.27; 95% CI, -1.25 to 1.79 vs ARD, -0.29; 95% CI, -1.22 to 1.80), those with specific comorbidities, or by vaccination status. A significant benefit was observed in asymptomatic but not in symptomatic persons (ARD, -2.80; 95% CI, -4.74 to -.87 vs ARD, 1.12; 95% CI -.31 to 2.55). Kaplan-Meier curves did not show a difference in proportion of persons who were hospitalized or died among MPV treated compared with untreated controls (logrank P = .7)., Conclusions: MPV was not associated with a reduction in hospitalization or death within 30 days of COVID-19 diagnosis. A subgroup of patients presenting without symptoms experienced a benefit., Competing Interests: Potential conflicts of interest. A. A. B. has received investigator initiated grant funding from Gilead Sciences and Merck and Company (to the institution, Veterans Health Foundation of Pittsburgh) unrelated to the work presented here. F. B. M. is supported by K23GM132688 from the National Institutes of Health. F. B. M. has participated in a physician advisory board hosted by Baxter unrelated to the current 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: The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may be less effective against the Omicron variant than against earlier variants. With recent resurgence of SARS-CoV-2 cases, the role of booster doses of the vaccine needs to be highlighted., Methods: Using a retrospective cohort study design emulating a target trial, we determined the relative vaccine effectiveness (RVE) of a homologous booster dose of a SARS-CoV-2 messenger RNA (mRNA) vaccine compared with the primary vaccine series alone in preventing infection, hospitalization, and intensive care unit admission, and death in the Department of Veterans Affairs healthcare system in the United States. Among infection-free survivors who received 2 doses of a mRNA vaccine before 30 April 2021, we identified those who received a booster between 22 September and 25 December 2021 and matched them 1:1 with individuals who did not receive a booster., Results: Among 2 384 272 previously uninfected persons with 2 doses of an mRNA vaccine by 30 April 2021, we identified 462 950 booster recipients between 22 September and 25 December 2021, who were matched 1:1 with non-booster recipients. The RVE (95% confidence interval) was 19% (17%-22%) for confirmed infection, 52% (46%-57%) for hospitalization, and 83% (65%-92%) for intensive care unit admission or death. Recipients of the mRNA-1273 vaccine had a lower cumulative incidence of infections and hospitalizations than recipients of the BNT162b2 vaccine (log-rank P <.001 for both comparisons)., Conclusions: While the RVE of SARS-CoV-2 mRNA booster vaccine dose in preventing infection against the Omicron variant is low, it is substantial in preventing hospitalization and high in preventing the most severe/critical disease., Competing Interests: Potential conflicts of interest. A. A. B. has received investigator-initiated grant funding from Gilead Sciences (to the institution, Veterans Health Foundation of Pittsburgh), unrelated to the work presented here. F. B. M. is supported by a grant from the National Institutes of Health (career development award K23GM132688), related to this 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 the Infectious Diseases Society of America 2022.)

Importance: Patients from racially and ethnically minoritized populations, such as Black and Hispanic patients, may be less likely to receive evidence-based COVID-19 treatments than White patients, contributing to adverse clinical outcomes., Objective: To determine whether clinical treatments and outcomes among patients hospitalized with COVID-19 were associated with race., Design, Setting, and Participants: This retrospective cohort study was conducted in 130 Department of Veterans Affairs Medical Centers (VAMCs) between March 1, 2020, and February 28, 2022, with a 60-day follow-up period until May 1, 2022. Participants included veterans hospitalized with COVID-19. Data were analyzed from May 6 to June 2, 2022., Exposures: Self-reported race., Main Outcomes and Measures: Clinical care processes (eg, intensive care unit [ICU] admission; organ support measures, including invasive and noninvasive mechanical ventilation; prone position therapy, and COVID-19-specific medical treatments) were quantified. Clinical outcomes of interest included in-hospital mortality, 60-day mortality, and 30-day readmissions. Outcomes were assessed with multivariable random effects logistic regression models to estimate the association of race with outcomes not attributable to known mediators, such as socioeconomic status and age, while adjusting for potential confounding between outcomes and mediators., Results: A total of 43 222 veterans (12 135 Black veterans [28.1%]; 31 087 White veterans [71.9%]; 40 717 [94.2%] men) with a median (IQR) age of 71 (62-77) years who were hospitalized with SARS-CoV-2 infection were included. Controlling for site of treatment, Black patients were equally likely to be admitted to the ICU (4806 Black patients [39.6%] vs 13 427 White patients [43.2%]; within-center adjusted odds ratio [aOR], 0.95; 95% CI, 0.88-1.02; P = .17). Two-thirds of patients treated with supplemental oxygen or noninvasive or invasive mechanical ventilation also received systemic steroids, but Black veterans were less likely to receive steroids (within-center aOR, 0.88; 95% CI, 0.80-0.96; P = .004; between-center aOR, 0.67; 95% CI, 0.48-0.96; P = .03). Similarly, Black patients were less likely to receive remdesivir (within-center aOR, 0.89; 95% CI, 0.83-0.95; P < .001; between-center aOR, 0.68; 95% CI, 0.47-0.99; P = .02) or treatment with immunomodulatory drugs (within-center aOR, 0.77; 95% CI, 0.67-0.87; P < .001). After adjusting for patient demographic characteristics, chronic health conditions, severity of acute illness, and receipt of COVID-19-specific treatments, there was no association of Black race with hospital mortality (within-center aOR, 0.98; 95% CI, 0.86-1.10; P = .71) or 30-day readmission (within-center aOR, 0.95; 95% CI, 0.88-1.04; P = .28)., Conclusions and Relevance: These findings suggest that Black veterans hospitalized with COVID-19 were less likely to be treated with evidence-based COVID-19 treatments, including systemic steroids, remdesivir, and immunomodulatory drugs.

Background: Knowledge of the vaccine effectiveness (VE) of a third or booster vaccine dose in preventing SARS-CoV-2 infection or its consequences is critical in developing recommendations for their use. We determined relative VE of 3 vs 2 doses of an mRNA vaccine in preventing symptomatic SARS-CoV-2 infection, hospitalization, and severe/critical disease., Methods: Among veterans who had received 2 doses of an mRNA vaccine by 30 April 2021, we identified those who received a third dose of the same vaccine between 22 September and 24 November 2021 and 1:1 matched controls who had not received their third dose by then. Using Cox proportional hazards model, we calculated adjusted hazards ratios for symptomatic infection, hospitalization, and intensive care unit (ICU) admission or death after SARS-CoV-2-positive test., Results: Among 2 321 366 veterans who received 2 doses of Pfizer BNT-162b2 or Moderna mRNA-1273 vaccine by 30 April 2021, we matched 395 686 persons who received a third dose of the same vaccine between 22 September and 24 November 2021 to controls who did not receive a third dose. Adjusted HRs (95% CI) were .15 (.11-.21) for symptomatic infection and .18 (.13-.26) for hospitalizations for 3 vs 2 doses, corresponding to relative VE of 85% and 82%. Five ICU admissions or deaths were observed (4 among recipients of 2 doses). There was no difference in VE between BNT162b2 versus mRNA-1273 recipients., Conclusions: A third dose of a SARS-CoV-2 mRNA vaccine is associated with high VE against symptomatic infection, hospitalization, and critical disease in the pre-Omicron era., (Published by Oxford University Press for the Infectious Diseases Society of America 2022.)

Background: Persons on chronic hemodialysis have a significantly diminished humoral immune response to SARS-CoV-2 vaccines. Whether this translates to reduced vaccine effectiveness (VE) is unknown., Methods: We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify all veterans who were tested for SARS-CoV-2 between 26 January and 31 August 2021. Using International Classification of Diseases, 10th edition, codes and attendance at a dialysis clinic/center, we identified those who were on chronic hemodialysis. We used a test-negative, case-control design using a doubly robust logistic regression model to determine the VE of the BNT-162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines in preventing confirmed SARS-CoV-2 infection., Results: Among 847 199 veterans tested for SARS-CoV-2 between 26 January and 31 August 2021, there were 6076 veterans on chronic hemodialysis. Among those, we identified 1270 cases (580 fully vaccinated) and 2959 controls (2120 fully vaccinated). The overall VE >14 days after the second dose in preventing documented infection was 68.2% (95% CI: 62.6-72.9%). VE was 68.9% (95% CI: 61.9-74.7%) for Pfizer BNT-162b2 and 66.7% (95% CI: 58.9-73.0%) for Moderna mRNA-1273 vaccine. There was no difference in VE by age (<70 vs >70 years), race, or sex. There were no events recorded in persons with a Charlson's comorbidity index score <2., Conclusions: VE of 2 doses of current mRNA vaccines in preventing SARS-CoV-2 infection in persons on chronic hemodialysis is lower than historic VE rates in the general population. Effects of additional doses in improving VE in this special population need further study., (Published by Oxford University Press for the Infectious Diseases Society of America 2022.)

The SARS-CoV-2 Omicron variant is thought to cause less severe disease among the general population, but disease severity among at-risk populations is unknown. We performed a retrospective analysis using a matched cohort of United States veterans to compare the disease severity of subjects infected during Omicron and Delta predominant periods within 14 days of initial diagnosis. We identified 22,841 matched pairs for both periods. During the Omicron period, 20,681 (90.5%) veterans had mild, 1308 (5.7%) moderate, and 852 (3.7%) severe disease. During the Delta predominant period, 19,356 (84.7%) had mild, 1467 (6.4%) moderate, and 2018 (8.8%) severe disease. Moderate or severe disease was less likely during the Omicron period and more common among older subjects and those with more comorbidities. Here we show that infection with the Omicron variant is associated with less severe disease than the Delta variant in a high-risk older veteran population, and vaccinations provide protection against severe or critical disease., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Comparative effectiveness of coronavirus disease 2019 (COVID-19) vaccines across patient subgroups is poorly understood and essential to precisely targeting vaccination strategies., Methods: We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infection before December 11, 2020. Using a test-negative case-control design (TND), we used conditional logistic regression with adjustment for covariates to estimate vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S., Results: We identified 4.8 million veterans with a mean age of 64 years, of whom 58% had ≥1 chronic disease. Vaccine effectiveness for symptomatic infections, hospitalizations, and ICU admission or death declined over time and varied by the type of vaccine ( P  < 0.01). VE estimates against symptomatic infection during months 1 and 7 for mRNA-1273 compared with BNT162b2 were 89.7% (95% CI, 84.4%-93.0%) and 57.3% (95% CI, 48.4%-64.7%) vs 81.6% (95% CI, 75.9%-85.9%) and 22.5% (95% CI, 7.2%-35.2%) for individuals age <65 years and 78.4% (95% CI, 71.1%-83.9%) and 36.2% (95% CI, 27.7%-43.6%) vs 66.3% (95% CI, 55.7%-74.4%) and -23.3% (95% CI, -40.5% to -8.2%) in subjects age ≥65 years; against hospitalization 92.0% (95% CI, 76.1%-97.3%) and 83.1% (95% CI, 66.8%-91.4%) vs 85.6% (95% CI, 72.6%-92.4%) and 57.0% (95% CI, 31.2%-73.2%) in subjects age <65 years and 66.1% (95% CI, 45.3%-79.0%) and 64.7% (95% CI, 55.2%-72.3%) vs 61.0% (95% CI, 41.3%-74.2%) and 1.7% (95% CI, -22.0% to 20.8%) in those age ≥65 years; against ICU admission or death 89.2% (95% CI, 49.5%-97.7%) and 84.4% (95% CI, 59.0%-94.1%) vs 87.6% (95% CI, 61.0%-96.1%) and 66.4% (95% CI, 7.7%-87.8%) in subjects age <65 years and 75.4% (95% CI, 51.7%-87.5%) and 73.8 (95% CI, 62.9%-81.5%) vs 67.4% (95% CI, 32.6%-84.3%) and 29.3% (95% CI, 2.3%-48.9%) in subjects age ≥65 years, respectively ( P interaction  < .01 for all comparisons). Similarly, mRNA-1273 was more effective than BNT162b2 in veterans with >1 chronic disease., Conclusions: mRNA-1273 was more effective than BNT162b2 in older veterans and those with chronic diseases., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Clinical trials require substantial effort and time to complete, and regulatory agencies may require two successful efficacy trials before approving a new drug. One way to improve the chance of follow-up success is to identify a subpopulation among whom treatment effects are estimated to be beneficial, and enrolling future studies from this subpopulation. In this article we study confirmable responder class (CRC) learning, where the objective is to learn in a random half of the dataset (training set) a subpopulation among whom the predicted conditional ATE (CATE) suggests clinically meaningful benefit, with maximum power of being confirmed via hypothesis test in the other half (test set). We studied a set of CRC learners across simulated datasets in which either all patients benefited, or only some did. Performance metrics included the rate of confirmation in the test set, and the classification accuracy of the CRC compared with the group with true CATE>0. In trials where all patients benefitted, only two learners were able to consistently identify most of the population as the CRC. One of these also performed especially well when only some patients benefitted, having relatively high confirmation rates, and showing robustness to the dimension of the covariate vector and population characteristics. This learner is based on cross-validation, and is a possible avenue for further development of model selection criteria for CRC learning. We also show that the performance of all methods can be improved by using both halves of the original dataset as training and test sets in turn., (© 2021 John Wiley & Sons Ltd.)

Background: Previous estimates of the incidence of necrotizing soft tissue infections (NSTI) in the United States have substantial limitations and underestimate its occurrence. Improvements in hospital mortality after NSTI have increased the number of survivors at risk for long-term sequelae. This study estimates the incidence of NSTI and the burden of re-admission and associated healthcare spending in patients who survived admission for NSTI. Methods: Index admissions for NSTI were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes combined with either Current Procedural Technology (CPT) or diagnosis-related group codes to increase specificity. Two separate datasets were used to provide primary and secondary estimates of the annual incidence of NSTIs in the United States: the National Inpatient Sample (NIS) for the years 2012-2016 and the Watson Health dataset for 2009-2013, respectively, and extrapolated to estimate the incidence for 2018. The Nationwide Readmissions Database (NRD) from 2013-2015 was used to estimate of the risk for re-admission, cost of re-admissions, and to compare 90-day re-admission rates for NSTI to common medical conditions. Results: National Inpatient Sample and Watson Health datasets demonstrated an increasing annual incidence and estimated 33,600 and 28,500 cases in 2018, respectively. The estimated annual incidences in the United States in 2018 were 10.3 and 8.7 per 100,000 persons, respectively. Risk of 90-day re-admission ranged from 24%-29% over the 3 years, 89% of which were unplanned. Of those re-admitted, 90% had one or more comorbidities, the most common diagnoses associated with re-admission were infection in 65%, acute kidney injury in 22%, and shock in 10%. The median re-admission length of stay was seven days (interquartile range [IQR]: 4-13 days) with a median cost of re-admission of $13,590 (IQR: $7186-$27440). Conclusion: The incidence of NSTI is more common than generally reported. Re-admission within 90 days is common, occurring in more than one in four survivors resulting in high healthcare costs.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care., Competing Interests: Dr. DeMerle’s institution received funding from R35 GM119519-03 and T32HL007820. Dr. Calfee is supported in part by grants from the National Institutes of Health (NIH; HL140026). Dr. Carcillo is supported in part by grants from the National Institutes of Health (R01GM108618). Dr. DeMerle is supported in part by grants from the National Institutes of Health (T32HL007820). Dr. Angus received funding from Ferring Pharmaceuticals, Bristol-Myers Squibb, Bayer AG, and Alung Technologies. Drs. Angus, Brant, Carcillo, Chang, Dickson, Kennedy, Lindsell, Liu, Randolph, Thompson, Tsalik, Wong, and Seymour received support for article research from the NIH. Dr. Baillie received support for article research from Wellcome Trust/Charity Open Access Fund (COAF), and Research Councils UK. Dr. Calfee’s institution received funding from Roche/Genentech and Bayer, and she received funding from Roche/Genentech, Quark, CSL Behring, Bayer, Gen1e Life Sciences, and Vasomune. Drs. Carcillo’s and Seymour’s institutions received funding from the National Institute of General Medical Sciences. Drs. Chang’s, Lindsell’s, Liu’s, Randolph’s, Shapiro’s, and Wong’s institutions received funding from the NIH. Dr. Gordon’s institution received funding from the National Institute for Health Research (NIHR) Research Professorship (RP-2015-06-18), NIHR Imperial Biomedical Research Centre, GlaxoSmithKline, and Bristol Myers Squibb. Dr. Knight received support for article research from Wellcome Trust/COAF. Dr. Lindsell’s institution received funding from the Centers for Disease Control and Prevention (CDC), Department of Defense, Marcus Foundation, Entegrion, Endpoint Health, and bioMerieux, and he disclosed he is a coinventor on patents related to risk stratification in septic shock. Dr. Marshall received funding from AM Pharma, AKPA Pharma, and the Society of Critical Care Medicine (Critical Care Medicine Associate Editor). Dr. Randolph’s institution received funding from the CDC, and she received funding from La Jolla Pharma. Dr. Shapiro’s institution received funding from rapid pathogen screening, Baxter, and Inflammatix, and he received funding from Diagnostic Robotics. Dr. Sweeney received funding from Inflammatix. Dr. Thompson’s institution received funding from the National Heart, Lung, and Blood Institute, and he received funding from Bayer and Thetis. Dr. Tsalik disclosed that he is a founder and holds equity in Predigen; he receives salary support from the Durham VA Healthcare System and Duke University; and he has received salary support and/or grant funding (paid to his university) from the NIH, DARPA, DTRA, Karius, and Sanofi US. Dr. Wong disclosed that he and his institutions hold U.S. patents for sepsis biomarkers. Dr. Yende received funding from serving as consultant for expert testimony and he disclosed government work. Dr. Knight is supported by a Wellcome Trust Investigator Award (204969/Z/16/Z) and the NIHR Oxford Biomedical Research Centre. Dr. Lindsell was supported in part by grants from the National Institutes of Health (R35GM126943, R01HL149422), a research grant to VUMC from Endpoint Health, and is also listed as co-inventor on patents for endotyping and risk-stratification in pediatric septic shock. Dr. Liu is supported in part by grants from the National Institutes of Health (R35GM128672). Dr. Marshall is supported in part by grants from the Canadian Institutes of Health Research. Dr. Randolph is supported in part by grants from the National Institutes of Health (R21HD095228). Dr. Shankar-Hari is supported by the National Institute for Health Research Clinician Scientist Award (CS-2016-16-011). Dr. Wong is supported in part by grants from the National Institutes of Health (R35 GM126943). Dr. Sweeney is an employee of, and shareholder in, Inflammatix. 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.)

Objectives: Timely empiric antimicrobial therapy is associated with improved outcomes in pediatric sepsis, but minimal data exist to guide empiric therapy. We sought to describe the prevalence of four pathogens that are not part of routine empiric coverage (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium difficile, and fungal infections) in pediatric sepsis patients in a contemporary nationally representative sample., Design: This was a retrospective cohort study using administrative data., Setting: We used the Nationwide Readmissions Database from 2014, which is a nationally representative dataset that contains data from nearly half of all discharges from nonfederal hospitals in the United States., Patients: Discharges of patients who were less than 19 years old at discharge and were not neonatal with a discharge diagnosis of sepsis., Interventions: None., Measurements and Main Results: Of the 19,113 pediatric admissions with sepsis (6,300 [33%] previously healthy and 12,813 [67%] with a chronic disease), 31% received mechanical ventilation, 19% had shock, and 588 (3.1%) died during their hospitalization. Among all admissions, 8,204 (42.9%) had a bacterial or fungal pathogen identified. S. aureus was the most common pathogen identified in previously healthy patients (n = 593, 9.4%) and those with any chronic disease (n = 1,430, 11.1%). Methicillin-resistant S. aureus, P. aeruginosa, C. difficile, and fungal infections all had high prevalence in specific chronic diseases associated with frequent contact with the healthcare system, early surgery, indwelling devices, or immunosuppression., Conclusions: In this nationally representative administrative database, the most common identified pathogen was S. aureus in previously healthy and chronically ill children. In addition, a high proportion of children with sepsis and select chronic diseases had infections with methicillin-resistant S. aureus, fungal infections, Pseudomonas infections, and C. difficile. Clinicians caring for pediatric patients should consider coverage of these organisms when administering empiric antimicrobials for sepsis.

Importance: Long-term immune sequelae after sepsis are poorly understood., Objective: To assess whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge., Design, Settings, and Participants: This prospective, multicenter cohort study enrolled and followed up for 1 year adults who survived a hospitalization for sepsis from January 10, 2012, to May 25, 2017, at 12 US hospitals., Exposures: Circulating levels of inflammation (interleukin 6 and high-sensitivity C-reactive protein [hs-CRP]), immunosuppression (soluble programmed death ligand 1 [sPD-L1]), hemostasis (plasminogen activator inhibitor 1 and D-dimer), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress biomarkers were measured at 5 time points during and after hospitalization for sepsis for 1 year. Individual biomarker trajectories and patterns of trajectories across biomarkers (phenotypes) were identified., Main Outcomes and Measures: Outcomes were adjudicated centrally and included all-cause and cause-specific readmissions and mortality., Results: A total of 483 patients (mean [SD] age, 60.5 [15.2] years; 265 [54.9%] male) who survived hospitalization for sepsis were included in the study. A total of 376 patients (77.8%) had at least 1 chronic disease, and their mean (SD) Sequential Organ Failure Assessment score was 4.2 (3.0). Readmissions were common (485 readmissions in 205 patients [42.5%]), and 43 patients (8.9%) died by 3 months, 56 patients (11.6%) died by 6 months, and 85 patients (17.6%) died by 12 months. Elevated hs-CRP levels were observed in 23 patients (25.8%) at 3 months, 26 patients (30.2%) at 6 months, and 23 patients (25.6%) at 12 months, and elevated sPD-L1 levels were observed in 45 patients (46.4%) at 3 months, 40 patients (44.9%) at 6 months, and 44 patients (49.4%) at 12 months. Two common phenotypes were identified based on hs-CRP and sPDL1 trajectories: high hs-CRP and sPDL1 levels (hyperinflammation and immunosuppression phenotype [326 of 477 (68.3%)]) and normal hs-CRP and sPDL1 levels (normal phenotype [143 of 477 (30.0%)]). These phenotypes had similar clinical characteristics and clinical course during hospitalization for sepsis. Compared with normal phenotype, those with the hyperinflammation and immunosuppression phenotype had higher 1-year mortality (odds ratio, 8.26; 95% CI, 3.45-21.69; P < .001), 6-month all-cause readmission or mortality (hazard ratio [HR], 1.53; 95% CI, 1.10-2.13; P = .01), and 6-month readmission or mortality attributable to cardiovascular disease (HR, 5.07; 95% CI, 1.18-21.84; P = .02) or cancer (HR, 5.15; 95% CI, 1.25-21.18; P = .02). These associations were adjusted for demographic characteristics, chronic diseases, illness severity, organ support, and infection site during sepsis hospitalization and were robust in sensitivity analyses., Conclusions and Relevance: In this study, persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and was associated with worse long-term outcomes.

Background and Objectives: The decline in hospital mortality in children hospitalized with sepsis has increased the number of survivors. These survivors are at risk for adverse long-term outcomes, including readmission and recurrent or unresolved infections. We described the epidemiology of 90-day readmissions after sepsis hospitalization in children. We tested the hypothesis that a sepsis hospitalization increases odds of 90-day readmissions., Methods: Retrospective cohort analysis of the Nationwide Readmissions Database. We included index unplanned admissions of non-neonatal pediatric patients and described the proportion of readmissions, including those involving infection or sepsis. We performed multivariable analysis to determine the odds of readmission after a sepsis and nonsepsis admission and compared costs of readmission after sepsis and nonsepsis admissions., Results: Of 562 817 pediatric admissions, 7634 (1.4%) and 555 183 (98.6%) were discharged alive after admissions with and without sepsis. The rate of 90-day readmission after sepsis was 21.4%: 7.2% and 25.5% in previously healthy and chronically ill patients. The adjusted mean cost during readmission was $7385. Half of readmissions (52.9%) involved recurrent infection or sepsis. Sepsis admissions were associated with higher odds of readmission at 90 days compared with nonsepsis admissions (adjusted odds ratio 1.15, 95% confidence interval 1.08-1.23). The results remained unchanged for 30-day and 6-month readmissions., Conclusions: Readmissions occur after 1 in 5 pediatric sepsis hospitalizations and increase health care costs. Sepsis hospitalization increased odds of readmission and commonly involved recurrent infection or sepsis. Clinicians caring for these patients should consider surveillance for recurrent or unresolved infection, and researchers should explore underlying mechanisms and potential interventions to reduce readmissions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Objective: To describe the contemporary epidemiology of pediatric sepsis in children with chronic disease, and the contribution of chronic diseases to mortality. We examined the incidence and hospital mortality of pediatric sepsis in a nationally representative sample and described the contribution of chronic diseases to hospital mortality., Study Design: We analyzed the 2013 Nationwide Readmissions Database using a retrospective cohort design. We included non-neonatal patients <19 years of age hospitalized with sepsis. We examined patient characteristics, the distribution of chronic disease, and the estimated national incidence, and described hospital mortality. We used mixed effects logistic regression to explore the association between chronic diseases and hospital mortality., Results: A total of 16 387 admissions, representing 14 243 unique patients, were for sepsis. The national incidence was 0.72 cases per 1000 per year (54 060 cases annually). Most (68.6%) had a chronic disease. The in-hospital mortality was 3.7% overall-0.7% for previously healthy patients and 5.1% for patients with chronic disease. In multivariable analysis, oncologic, hematologic, metabolic, neurologic, cardiac and renal disease, and solid organ transplantation were associated with increased in-hospital mortality., Conclusions: More than 2 of 3 children admitted with sepsis have ≥1 chronic disease and these patients have a higher in-hospital mortality than previously healthy patients. The burden of sepsis in hospitalized children is greatest in pediatric patients with chronic disease., (Published by Elsevier Inc.)

Sepsis is life-threatening organ dysfunction due to dysregulated response to infection. Patients with sepsis exhibit wide heterogeneity stemming from genetic, molecular, and clinical factors as well as differences in pathogens, creating challenges for the development of effective treatments. Several gaps in knowledge also contribute: (i) biomarkers that identify patients likely to benefit from specific treatments are unknown; (ii) therapeutic dose and duration is often poorly understood; and (iii) short-term mortality, a common outcome measure, is frequently criticized for being insensitive. To date, the majority of sepsis trials use traditional design features, and have largely failed to identify new treatments with incremental benefit over standard of care. Traditional trials are also frequently conducted as part of a drug evaluation process that is segmented into several phases, each requiring separate trials, with a long time delay from inception through design and execution to incorporation of results into clinical practice. By contrast, adaptive clinical trial designs facilitate the evaluation of several candidate treatments simultaneously, learn from emergent discoveries during the course of the trial, and can be structured efficiently to lead to more timely conclusions compared to traditional trial designs. Adoption of new treatments in clinical practice can be accelerated if these trials are incorporated in electronic health records as part of a learning health system. In this review, we discuss challenges in the evaluation of treatments for sepsis, and explore potential benefits and weaknesses of recent advances in adaptive trial methodologies to address these challenges.

Although it is suspected that anxiety modifies the clinical presentation of autism in fragile X syndrome (FXS), neuropsychiatric co-morbidity profiles of these two disorders have not been extensively studied. The National Fragile X Survey was completed for 1,027 males with FXS, for whom yes/no information regarding the presence of several disorders is provided. Although the survey exhibited limited depth and lacked validation by standardized measures, this exploratory study was conducted to take advantage of the data as an opportunity for identifying future lines of inquiry. We addressed the following questions: (i) how do the co-morbidity profiles of FXS males with both autism and anxiety compare to those without anxiety?; (ii) do individuals with autism exhibit specific co-morbidity profiles compared to FXS males with anxiety only, or without either autism or anxiety?; (iii) how do co-morbidity profiles in children ages 3-11 differ from profiles of individuals >12 years? The group with autism and anxiety reported the highest prevalence of attention problems, hyperactivity/impulsivity, self-injurious behavior and aggressiveness. In addition, the lowest prevalence rates of these conditions were often observed in non-anxious groups regardless of autism status. Overall, this exploratory analysis generated several hypotheses for further study: (i) anxiety increases the severity of autism in FXS, particularly through additional behavioral abnormalities; (ii) some neuropsychiatric and behavioral conditions (i.e., attention problems, hyperactivity/impulsivity, aggressiveness) are primarily related to comorbid anxiety, not autism; (iii) prevalence of behavioral abnormalities increases with age. Future studies evaluating these hypotheses should incorporate validated neurobehavioral assessments, and control for cognitive level., (© 2014 Wiley Periodicals, Inc.)

The first two years of life for children with Rett syndrome (RTT) have previously been viewed as relatively asymptomatic. However, it is possible that subtle symptoms may be present in early development. To identify possible early indicators of RTT, we analysed videotapes of two twin girls with RTT. The videotapes were analysed to (a) describe the motor and communicative development of this twin pair with RTT; and to (b) explore whether early abnormalities and their age of onset differed between the twins and were related to their later clinical phenotypes. The results indicated several neurodevelopmental abnormalities present before the children exhibited any obvious signs of regression. Abnormalities were evident in the motor, speech-language and communicative domains. These data support an emerging evidence base showing the presence of developmental abnormalities in children with RTT during the first year of life. The results have implications for early screening and clinical assessment., Competing Interests: Declaration of Interests The authors report no conflict of interests. The authors alone are solely responsible for the content and writing of this paper.

Background: Both intra-uterine exposure to maternal drugs and HIV are known to adversely affect the developing central nervous system., Aims: (1) To describe the quality of GMs in infants who were intra-uterinely exposed to maternal opiate abuse and HIV; and (2) to analyze to what extent (a) perinatal events, (b) status of HIV-infection, and (c) the quality of GMs are associated with the neurodevelopmental outcome at 2 to 3years of age., Patients and Method: Seventy-seven children intra-uterinely exposed to both maternal opiate abuse and HIV in utero (41 boys and 36 girls; 39 born preterm) were videoed twice: first during the first 2months after term (writhing GMs) and again at 3-5months (fidgety GMs). Neurodevelopmental outcome was assessed at 2-3years of age., Results: Thirty-eight infants showed abnormal writhing GMs; 25 infants had abnormal or absent fidgety movements; 22 children had an adverse neurodevelopmental outcome. The association between GM trajectories and outcome revealed a Cramer-V=0.75 (p<0.001). Those infants with active HIV-infection (n=10) did not differ from the 67 infants who were HIV-exposed but uninfected with respect to their GM quality or outcome., Conclusions: Serial assessment of GMs in infants who were intra-uterinely exposed to maternal opiates and to HIV can be utilized for early identification of infants at a higher risk for later deficits and needing early intervention., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: This study examined features of early language and motor milestones in children with fragile X syndrome (FXS) and contrasted these features with a diagnosis of Autism Spectrum Disorder (ASD) later in life in these children., Methods: We retrospectively examined parental report of age of onset for walking and first words for primarily boys with FXS, both with ASD (FXS + ASD) and FXS-only. The diagnosis of ASD was established by DSM-IV criteria, which were complemented by the ADOS. The age of onset was analyzed as a continuous and categorical variable, which were compared to the upper limit of typically developing children., Results: Individuals with FXS-only are more delayed in the onset of first words than first walks. The finding represents a pattern suggesting a continuum as robustly demonstrated in individuals with FXS + ASD vs. FXS-only., Conclusion: Our results support validity of FXS + ASD co-morbidity as a distinct phenotype in individuals with FXS.

We studied the gestures used by children with classic Rett syndrome (RTT) to provide evidence as to how this essential aspect of communicative functions develops. Seven participants with RTT were longitudinally observed between 9 and 18 months of life. The gestures used by these participants were transcribed and coded from a retrospective analysis of a video footage. Gestures were classified as deictic gestures, play schemes, and representational gestures. Results of the analysis showed that the majority of gestures observed were of deictic character. There were no gestures that could be classified as play schemes and only two (e.g., head nodding and waving bye bye) that were coded as representational or symbolic gestures. The overall repertoire of gestures, even though not necessarily delayed in it's onset, was characterized by little variability and a restricted pragmatic functionality. We conclude that the gestural abilities in girls with RTT appear to remain limited and do not constitute a compensatory mechanism for the verbal language modality., (Copyright © 2012 Elsevier Ltd. All rights reserved.)