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Background: Influenza is associated with significant global morbidity and mortality, with vaccination being the primary preventive strategy. Despite recommendations, influenza vaccine uptake among healthcare providers (HCPs) remains suboptimal, especially in the Eastern Mediterranean. We aimed to assess the attitudes and practices of HCPs in Jordan regarding seasonal influenza vaccination and assess sources of variation thereof., Methods: We conducted a cross-sectional survey study among a sample of HCPs practicing in Jordan (12/29/2020-04/26/2021). Participants completed a questionnaire assessing demographics, influenza vaccination history, attitudes, and practices. We used logistic regression to evaluate factors related to vaccine receipt and reasons for non-vaccination. We used proportional odds models to evaluate factors related to HCP recommendations and to compare opinions on influenza vaccination between ever- and never-vaccinated HCPs., Results: Of 305 survey initiates, 206 HCPs (67.5%) comprised the analytic sample. The median age was 35 years; 61.2% were women, and 43.7% were pharmacists. Over half (52.9%) never received an influenza vaccine; however, older age and self-identifying as a physician were associated with higher odds of having ever received the influenza vaccine. The main reasons for non-vaccination were related to the misassessment of risks and benefits. Prior receipt of influenza vaccination was strongly associated with odds of recommending vaccination (or = 10.5; 95% CI = [5.38-20.3]; p<0.001). The COVID-19 pandemic reportedly enhanced influenza vaccine acceptance among 48.5% of HCPs surveyed., Conclusions: Low influenza vaccine uptake among healthcare providers in Jordan is related to misassessment of risks and benefits. Enhancing attitudes and confidence through tailored education is crucial to overcoming hesitancy and promoting sustained improvements in vaccination attitudes and practices among HCPs in Jordan., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: N.B.H. received grant support from Sanofi and Quidel and a current grant from Merck. A.J.S. reports grant support from NIH. All other authors report no potential conflicts., (Copyright: © 2024 Hamdan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Given the high prevalence of both mental health and acute pain conditions during pregnancy, use of antidepressants and analgesic opioids in this period is widespread. Whether single and combined use of these medications is associated with spontaneous preterm birth (sPTB) remains unclear., Objectives: To investigate the association between maternal prescription opioid and antidepressant medication exposures for co-occurring mental health and acute pain management, either alone or in combination, and sPTB., Methods: We used Tennessee Medicaid data (2007-2019) linked to birth certificates to conduct a nested case-control study among 15- to 44-year-old pregnant patients with singleton live births. Cases were identified as spontaneous live births between 24 and <37 gestational weeks using a validated birth certificate-based algorithm. We selected up to 10 controls per case, matched on estimated pregnancy start date and other factors. We identified analgesic opioid and antidepressant pharmacy fills to define medication exposures in the 60 days before index date (case delivery date) and categorised them as unexposed, opioid-only, antidepressant-only and combined exposure. We estimated odds ratios (OR) and 95% confidence intervals (CI) using conditional logistic regression, adjusting for confounders. We assessed the additive interaction between opioids and antidepressants by estimating relative excess risk due to interaction., Results: We identified 25,406 eligible cases of sPTB and 225,771 matched controls. Opioid-only and combined exposures were associated with higher odds of sPTB relative to unexposed (adjusted OR 1.29, 95% CI 1.23, 1.35 and 1.22, 95% CI 1.06, 1.40, respectively), while antidepressant-only exposure was not (1.04, 95% CI 0.96, 1.12). No additive interaction was identified for combined exposure., Conclusions: Exposure to prescription opioids during pregnancy, but not antidepressants, was associated with increased relative odds of sPTB. Co-exposure to opioids and antidepressants did not elevate the odds of sPTB above what we observed for opioid-only exposure., (© 2024 The Author(s). Paediatric and Perinatal Epidemiology published by John Wiley & Sons Ltd.)

Background: Continuous glucose monitor (CGM) use is increasing rapidly among people with type 2 diabetes, although little is known about predictors of CGM use beyond clinical and demographic information available in electronic medical records. Behavioral and psychosocial characteristics may also predict CGM use., Objective: We examined clinical, psychosocial, and behavioral characteristics that may predict CGM use in adults with type 2 diabetes., Design: This longitudinal observational study comprised a secondary analysis of data collected in a larger trial. Enrollment included HbA1c tests and surveys assessing demographic, clinical, psychosocial, and behavioral characteristics. We queried participants regarding their CGM use during the study on their final self-report surveys, 15 months post-enrollment., Participants: Participants were 245 community-dwelling adults with type 2 diabetes recruited from primary care., Approach: We used logistic regression to predict CGM use during the 15-month trial period from baseline characteristics., Key Results: Around one-third of participants (37.1%; 91/245) started CGM. Predictors of starting CGM in bivariate models included younger age, higher socioeconomic status, insulin use, higher HbA1c, and more diabetes distress. When including all potential predictors in a single multivariable model, only younger age (aOR = 0.95, p = 0.001), insulin use (aOR = 2.33, p = 0.006), and higher socioeconomic status (aOR = 0.44, p = 0.037) were significant predictors. Despite the association between higher HbA1c and CGM use, neither diabetes self-care behaviors nor diabetes self-efficacy significantly predicted CGM use. Of participants who tried a CGM, 14.3% (13/91) had stopped, with cost being the most-cited reason., Conclusions: Even when including behavioral and psychological characteristics, younger age, using insulin, and higher socioeconomic status remain key predictors of CGM use. These findings emphasize the importance of access and affordability for people who may benefit from CGM. Providers should not bias their introduction of CGM towards those with (perceived or actual) optimal or sub-optimal self-care behaviors., (© 2024. The Author(s).)

Background: Pediatric hematopoietic cell transplant (HCT) recipients are at high-risk for morbidity from influenza virus infection. We demonstrated in a primary phase II randomized controlled trial that two post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart were more immunogenic than two doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen., Methods: A subcohort of study participants re-enrolled and had hemagglutinin inhibition (HAI) titers measured at baseline and four weeks after each vaccine dose in year two. We estimated geometric mean fold rise (GMFR) in HAI titer from baseline for each group and used linear mixed effects models to estimate adjusted geometric mean ratios (aGMR, comparing HD-TIV to SD-QIV) for each antigen at each time point. We described systemic and injection-site reactions., Results: A total of 65 subcohort patients participated (33 SD-QIV, 32 HD-TIV). Post-vaccine GMFR and aGMR estimates were higher for both groups following a single influenza vaccine dose in year two compared to two doses of the same formulation in year one. Both groups had similar frequencies of injection-site and systemic reactions., Conclusions: A single dose of HD-TIV or SD-QIV was more immunogenic in year two than two doses of the same formulation in year one. Reactogenicity was comparable between groups. One dose of influenza vaccine may be sufficient after a two-dose schedule in the prior year post-HCT., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Pharmacoepidemiological studies commonly examine the association between drug dose and adverse health outcomes. In situations where no safe dose exists, the choice of modeling strategy can lead to identification of an apparent safe low dose range in the presence of a non-linear relationship or due to the modeling strategy forcing a linear relationship through a dose of 0. We conducted a simulation study to assess the performance of several regression approaches to model the drug dose-response curve at low doses in a setting where no safe range exists, including the use of a (1) linear dose term, (2) categorical dose term, and (3) natural cubic spline terms. Additionally, we introduce and apply an expansion of prior work related to modeling dose-response curves at low and infrequently used doses in the setting of no safe dose ("spike-at-zero" and "slab-and-spline"). Furthermore, we demonstrate and empirically assess the use of these regression strategies in a practical scenario examining the association between the dose of the initial postpartum opioid prescribed after vaginal delivery and the subsequent total dose of opioids prescribed in the entire postpartum period among a cohort of opioid-naïve women with a vaginal delivery enrolled in a State Medicaid program (2007-2014)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Objective: Acute gastroenteritis (AGE) is the second leading cause of death in children worldwide. Objectively evaluating disease severity is critical for assessing future interventions. We used data from a large, prospective surveillance study to assess risk factors associated with severe presentation using modified Vesikari score (MVS) and Clark score (CS) of severity., Methods: From December 1, 2012 to June 30, 2016, AGE surveillance was performed for children between 15 days and 17 years old in the emergency, inpatient, and outpatient settings at Vanderbilt's Monroe Carell Jr. Children's Hospital in Nashville, TN. Stool specimens were tested for norovirus, sapovirus, rotavirus, and astrovirus. We compared demographic and clinical characteristics, along with the MVS and CS, by viral detection status and by setting., Results: Of the 6309 eligible children, 4216 (67%) were enrolled, with 3256 (77%) providing a stool specimen. The median age was 1.9 years, 52% were male, and 1387 (43%) of the stool samples were virus positive. Younger age, male sex, hospitalization, and rotavirus detection were significantly associated with higher mean MVS and CS. Non-Hispanic Black race and ethnicity was associated with a lower mean MVS and CS as compared with non-Hispanic white race and ethnicity. Prematurity and enrollment in the ED were associated with higher mean CS. The 2 scoring systems were highly correlated., Conclusions: Rotavirus continues to be associated with more severe pediatric illness compared with other viral causes of AGE. MVS and CS systems yielded comparable results and can be useful tools to assess AGE severity.

Background: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illnesses in children. RSV can be broadly categorized into 2 major subtypes: A and B. RSV subtypes have been known to cocirculate with variability in different regions of the world. Clinical associations with viral subtype have been studied among children with conflicting findings such that no conclusive relationships between RSV subtype and severity have been established., Methods: During 2016-2020, children aged <5 years were enrolled in prospective surveillance in the emergency department or inpatient settings at 7 US pediatric medical centers. Surveillance data collection included parent/guardian interviews, chart reviews, and collection of midturbinate nasal plus/minus throat swabs for RSV (RSV-A, RSV-B, and untyped) using reverse transcription polymerase chain reaction., Results: Among 6398 RSV-positive children aged <5 years, 3424 (54%) had subtype RSV-A infections, 2602 (41%) had subtype RSV-B infections, and 272 (5%) were not typed, inconclusive, or mixed infections. In both adjusted and unadjusted analyses, RSV-A-positive children were more likely to be hospitalized, as well as when restricted to <1 year. By season, RSV-A and RSV-B cocirculated in varying levels, with 1 subtype dominating proportionally., Conclusions: Findings indicate that RSV-A and RSV-B may only be marginally clinically distinguishable, but both subtypes are associated with medically attended illness in children aged <5 years. Furthermore, circulation of RSV subtypes varies substantially each year, seasonally and geographically. With introduction of new RSV prevention products, this highlights the importance of continued monitoring of RSV-A and RSV-B subtypes., Competing Interests: Potential conflicts of interest. J. A. E. reports research support from AstraZeneca, GSK, and Pfizer and has consulted for AbbVie, AstraZeneca, Meissa Vaccines, Moderna, Pfizer, and Sanofi. G. A. W. reports honoraria from Merck & Co for writing and revision of chapters in the Merck Manual. E. P. S. reports serving as the principal investigator for the Pfizer Maternal Immunization Study for Safety and Efficacy; honoraria from Sanofi-Pasteur for writing or educational events; grants from Pfizer; support for meetings and/or travel from the Pediatric Infectious Diseases Society; participation on Data Safety Monitoring Board for Division of Microbiology and Infectious Diseases; and serving as board member for the World Society of Pediatric Infectious Diseases and committee chair for the Pediatric Diseases Society. C. J. H.'s institution (where employed at the time of this study) received research funding from GSK, Merck, and Pfizer for vaccine studies for which he is an investigator and honoraria from Pediatric News. R. S. reports research funds from Merck; serving on an advisory board for GSK; and grants from Hologic, BioFire, Becton Dickinson, Luminex, and Cepheid. N. B. H. reports research support from Sanofi and Quidel and honoraria from Genetech. J. V. W. reports grant support from the National Institutes of Health (for work unrelated to this study); consulting fees from Quidel's scientific advisory board; honorarium from the Infectious Disease of Children for a conference presentation; and participation on a GSK independent data monitoring committee and on a data and safety monitoring board for the National Institute of Allergy and Infectious Diseases IMPAACT Study. J. C. reports grant support from Merck. P. A. P. reports grant support from Icosavax, Merck, GSK, Shionogi, IgM Bioscience, Mapp Biologics, Sanofi-Pasteur, and Blue Lake Biotechnology and consulting fees from Takada, Moderna, Merck, and Sanofi-Pasteur. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Abstract: Pediatric hematopoietic cell transplant (HCT) recipients exhibit poor serologic responses to influenza vaccination early after transplant. To facilitate the optimization of influenza vaccination timing, we sought to identify B- and T-cell subpopulations associated with influenza vaccine immunogenicity in this population. We used mass cytometry to phenotype peripheral blood mononuclear cells collected from pediatric HCT recipients enrolled in a multicenter influenza vaccine trial comparing high- and standard-dose formulations over 3 influenza seasons (2016-2019). We fit linear regression models to estimate relationships between immune cell subpopulation numbers before vaccination and prevaccination to postvaccination geometric mean fold rises in antigen-specific (A/H3N2, A/H1N1, and B/Victoria) serum hemagglutination inhibition antibody titers (28-42 days, and ∼6 months after 2 doses). For cell subpopulations identified as predictive of a response to all 3 antigens, we conducted a sensitivity analysis including time after transplant as an additional covariate. Among 156 HCT recipients, we identified 33 distinct immune cell subpopulations; 7 significantly predicted responses to all 3 antigens 28 to 42 days after a 2-dose vaccine series, irrespective of vaccine dose. We also found evidence that baseline absolute numbers of naïve B cells, naïve CD4+ T cells, and circulating T follicular helper cells predicted peak and sustained vaccine-induced titers irrespective of dose or timing of posttransplant vaccine administration. In conclusion, several B- and T-cell subpopulations predicted influenza vaccine immunogenicity in pediatric HCT recipients. This study provides insights into the immune determinants of vaccine responses and may help guide the development of tailored vaccination strategies for this vulnerable population., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Importance: Studies of influenza in children commonly rely on coded diagnoses, yet the ability of International Classification of Diseases, Ninth Revision codes to identify influenza in the emergency department (ED) and hospital is highly variable. The accuracy of newer International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes to identify influenza in children is unknown., Objective: To determine the accuracy of ICD-10 influenza discharge diagnosis codes in the pediatric ED and inpatient settings., Design, Setting, and Participants: Children younger than 18 years presenting to the ED or inpatient settings with fever and/or respiratory symptoms at 7 US pediatric medical centers affiliated with the Centers for Disease Control and Prevention-sponsored New Vaccine Surveillance Network from December 1, 2016, to March 31, 2020, were included in this cohort study. Nasal and/or throat swabs were collected for research molecular testing for influenza, regardless of clinical testing. Data, including ICD-10 discharge diagnoses and clinical testing for influenza, were obtained through medical record review. Data analysis was performed in August 2023., Main Outcomes and Measures: The accuracy of ICD-10-coded discharge diagnoses was characterized using molecular clinical or research laboratory test results as reference. Measures included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Estimates were stratified by setting (ED vs inpatient) and age (0-1, 2-4, and 5-17 years)., Results: A total of 16 867 children in the ED (median [IQR] age, 2.0 [0.0-4.0] years; 9304 boys [55.2%]) and 17 060 inpatients (median [IQR] age, 1.0 [0.0-4.0] years; 9798 boys [57.4%]) were included. In the ED, ICD-10 influenza diagnoses were highly specific (98.0%; 95% CI, 97.8%-98.3%), with high PPV (88.6%; 95% CI, 88.0%-89.2%) and high NPV (85.9%; 95% CI, 85.3%-86.6%), but sensitivity was lower (48.6%; 95% CI, 47.6%-49.5%). Among inpatients, specificity was 98.2% (95% CI, 98.0%-98.5%), PPV was 82.8% (95% CI, 82.1%-83.5%), sensitivity was 70.7% (95% CI, 69.8%-71.5%), and NPV was 96.5% (95% CI, 96.2%-96.9%). Accuracy of ICD-10 diagnoses varied by patient age, influenza season definition, time between disease onset and testing, and clinical setting., Conclusions and Relevance: In this large cohort study, influenza ICD-10 discharge diagnoses were highly specific but moderately sensitive in identifying laboratory-confirmed influenza; the accuracy of influenza diagnoses varied by clinical and epidemiological factors. In the ED and inpatient settings, an ICD-10 diagnosis likely represents a true-positive influenza case.

Background: Multisystem inflammatory syndrome in children (MIS-C) is a rare but serious complication of severe acute respiratory syndrome coronavirus 2 infection. Features of MIS-C overlap with those of Kawasaki disease (KD)., Objective: The study objective was to develop a prediction model to assist with this diagnostic dilemma., Methods: Data from a retrospective cohort of children hospitalized with KD before the coronavirus disease 2019 pandemic were compared to a prospective cohort of children hospitalized with MIS-C. A bootstrapped backwards selection process was used to develop a logistic regression model predicting the probability of MIS-C diagnosis. A nomogram was created for application to individual patients., Results: Compared to children with incomplete and complete KD (N = 602), children with MIS-C (N = 105) were older and had longer hospitalizations; more frequent intensive care unit admissions and vasopressor use; lower white blood cell count, lymphocyte count, erythrocyte sedimentation rate, platelet count, sodium, and alanine aminotransferase; and higher hemoglobin and C-reactive protein (CRP) at admission. Left ventricular dysfunction was more frequent in patients with MIS-C, whereas coronary abnormalities were more common in those with KD. The final prediction model included age, sodium, platelet count, alanine aminotransferase, reduction in left ventricular ejection fraction, and CRP. The model exhibited good discrimination with AUC 0.96 (95% confidence interval: [0.94-0.98]) and was well calibrated (optimism-corrected intercept of -0.020 and slope of 0.99)., Conclusions: A diagnostic prediction model utilizing admission information provides excellent discrimination between MIS-C and KD. This model may be useful for diagnosis of MIS-C but requires external validation., (© 2024 Society of Hospital Medicine.)

Importance: Opioid exposure during pregnancy has been associated with preterm birth, but prior studies have not differentiated between spontaneous and indicated preterm birth or fully investigated these associations as functions of opioid dose., Objective: To determine whether prescription opioid use during pregnancy is associated with spontaneous preterm birth and whether the association is dose-dependent., Design, Setting, and Participants: This case-control study examined a retrospective cohort of pregnant patients enrolled in Tennessee Medicaid. Enrollment files were linked to health care encounters, hospital discharge information, birth certificate data, and prescription fills. Eligible participants were pregnant people ages 15 to 44 years without opioid use disorder who experienced birth of a single fetus at 24 weeks gestation or greater between 2007 and 2019 with linked birth certificate data. Cases of spontaneous preterm birth were matched with up to 10 controls based on pregnancy start date, race, ethnicity, age at delivery within 2 years, and history of prior preterm birth. Cases and matched controls were continuously enrolled in TennCare for at least 90 days prior to the index date (case delivery date)., Exposure: Total opioid MME filled during the 60 days prior to the index date., Main Outcomes and Measures: The primary outcome was spontaneous preterm birth determined by a validated algorithm using birth certificate data. Conditional logistic regression was used to estimate the association between spontaneous preterm birth and total opioid morphine milligram equivalents (MME) dispensed, adjusting for parity, prepregnancy body mass index, education level, tobacco use, hepatitis infections, and pain indications., Results: A total of 25 391 cases (median [IQR] age, 23 [20-28] years; 127 Asian [0.5%], 9820 Black [38.7%], 664 Hispanic [2.6%]; 14 748 non-Hispanic White [58.1%]) with spontaneous preterm birth were identified and matched with 225 696 controls (median [IQR] age, 23 [20-27] years; 229 Asian [0.1%], 89 819 Black [39.8%], 3590 Hispanic [1.6%]; 132 002 non-Hispanic White [58.5%]) (251 087 patients total), with 18 702 patients (7.4%) filling an opioid prescription in the 60 days prior to the index date. Each doubling of nonzero opioid MME was associated with a 4% increase in the odds of spontaneous preterm birth compared with no opioid exposure (adjusted odds ratio, 1.04; 95% CI, 1.01-1.08)., Conclusions and Relevance: In this case-control study, a positive association was found between total prescription opioid dose dispensed and the odds of spontaneous preterm birth. These findings support guidance to minimize opioid exposure during pregnancy and prescribe the lowest dose necessary.

Background: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown., Methods: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each dose, and 138-222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3-5 and 6-35 months post-HCT, respectively., Results: During 3 influenza seasons (2016-2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14-4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60-6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01-3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59-1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68-2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56-2.03])., Conclusions: Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season., Clinical Trials Registration: NCT02860039., Competing Interests: Potential conflicts of interest . N. B. H. received grant support from Sanofi and Quidel and a current grant from Merck. C. E. B. receives grant support from Pfizer and Merck. J. A. E. reports grant support from AstraZeneca, Merck, Pfizer, and GlaxoSmithKline (GSK) (all paid to institution); consultant fees for Abbvie, AstraZeneca, Meissa Vaccines, Moderna, Pfizer, Sanofi Pasteur, Shinogi, and Ark Biopharma. G. M. reports Research support from Astellas Inc and SymBio Pharmaceuticals. C. L. K. reports payment for partipcation on an advisory board for Horizon Therapeutics; payment for educational lectures from Medscape, i3Health, Physicians Education Resource, and Dava Oncology; travel support for global summit on Hematologic Malignancies from Dava Oncology; and payment from CSL Behring for providing graft versus host disease (GVHD) adjudication for a clinical trial. M. I. A. reports institutional research grants from Miravista Dianostics and Merck; consulting fees from Karius; travel support for meeting attendance from Pediatric Infectious Diseases Society and American Academy of Pediatrics; and an unpaid position on Pediatric Infectious Diseases Society Board of Directors. C. J. H. reports grants or contracts from GSK, Pfizer, Merck, and Astellas; royalties from UpToDate; payment or honoraria for educational material from Pediatric News; and non-financial interests in the American Board of Pediatrics. J. L. F. reports consulting fees and stock options from Massive Bio, Inc. J. E. S. reports institutional grants or contracts from the Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and Food and Drug Administration (FDA); personal consulting fees from Association of Professionals in Infection Control and Epidemiology and Association of American Medical Colleges; and honoraria for speaking engagements from Missouri American Academy of Pediatrics. E. A. M. reports institutional grants or contracts for clinical trials of pediatric coronavirus disease (COVID) vaccines and therapeutics from Pfizer. G. C. P. reports institutional grants or contracts for coronavirus disease 2019 (COVID-19) clinical trials from Pfizer and Moderna, Inc. F. M. M. reports grants or contracts paid to institution from Gilead for antiviral research and from Pfizer for vaccine research, and grant support from NIH and CDC; participation as DSMB member, payments to author, for Pfizer and Moderna. A. J. S. reports grant support from NIH. 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.)

Background: Mobile health (mHealth) has the potential to radically improve health behaviors and quality of life; however, there are still key gaps in understanding how to optimize mHealth engagement. Most engagement research reports only on system use without consideration of whether the user is reflecting on the content cognitively. Although interactions with mHealth are critical, cognitive investment may also be important for meaningful behavior change. Notably, content that is designed to request too much reflection could result in users' disengagement. Understanding how to strike the balance between response burden and reflection burden has critical implications for achieving effective engagement to impact intended outcomes., Objective: In this observational study, we sought to understand the interplay between response burden and reflection burden and how they impact mHealth engagement. Specifically, we explored how varying the response and reflection burdens of mHealth content would impact users' text message response rates in an mHealth intervention., Methods: We recruited support persons of people with diabetes for a randomized controlled trial that evaluated an mHealth intervention for diabetes management. Support person participants assigned to the intervention (n=148) completed a survey and received text messages for 9 months. During the 2-year randomized controlled trial, we sent 4 versions of a weekly, two-way text message that varied in both reflection burden (level of cognitive reflection requested relative to that of other messages) and response burden (level of information requested for the response relative to that of other messages). We quantified engagement by using participant-level response rates. We compared the odds of responding to each text and used Poisson regression to estimate associations between participant characteristics and response rates., Results: The texts requesting the most reflection had the lowest response rates regardless of response burden (high reflection and low response burdens: median 10%, IQR 0%-40%; high reflection and high response burdens: median 23%, IQR 0%-51%). The response rate was highest for the text requesting the least reflection (low reflection and low response burdens: median 90%, IQR 61%-100%) yet still relatively high for the text requesting medium reflection (medium reflection and low response burdens: median 75%, IQR 38%-96%). Lower odds of responding were associated with higher reflection burden (P<.001). Younger participants and participants who had a lower socioeconomic status had lower response rates to texts with more reflection burden, relative to those of their counterparts (all P values were <.05)., Conclusions: As reflection burden increased, engagement decreased, and we found more disparities in engagement across participants' characteristics. Content encouraging moderate levels of reflection may be ideal for achieving both cognitive investment and system use. Our findings provide insights into mHealth design and the optimization of both engagement and effectiveness., (© Lyndsay A Nelson, Andrew J Spieker, Lauren M LeStourgeon, Robert A Greevy Jr, Samuel Molli, McKenzie K Roddy, Lindsay S Mayberry. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org).)

Background: Adult hematopoietic cell transplant (HCT) recipients are at high risk for influenza-related morbidity and mortality and have suboptimal influenza vaccine immune responses compared to healthy adults, particularly within 2 years of transplant., Methods: This phase II, double-blind, multicenter randomized controlled trial compared 2 doses of high-dose trivalent (HD-TIV) to 2 doses of standard-dose quadrivalent (SD-QIV) influenza vaccine administered 1 month apart in adults 3-23 months post-allogeneic HCT. Hemagglutinin antibody inhibition (HAI) titers were measured at baseline, 4 weeks following each vaccine dose, and approximately 7 months post-second vaccination. Injection-site and systemic reactions were assessed for 7 days post-vaccination. The primary immunogenicity comparison was geometric mean HAI titer (GMT) at visit 3 (4 weeks after the second dose); we used linear mixed models to estimate adjusted GMT ratios (aGMRs) comparing HD-TIV/SD-QIV for each antigen., Results: We randomized 124 adults; 64 received SD-QIV and 60 received HD-TIV. Following the second vaccination, HD-TIV was associated with higher GMTs compared to SD-QIV for A/H3N2 (aGMR = 2.09; 95% confidence interval [CI]: [1.19, 3.68]) and B/Victoria (aGMR = 1.61; 95% CI: [1.00, 2.58]). The increase was not statistically significant for A/H1N1 (aGMR = 1.16; 95% CI: [0.67, 2.02]). There was a trend to more injection-site reactions for HD-TIV after the second vaccination compared to SD-QIV (50% vs 33%; adjusted odds ratio [aOR] = 4.53; 95% CI: [0.71, 28.9]), whereas systemic reactions were similar between groups with both injections., Conclusions: Adult allogeneic HCT recipients who received 2 doses of HD-TIV produced higher HAI antibody responses for A/H3N2 and B/Victoria compared with 2 doses of SD-QIV, with comparable injection-site or systemic reactions., Competing Interests: Potential conflicts of interest. M. I. has received research support, paid to Northwestern University, from GlaxoSmithKline and reports grant number UL1TR001422, which supported the author and the research capacity used for this project; payment for consultation from Adagio, ADMA Biologics, Adamis, AlloVir, Atea, Cidara, Genetech, Invivyd, Inc, Roche, Janssen, Shionogi, Takeda, Telaris, and Viracor Eurofins; royalties from UpToDate, and is a paid member of an independent data monitoring committee for Adamis, AlloVir, Merck, Sequiris/CSL, Takeda and Talaris. He also reports a role as Chair of ISIRV AVG and as Editor-in-Chief of Transplant Infectious Disease. All conflicts were ended effective 4 December 2022 except for UpToDate. S. A. P. receives research support from Global Life Technologies, Inc, and he participates in clinical trials with F2G, Symbio, and Cidarra. He also reports that Sanofi Pasteur supplied vaccines and hemagglutination titers for this study. N. B. H. has formerly received grant funding from SANOFI and Quidel. She currently receives funding from Merck for an investigator-initiated grant. D. D. reports that Eurofins-Viracor provided assay performance for investigator-initiated research on cytomegalovirus (no payments made); consulting fees paid to author from Horizon Pharmaceuticals. S. K. reports that Sanofi Pasteur supplied vaccines and hemagglutination titers for this study. A. J. S reports participation on a Data Safety Monitoring Board or Advisory Board for Integrated Health Services to reduce opioid use while managing chronic pain and the effect and contribution of a perioperative ketamine infusion in an established enhanced recovery pathway. H. H. reports VIPER T32 grant. E. T. O. reports grants or contracts paid to institution from ViiV Healthcare, Gilead Sciences, and Janssen. L. D. T. reports Sanofi Pasteur supplied vaccines and hemagglutination titers for this study. 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.)

Aims: Family/friend Activation to Motivate Self-care (FAMS) is a self-care support intervention delivered via mobile phones. We evaluated FAMS' effects on hemoglobin A1c (HbA1c) and intervention targets among adults with type 2 diabetes in a 15-month RCT., Methods: Persons with diabetes (PWDs) were randomized to FAMS or control with their support person (family/friend, optional). FAMS included monthly phone coaching and text messages for PWDs, and text messages for support persons over a 9-month intervention period., Results: PWDs (N = 329) were 52 % male, 39 % reported minoritized race or ethnicity, with mean HbA1c 8.6 ± 1.7 %. FAMS improved HbA1c among PWDs with a non-cohabitating support person (-0.64 %; 95 % CI [-1.22 %, -0.05 %]), but overall mean effects were not significant. FAMS improved intervention targets including self-efficacy, dietary behavior, and family/friend involvement during the intervention period; these improvements mediated post-intervention HbA1c improvements (total indirect effect -0.27 %; 95 % CI [-0.49 %, -0.09 %]) and sustained HbA1c improvements at 12 months (total indirect effect -0.19 %; 95 % CI [-0.40 %, -0.01 %])., Conclusions: Despite improvements in most intervention targets, HbA1c improved only among PWDs engaging non-cohabitating support persons suggesting future family interventions should emphasize inclusion of these relationships. Future work should also seek to identify intervention targets that mediate improvements in HbA1c., 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 Elsevier B.V. All rights reserved.)

Objective: We validated longitudinally a typology of diabetes-specific family functioning (named Collaborative and Helpful, Satisfied with Low Involvement, Want More Involvement, and Critically Involved) in adults with type 2 diabetes., Research Design and Methods: We conducted k-means cluster analyses with nine dimensions to determine if the typology replicated in a diverse sample and if type assignment was robust to variations in sampling and included dimensions. In a subsample with repeated assessments over 9 months, we examined the stability and validity of the typology. We also applied a multinomial logistic regression approach to make the typology usable at the individual level, like a diagnostic tool., Results: Participants (N = 717) were 51% male, more than one-third reported minority race or ethnicity, mean age was 57 years, and mean hemoglobin A1c (HbA1c) was 7.9% (63 mmol/mol; 8.7% [72 mmol/mol] for the longitudinal subsample). The typology was replicated with respect to the number of types and dimension patterns. Type assignment was robust to sampling variations (97% consistent across simulations). Type had an average 52% stability over time within participants; instability was not explained by measurement error. Over 9 months, type was independently associated with HbA1c, diabetes self-efficacy, diabetes medication adherence, diabetes distress, and depressive symptoms (all P < 0.05)., Conclusions: The typology of diabetes-specific family functioning was replicated, and longitudinal analyses suggest type is more of a dynamic state than a stable trait. However, type varies with diabetes self-management and well-being over time as a consistent independent indicator of outcomes. The typology is ready to be applied to further precision medicine approaches to behavioral and psychosocial diabetes research and care., (© 2023 by the American Diabetes Association.)

Aims: Type 2 diabetes self-management occurs within social contexts. We sought to test the effects of Family/friend Activation to Motivate Self-care (FAMS), a self-care support intervention delivered via mobile phones, on psychosocial outcomes for persons with diabetes (PWDs) and their support persons., Methods: PWDs had the option to enroll with a friend/family member as a support person in a 15-month RCT to evaluate FAMS versus enhanced usual care. FAMS included 9 months of monthly phone coaching and text message support for PWDs, and text message support for enrolled support persons., Results: PWDs (N = 329) were 52% male and 39% reported minoritized race or ethnicity ; 50% enrolled with elevated diabetes distress. Support persons (N = 294) were 26% male and 33% reported minoritized race or ethnicity. FAMS improved PWDs' diabetes distress (d = -0.19) and global well-being (d = 0.21) during the intervention, with patterns of larger effects among minoritized groups. Post-intervention (9-month) and sustained (15-month) improvements were driven by changes in PWDs' self-efficacy, self-care behaviors, and autonomy support. Among support persons, FAMS improved helpful involvement without increasing burden or harmful involvement., Conclusions: FAMS improved PWDs' psychosocial well-being, with post-intervention and sustained improvements driven by improved self-efficacy, self-care, and autonomy support. Support persons increased helpful involvement without adverse effects., 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 Elsevier B.V. All rights reserved.)

Objective: Family/friend involvement and diabetes distress are associated with outcomes for persons with type 2 diabetes (PWDs), but little is known about how they relate to each other. We aim to (1) describe associations between PWD and support person (SP) distress; (2) describe associations between involvement and diabetes distress for PWDs, for SPs, and across the dyad; and (3) explore whether associations differ by PWD-SP cohabitation., Methods: PWDs and SPs co-enrolled in a study evaluating the effects of a self-care support intervention and completed self-report measures at baseline., Results: PWDs and SPs (N = 297 dyads) were, on average, in their mid-50s and around one-third identified as racial or ethnic minorities. The association between PWD and SP diabetes distress was small (Spearman's ρ = 0.25, p < 0.01). For PWDs, experienced harmful involvement from family/friends was associated with more diabetes distress (standardized β = 0.23, p < 0.001) independent of helpful involvement in adjusted models. Separately, SPs' self-reported harmful involvement was associated with their own diabetes distress (standardized β = 0.35, p < 0.001) and with PWDs' diabetes distress (standardized β = 0.25, p = 0.002), independent of SPs' self-reported helpful involvement., Conclusion and Practice Implications: Findings suggest dyadic interventions may need to address both SP harmful involvement and SP diabetes distress, in addition to PWD distress., Competing Interests: Declaration of Competing Interest The authors have no other declarations of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Importance: The risk of serious long-term outcomes for infants born to individuals with opioid use disorder (OUD) is not fully characterized, nor is it well understood whether risks are modified by infant diagnosis of neonatal opioid withdrawal syndrome (NOWS)., Objective: To characterize the risk of postneonatal infant mortality among infants with a NOWS diagnosis or born to individuals with OUD., Design, Setting, and Participants: The study team conducted a retrospective cohort study of 390 075 infants born from 2007 through 2018 to mothers who were enrolled in Tennessee Medicaid from 183 days prior to delivery through 28 days post partum (baseline). Maternal and infant baseline characteristics were measured using administrative claims and birth certificates, and infants were followed up from day 29 post partum through day 365 or death. Deaths were identified using linked death certificates through 2019. These data were analyzed from February 10, 2022, through March 3, 2023., Exposure: Infant exposures included birth to an individual with OUD or postnatal diagnosis of NOWS. The study team defined a pregnant individual's OUD status (maternal OUD) as having OUD diagnosis or a maintenance medication prescription fill during baseline; this study defined NOWS as having NOWS diagnosis up to day 28. Groups were categorized by exposures as maternal OUD with NOWS (OUD positive/NOWS positive), maternal OUD without NOWS (OUD positive/NOWS negative), no documented maternal OUD with NOWS (OUD negative/NOWS positive), and no documented maternal OUD or NOWS (OUD negative/NOWS negative, unexposed)., Main Outcome and Measures: The outcome was postneonatal infant death, confirmed by death certificates. Cox proportional hazards models were used, adjusting for baseline maternal and infant characteristics, to estimate adjusted hazard ratios (aHRs) and 95% CIs for the association between maternal OUD or NOWS diagnosis with postneonatal death., Results: Pregnant individuals in the cohort had a mean (SD) age of 24.5 (5.2) years; 51% of infants were male. The study team observed 1317 postneonatal infant deaths and incidence rates of 3.47 (OUD negative/NOWS negative, 375 718), 8.41 (OUD positive/NOWS positive, 4922); 8.95 (OUD positive/NOWS negative, 7196), and 9.25 (OUD negative/NOWS positive, 2239) per 1000 person-years. After adjustment, the risk of postneonatal death was elevated for all groups, relative to the unexposed: OUD positive/NOWS positive (aHR, 1.54; 95% CI, 1.07-2.21), OUD positive/NOWS negative (aHR, 1.62; 95% CI, 1.21-2.17), and OUD negative/NOWS positive (aHR, 1.64; 95% CI, 1.02-2.65)., Conclusions and Relevance: Infants born to individuals with OUD or with a NOWS diagnosis had an increased risk of postneonatal infant mortality. Future work is necessary to create and evaluate supportive interventions for individuals with OUD during and after pregnancy to reduce adverse outcomes.

Few studies have defined the incidence of and risk factors for influenza infection in pediatric solid organ transplant (SOT) recipients. We used a linkage between the Pediatric Health Information System and the Scientific Registry of Transplant Recipients databases to identify posttransplant influenza-associated hospital encounters (IAHEs) in pediatric SOT recipients of single-organ transplants. Among 7997 unique pediatric SOT recipients transplanted between January 01, 2006, and January 06, 2016, estimated 1- and 3-year posttransplant cumulative incidence rates of IAHEs were 2.7% (95% CI, 2.4%-3.1%) and 7.4% (95% CI, 6.8%-8.0%), respectively. One- and 3-year cumulative incidence rates of severe IAHEs were 0.3% (95% CI, 0.2%-0.5%) and 0.9% (95% CI, 0.7%-1.2%), respectively. Multivariable analysis showed that the organ type (adjusted subdistribution hazard ratio [aSHR]-kidney: reference, liver: 0.64 [95% CI, 0.49-0.84], and heart: 0.72 [95% CI, 0.57-0.93]), race/ethnicity (aSHR-non-Hispanic White: reference, non-Hispanic Black: 1.63 [95% CI, 1.29-2.07], Hispanic 1.57 [95% CI, 1.27-1.94]), and increasing age at transplant (aSHR, 0.93 [95% CI, 0.91-0.94]) were significantly associated with IAHE occurrence. Heart transplant recipients had a near statistically significant increase in hazard for severe IAHE (aSHR 1.96 [0.92-3.49]). Our findings may help guide future influenza prevention efforts and facilitate intervention impact assessment measurement in pediatric SOT recipients., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Our study examines the association between social vulnerability index (SVI) and pharmacotherapy initiation for gestational diabetes mellitus (GDM)., Methods: We studied a retrospective cohort of pregnant patients with GDM, enrolled in Tennessee Medicaid, who gave birth between 2007 and 2019. Enrollment files were linked to birth and death certificates, state hospitalization registries, and pharmacy claims. SVI, measured at the community level and determined by residential census tract, ranged from 0 to 100 (low to high vulnerability). Multivariable logistic regression assessed the association between SVI and the odds of initiating the most common pharmacotherapies for GDM-insulin, glyburide, or metformin-and adjusted for relevant covariates. SVI was modeled with restricted cubic splines to account for nonlinear associations, using the median Tennessee SVI as a reference. Secondary analysis assessed associations with the SVI subthemes., Results: Among 33,291 patients with GDM, 21.7% (7,209) initiated pharmacotherapy during pregnancy. Patients from areas with higher SVI were more likely to be non-Hispanic Black with higher body mass index, whereas those with lower SVI were more likely to be nulliparous. Multivariable modeling demonstrated a complex nonlinear association between SVI and GDM pharmacotherapy initiation, relative to the reference. Higher SVI was associated with elevated odds of GDM pharmacotherapy initiation (e.g., odds ratio 1.11 [95% confidence interval 1.02-1.22] for SVI 80) and low to medium SVI had variable nonsignificant associations with GDM pharmacotherapy initiation, relative to the reference (lower odds of initiation for values 25-50, higher odds of initiation for values < 25). Secondary analysis demonstrated a nonlinear association between subtheme 3 and the odds of GDM pharmacotherapy initiation., Conclusion: Social vulnerability is associated with initiation of pharmacotherapy for GDM, highlighting the possible role of social determinants of health in achieving glycemic control., (Copyright © 2022 Jacobs Institute of Women's Health, George Washington University. Published by Elsevier Inc. All rights reserved.)

Background: Rhinovirus (RV) is one of the most common etiologic agents of acute respiratory infection (ARI), which is a leading cause of morbidity and mortality in young children. The clinical significance of RV co-detection with other respiratory viruses, including respiratory syncytial virus (RSV), remains unclear. We aimed to compare the clinical characteristics and outcomes of children with ARI-associated RV-only detection and those with RV co-detection-with an emphasis on RV/RSV co-detection., Methods: We conducted a prospective viral surveillance study (11/2015-7/2016) in Nashville, Tennessee. Children < 18 years old who presented to the emergency department (ED) or were hospitalized with fever and/or respiratory symptoms of < 14 days duration were eligible if they resided in one of nine counties in Middle Tennessee. Demographics and clinical characteristics were collected by parental interviews and medical chart abstractions. Nasal and/or throat specimens were collected and tested for RV, RSV, metapneumovirus, adenovirus, parainfluenza 1-4, and influenza A-C using reverse transcription quantitative polymerase chain reaction assays. We compared the clinical characteristics and outcomes of children with RV-only detection and those with RV co-detection using Pearson's χ 2 test for categorical variables and the two-sample t-test with unequal variances for continuous variables., Results: Of 1250 children, 904 (72.3%) were virus-positive. RV was the most common virus (n = 406; 44.9%), followed by RSV (n = 207; 19.3%). Of 406 children with RV, 289 (71.2%) had RV-only detection, and 117 (28.8%) had RV co-detection. The most common virus co-detected with RV was RSV (n = 43; 36.8%). Children with RV co-detection were less likely than those with RV-only detection to be diagnosed with asthma or reactive airway disease both in the ED and in-hospital. We did not identify differences in hospitalization, intensive care unit admission, supplemental oxygen use, or length of stay between children with RV-only detection and those with RV co-detection., Conclusion: We found no evidence that RV co-detection was associated with poorer outcomes. However, the clinical significance of RV co-detection is heterogeneous and varies by virus pair and age group. Future studies of RV co-detection should incorporate analyses of RV/non-RV pairs and include age as a key covariate of RV contribution to clinical manifestations and infection outcomes., (© 2023. The Author(s).)

Background: Clinical differences between critical illness from influenza infection vs coronavirus disease 2019 (COVID-19) have not been well characterized in pediatric patients., Methods: We compared demographics, clinical characteristics, and outcomes of US children (aged 8 months to 17 years) admitted to the intensive care or high-acuity unit with influenza or COVID-19. Using mixed-effects models, we assessed the odds of death or requiring life support for influenza vs COVID-19 after adjustment for age, sex, race and Hispanic origin, and underlying conditions including obesity., Results: Children with influenza (n = 179) were younger than those with COVID-19 (n = 381; median, 5.2 years vs 13.8 years), less likely to be non-Hispanic Black (14.5% vs 27.6%) or Hispanic (24.0% vs 36.2%), and less likely to have ≥1 underlying condition (66.4% vs 78.5%) or be obese (21.4% vs 42.2%), and a shorter hospital stay (median, 5 days vs 7 days). They were similarly likely to require invasive mechanical ventilation (both 30.2%), vasopressor support (19.6% and 19.9%), or extracorporeal membrane oxygenation (2.2% and 2.9%). Four children with influenza (2.2%) and 11 children with COVID-19 (2.9%) died. The odds of death or requiring life support in children with influenza vs COVID-19 were similar (adjusted odds ratio, 1.30; 95% confidence interval, .78-2.15; P = .32)., Conclusions: Despite differences in demographics and clinical characteristics of children with influenza or COVID-19, the frequency of life-threatening complications was similar. Our findings highlight the importance of implementing prevention measures to reduce transmission and disease severity of influenza and COVID-19., Competing Interests: Potential conflicts of interest. N. B. H. reports grants or contracts from Sanofi and Quidell outside of the submitted work and an educational grant for honorarium from Genentech. M. M. B. reports grants or contracts from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke, Grifols Investigator Sponsored Research Grant, and NIH/ Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) outside of the submitted work and paid to institution. B. M. C. reports grants or contracts from the NIH, American Thoracic Society, and American Lung Association outside the submitted work and paid to institution and payment to author for expert testimony from Triplett Woolf Garretson, LLC. N. Z. C. reports grants or contracts from the NIH outside of the submitted work. H. R. F. reports grants or contracts from the NIH, National Heart, Lung, and Blood Institute (NHLBI), and NICHD outside of the submitted work; support for attending meetings and/or travel from the Society of Critical Care Medicine; participation on a data and safety monitoring board (DSMB) for a cardiothoracic surgery trial (single center) and a DSMB for an intrathecal chemotherapy trial; an unpaid position on the Michigan Thoracic Society Executive Committed and Pediatric Acute Lung Injury and Sepsis Investigators network Executive Committee; and the following other financial or nonfinancial interests: Lucira Health advisory committee and Aerogen Pharma advisory unfunded. M. W. H. reports grants or contracts from the NIH and royalties from Kiadis outside of the submitted work; participation on a DSMB or advisory board for AbbVie and La Jolla Pharmaceuticals (payment to author); and leadership or fiduciary role on the American Board of Pediatrics (payment to author). J. R. H. reports grants or contracts from the NIH–NICHD outside of the submitted work and participation on a DSMB for an institutional study at the University of Minnesota (no financial reimbursements). M. K. reports grants or contracts from the NIH outside of the submitted work to institution. E. R. L. reports grants or contracts from the NIH outside of the submitted work and paid to institution. M. M. Nakamura reports grants or contracts from Gilead for participation in their remdesivir trial. R. A. N. reports grants or contracts from the NIH outside of the submitted work. C. M. R. reports grants or contracts from the NIH outside of the submitted work and payment for honoraria to author for the Contemporary Critical Care Complications of SCT/Cellular Therapies Conference by MD Anderson. J. E. S. reports grants or contracts from Merck outside of the submitted work and paid to institution. M. S. Z. reports grants or contracts from the NIH outside of the submitted work and paid to institution. A. G. R. reports grants or contracts from the National Institute of Allergy and Infectious Diseases to institution outside of the submitted work; royalties or licenses from UpToDate as a Pediatric Critical Care Section Editor paid to author; and is an unpaid treasurer for International Sepsis Forum. M. L. C. reports grants or contracts to institution for projects unrelated to this work from the CDC. J.C.F. reports an NIH award unrelated to this study and paid to institution. C. V. H. reports payment or honoraria as a consultant for Biofire (bioMérieux). G. E. M. reports payment for expert testimony in a malpractice case involving influenza related death. All remaining authors: No reported conflicts of interest. 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) 2022. 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.)

Importance: Rhinoviruses and/or enteroviruses, which continued to circulate during the COVID-19 pandemic, are commonly detected in pediatric patients with acute respiratory illness (ARI). Yet detailed characterization of rhinovirus and/or enterovirus detection over time is limited, especially by age group and health care setting., Objective: To quantify and characterize rhinovirus and/or enterovirus detection before and during the COVID-19 pandemic among children and adolescents seeking medical care for ARI at emergency departments (EDs) or hospitals., Design, Setting, and Participants: This cross-sectional study used data from the New Vaccine Surveillance Network (NVSN), a multicenter, active, prospective surveillance platform, for pediatric patients who sought medical care for fever and/or respiratory symptoms at 7 EDs or hospitals within NVSN across the US between December 2016 and February 2021. Persons younger than 18 years were enrolled in NVSN, and respiratory specimens were collected and tested for multiple viruses., Main Outcomes and Measures: Proportion of patients in whom rhinovirus and/or enterovirus, or another virus, was detected by calendar month and by prepandemic (December 1, 2016, to March 11, 2020) or pandemic (March 12, 2020, to February 28, 2021) periods. Month-specific adjusted odds ratios (aORs) for rhinovirus and/or enterovirus-positive test results (among all tested) by setting (ED or inpatient) and age group (<2, 2-4, or 5-17 years) were calculated, comparing each month during the pandemic to equivalent months of previous years., Results: Of the 38 198 children and adolescents who were enrolled and tested, 11 303 (29.6%; mean [SD] age, 2.8 [3.7] years; 6733 boys [59.6%]) had rhinovirus and/or enterovirus-positive test results. In prepandemic and pandemic periods, rhinoviruses and/or enteroviruses were detected in 29.4% (9795 of 33 317) and 30.9% (1508 of 4881) of all patients who were enrolled and tested and in 42.2% (9795 of 23 236) and 73.0% (1508 of 2066) of those with test positivity for any virus, respectively. Rhinoviruses and/or enteroviruses were the most frequently detected viruses in both periods and all age groups in the ED and inpatient setting. From April to September 2020 (pandemic period), rhinoviruses and/or enteroviruses were detectable at similar or lower odds than in prepandemic years, with aORs ranging from 0.08 (95% CI, 0.04-0.19) to 0.76 (95% CI, 0.55-1.05) in the ED and 0.04 (95% CI, 0.01-0.11) to 0.71 (95% CI, 0.47-1.07) in the inpatient setting. However, unlike some other viruses, rhinoviruses and/or enteroviruses soon returned to prepandemic levels and from October 2020 to February 2021 were detected at similar or higher odds than in prepandemic months in both settings, with aORs ranging from 1.47 (95% CI, 1.12-1.93) to 3.01 (95% CI, 2.30-3.94) in the ED and 1.36 (95% CI, 1.03-1.79) to 2.44 (95% CI, 1.78-3.34) in the inpatient setting, and in all age groups. Compared with prepandemic years, during the pandemic, rhinoviruses and/or enteroviruses were detected in patients who were slightly older, although most (74.5% [1124 of 1508]) were younger than 5 years., Conclusions and Relevance: Results of this study show that rhinoviruses and/or enteroviruses persisted and were the most common respiratory virus group detected across all pediatric age groups and in both ED and inpatient settings. Rhinoviruses and/or enteroviruses remain a leading factor in ARI health care burden, and active ARI surveillance in children and adolescents remains critical for defining the health care burden of respiratory viruses.

Rhinovirus (RV)-specific surveillance studies in the Middle East are limited. Therefore, we aimed to study the clinical characteristics, outcomes, and seasonality of RV-associated acute respiratory infection among hospitalized young children in Jordan. We conducted a prospective viral surveillance study and enrolled children <2 years old admitted to a large public hospital in Amman, Jordan (2010-2013). Demographic and clinical data were collected by structured interviews and chart abstractions. Nasal and/or throat swabs were collected and tested for a panel of respiratory viruses, and RV genotyping and speciation was performed. At least one virus was detected in 2641/3168 children (83.4%). RV was the second most common virus detected (n = 1238; 46.9%) and was codetected with another respiratory virus in 730 cases (59.0%). Children with RV codetection were more likely than those with RV-only detection to have respiratory distress but had similar outcomes. RV-A accounted for about half of RV-positive cases (54.7%), while children with RV-C had a higher frequency of wheezing and reactive airway disease. RV was detected year-round and peaked during winter. In conclusion, though children with RV codetection had worse clinical findings, neither codetection nor species affected most clinical outcomes., (© 2022 Wiley Periodicals LLC.)

Compared to adults, the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) illness in children has been lower and less severe. However, reports comparing SARS-CoV-2 infection among children and adults are limited. As part of our longitudinal cohort study of adults and children with SARS-CoV-2 infection and their household contacts in Nashville, Tennessee, we compared the clinical characteristics and outcomes of SARS-CoV-2 infections between children and adults. Children were more likely to be asymptomatically infected and had a shorter illness duration compared to adults. The differences observed in clinical presentation across ages may inform symptom-specific testing, screening, and management algorithms., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Background: Human adenovirus (HAdV) is commonly associated with acute respiratory illnesses (ARI) in children and is also frequently co-detected with other viral pathogens. We compared clinical presentation and outcomes in young children with HAdV detected alone vs co-detected with other respiratory viruses., Methods: We used data from a multicenter, prospective, viral surveillance study of children seen in the emergency department and inpatient pediatric settings at seven US sites. Children less than 18 years old with fever and/or respiratory symptoms were enrolled between 12/1/16 and 10/31/18 and tested by molecular methods for HAdV, human rhinovirus/enterovirus (HRV/EV), respiratory syncytial virus (RSV), parainfluenza (PIV, types 1-4), influenza (flu, types A-C), and human metapneumovirus (HMPV). Our primary measure of illness severity was hospitalization; among hospitalized children, secondary severity outcomes included oxygen support and length of stay (LOS)., Results: Of the 18,603 children enrolled, HAdV was detected in 1,136 (6.1%), among whom 646 (56.9%) had co-detection with at least one other respiratory virus. HRV/EV (n = 293, 45.3%) and RSV (n = 123, 19.0%) were the most frequent co-detections. Children with HRV/EV (aOR = 1.61; 95% CI = [1.11-2.34]), RSV (aOR = 4.48; 95% CI = [2.81-7.14]), HMPV (aOR = 3.39; 95% CI = [1.69-6.77]), or ≥ 2 co-detections (aOR = 1.95; 95% CI = [1.14-3.36]) had higher odds of hospitalization compared to children with HAdV alone. Among hospitalized children, HAdV co-detection with RSV or HMPV was each associated with higher odds of oxygen support, while co-detection with PIV or influenza viruses was each associated with higher mean LOS., Conclusions: HAdV co-detection with other respiratory viruses was associated with greater disease severity among children with ARI compared to HAdV detection alone., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Shortly after the implementation of community mitigation measures in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), sharp declines in respiratory syncytial virus and influenza circulation were noted; post-mitigation circulation of other respiratory pathogens has gone unexplored. We retrospectively analyzed all records of a provider-ordered multiplex test between April 1, 2018, and July 31, 2021, in Nashville, Tennessee, and we noted disrupted historical seasonal patterns for common respiratory pathogens during the SARS-CoV-2 pandemic., Competing Interests: Natasha Halasa, MD, MPH receives grant support from Sanofi Pasteur, Quidel, and speaker compensation from an education grant supported by Genentech. Sanofi Pasteur also donated vaccines and influenza antibody testing for influenza vaccine trial. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Penile intraepithelial neoplasia (PeIN) is classified as human papillomavirus (HPV)- and non-HPV-related. This classification is associated with distinct morphologic subtypes. The natural history and prognosis of PeIN subtypes are not well known. This study aims to evaluate clinicopathological features, HPV status, and outcome of PeIN subtypes. Eighty-two lesions from 64 patients with isolated PeIN were retrospectively reviewed. Mean age was 59 years. Lesions were multicentric in 34% of patients and affected glans (33%), shaft (26%), and foreskin (20%). Histologically, 22% of patients had coexisting lesions, classified as hybrid and mixed. HPV-related PeIN (97%) included basaloid (59%), warty (8%), warty-basaloid (8%), hybrid (19%) and mixed (3%) types. P16 and HPV positivity occurred in 99% and 82% of lesions, respectively. HPV 16 was more common in basaloid PeIN. Multiple genotypes were detected in 35%, more commonly in hybrid PeIN (P = 0.051). Positive margins occurred in 63% of excisions. PeIN recurred in 48% of excisions and 30% of overall repeated procedures, and progression to invasive carcinoma occurred in 2%. At follow-up, 86% of patients had no evidence of disease and 12% were alive with disease. Lichen sclerosus occurred in non-HPV and HPV-related PeIN (100% and 47%).In conclusion, HPV-related and, more specifically basaloid PeIN were the predominant types and preferentially associated with HPV 16. While PeIN had a high recurrence rate, there was a slow and infrequent progression to invasive or metastatic carcinoma with multimodal treatments. Additional studies are needed to understand biology and natural history of PeIN., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)

Background: The burden of respiratory syncytial virus (RSV)-associated acute respiratory illnesses among healthy infants (<1 year) in the inpatient setting is well established. The focus on RSV-associated illnesses in the outpatient (OP) and emergency department (ED) settings are however understudied. We sought to determine the spectrum of RSV illnesses in infants at three distinct healthcare settings., Methods: From 16 December 2019 through 30 April 2020, we performed an active, prospective RSV surveillance study among infants seeking medical attention from an inpatient (IP), ED, or OP clinic. Infants were eligible if they presented with fever and/or respiratory symptoms. Demographics, clinical characteristics, and illness histories were collected during parental/guardian interviews, followed by a medical chart review and illness follow-up surveys. Research nasal swabs were collected and tested for respiratory pathogens for all enrolled infants., Results: Of the 627 infants screened, 475 were confirmed eligible; 360 were enrolled and research tested. Within this final cohort, 101 (28%) were RSV-positive (IP = 37, ED = 18, and OP = 46). Of the RSV-positive infants, the median age was 4.5 months and 57% had ⩾2 healthcare encounters. The majority of RSV-positive infants were not born premature (88%) nor had underlying medical conditions (92%). RSV-positive infants, however, were more likely to have a lower respiratory tract infection than RSV-negative infants (76% vs 39%, p  < 0.001). Hospitalized infants with RSV were younger, 65% required supplemental oxygen, were more likely to have lower respiratory tract symptoms, and more often had shortness of breath and rales/rhonchi than RSV-positive infants in the ED and OP setting., Conclusion: Infants with RSV illnesses seek healthcare for multiple encounters in various settings and have clinical difference across settings. Prevention measures, especially targeted toward healthy, young infants are needed to effectively reduce RSV-associated healthcare visits., Competing Interests: Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NH receives funding from Sanofi Pasteur, Quidel, and speaker compensation from an education grant supported by Genentech. CBN is an employee of Sanofi Pasteur and may hold shares and/or stock options in the company. JF, MS, and DSS received funding from Sanofi Pasteur for this and other contracted work. All other authors report no other conflicts of interest., (© The Author(s), 2022.)

To make informed health policy decisions regarding a treatment, we must consider both its cost and its clinical effectiveness. In past work, we introduced the net benefit separation (NBS) as a novel measure of cost-effectiveness. The NBS is a probabilistic measure that characterizes the extent to which a treated patient will be more likely to experience benefit as compared to an untreated patient. Due to variation in treatment response across patients, uncovering factors that influence cost-effectiveness can assist policy makers in population-level decisions regarding resource allocation. In this paper, we introduce a regression framework for NBS in order to estimate covariate-specific NBS and find determinants of variation in NBS. Our approach is able to accommodate informative cost censoring through inverse probability weighting techniques, and addresses confounding through a semiparametric standardization procedure. Through simulations, we show that NBS regression performs well in a variety of common scenarios. We apply our proposed regression procedure to a realistic simulated data set as an illustration of how our approach could be used to investigate the association between cancer stage, comorbidities and cost-effectiveness when comparing adjuvant radiation therapy and chemotherapy in post-hysterectomy endometrial cancer patients., (© 2022 John Wiley & Sons Ltd.)

Objective: We examined users' preferences for and engagement with text messages delivered as part of an emergency department (ED)-based intervention to improve antihypertensive medication adherence., Methods: We recruited ED patients with elevated blood pressure for a pilot randomized trial evaluating a medication adherence intervention with text messages. Intervention participants chose text content and frequency, received texts for 45 days, and completed a feedback survey. We defined engagement via responses to texts. We examined participant characteristics associated with text preferences, engagement, and feedback., Results: Participants (N = 101) were 57% female and 46% non-White. Most participants (71%) chose to receive both reminder and informational texts; 94% chose reminder texts once per day and 97% chose informational texts three times per week. Median text message response rate was 56% (IQR 26-80%). Participants who were Black (p < 0.01), had lower income (p = 0.03), or had lower medication adherence (p < 0.01) rated the program as more helpful and wanted additional functionalities for adherence support., Conclusions and Practice Implications: While overall engagement was modest, participants at risk of worse health outcomes expressed more value and interest in the program. Findings inform the design of text messaging interventions for antihypertensive medication adherence and support targeting vulnerable patients to reduce health disparities., Clinical Trials Registration: NCT02672787., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The most common clinical manifestation of adenovirus (AdV) infection is acute respiratory illness (ARI). Specific AdV species associated with ARI hospitalizations are not well defined in the Middle East., Methods: A viral surveillance study was conducted among children <2 years hospitalized in Amman, Jordan, from March 2010 to March 2013. Nasal and throat respiratory specimens were obtained from enrolled children and tested for viruses using a real-time reverse-transcription quantitative polymerase chain reaction. AdV-positive specimens were typed by partial hexon gene sequencing. Demographic and clinical features were compared between AdV detected as single pathogen versus co-detected with other respiratory viruses, and between AdV-B and AdV-C species., Results: AdV was detected in 475/3168 (15%) children hospitalized with ARI; of these, 216 (45%) specimens were successfully typed with AdV-C as the most common species detected (140/216; 65%). Children with AdV-single detection (88/475; 19%) had a higher frequency of fever (71% vs. 56%; P=0.015), diarrhea (18% vs. 11%; p=0.048), and/or seizures/abnormal movements (14% vs. 5%; p=0.003). Children with AdV co-detected with other viruses more likely required oxygen support [adjusted odds ratio (aOR) 1.91 (95% CI: 1.08, 3.39), P = 0.027] than those with AdV-single detection. Children with AdV-C had higher odds of co-detections with other viruses compared with those with AdV-B [aOR 4.00 (95% CI: 1.91, 8.44), P < 0.001]., Conclusion: Clinical differences were identified between AdV-single and AdV co-detected with other viruses, and between AdV-B and AdV-C. Larger studies with AdV typing are needed to determine additional epidemiological and clinical differences between specific AdV species and types., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Antiviral treatment is recommended for all hospitalized children with suspected or confirmed influenza, regardless of their risk profile. Few data exist on adherence to these recommendations, so we sought to determine factors associated with influenza testing and antiviral treatment in children., Methods: Hospitalized children <18 years of age with acute respiratory illness (ARI) were enrolled through active surveillance at pediatric medical centers in seven cities between 11/1/2015 and 6/30/2016; clinical information was obtained from parent interview and chart review. We used generalized linear mixed-effects models to identify factors associated with influenza testing and antiviral treatment., Results: Of the 2299 hospitalized children with ARI enrolled during one influenza season, 51% (n = 1183) were tested clinically for influenza. Clinicians provided antiviral treatment for 61 of 117 (52%) patients with a positive influenza test versus 66 of 1066 (6%) with a negative or unknown test result. In multivariable analyses, factors associated with testing included neuromuscular disease (aOR = 5.35, 95% CI [3.58-8.01]), immunocompromised status (aOR = 2.88, 95% CI [1.66-5.01]), age (aOR = 0.93, 95% CI [0.91-0.96]), private only versus public only insurance (aOR = 0.78, 95% CI [0.63-0.98]), and chronic lung disease (aOR = 0.64, 95% CI [0.51-0.81]). Factors associated with antiviral treatment included neuromuscular disease (aOR = 1.86, 95% CI [1.04, 3.31]), immunocompromised state (aOR = 2.63, 95% CI [1.38, 4.99]), duration of illness (aOR = 0.92, 95% CI [0.84, 0.99]), and chronic lung disease (aOR = 0.60, 95% CI [0.38, 0.95])., Conclusion: Approximately half of children hospitalized with influenza during the 2015-2016 influenza season were treated with antivirals. Because antiviral treatment for influenza is associated with better health outcomes, further studies of subsequent seasons would help evaluate current use of antivirals among children and better understand barriers for treatment., (© 2021 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background Emergency department (ED) visits can be opportunities to address uncontrolled hypertension. We sought to compare short-term blood pressure measures between the Vanderbilt Emergency Room Bundle (VERB) intervention and usual care plus education. Methods and Results We conducted a randomized trial of 206 adult patients with hypertension and elevated systolic blood pressure (SBP) presenting to 2 urban emergency departments in Tennessee, USA. The VERB intervention included educational materials, a brief motivational interview, pillbox, primary care engagement letter, pharmacy resources, and 45 days of informational and reminder text messages. The education arm received a hypertension pamphlet. After 78 participants were enrolled, text messages requested confirmation of receipt. The primary clinical outcome was 30-day SBP. The median 30-day SBP was 122 and 126 mm Hg in the VERB and education arms, respectively. We estimated the mean 30-day SBP to be 3.98 mm Hg lower in the VERB arm (95% CI, -2.44 to 10.4; P =0.22). Among participants enrolled after text messages were adapted, the respective median SBPs were 121 and 130 mm Hg, and we estimated the mean 30-day SBP to be 8.57 mm Hg lower in the VERB arm (95% CI, 0.98‒16.2; P =0.027). In this subgroup, the median response rate to VERB text messages was 56% (interquartile range, [26%‒80%]). Conclusions This pilot study demonstrated feasibility and found an improvement in SBP for the subgroup for whom interactive messages were featured. Future studies should evaluate the role of interactive text messaging as part of a comprehensive emergency department intervention to improve blood pressure control. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02672787.

Estimation of local average treatment effects in randomized trials typically relies upon the exclusion restriction assumption in cases where we are unwilling to rule out the possibility of unmeasured confounding. Under this assumption, treatment effects are mediated through the post-randomization variable being conditioned upon, and directly attributable to neither the randomization itself nor its latent descendants. Recently, there has been interest in mobile health interventions to provide healthcare support. Mobile health interventions such as the Rapid Encouragement/Education and Communications for Health (REACH), designed to support self-management for adults with type 2 diabetes, often involve both one-way and interactive messages. In practice, it is highly likely that any benefit from the intervention is achieved both through receipt of the intervention content and through engagement with/response to it. Application of an instrumental variable analysis in order to understand the role of engagement with REACH (or a similar intervention) requires the traditional exclusion restriction assumption to be relaxed. We propose a conceptually intuitive sensitivity analysis procedure for the REACH randomized trial that places bounds on local average treatment effects. Simulation studies reveal this approach to have desirable finite-sample behavior and to recover local average treatment effects under correct specification of sensitivity parameters.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with increased morbidity and mortality in solid organ transplant (SOT) recipients. Despite exclusion from SARS-CoV-2 vaccine clinical trials, these individuals were identified as high-risk and prioritized for vaccination in public health guidelines., Methods: We prospectively evaluated humoral and cellular immune responses to two doses of the SARS-CoV-2 mRNA vaccine, BNT162b2, in 56 SOT recipients and 26 healthy controls (HCs). Blood specimens collected from participants prior to each dose and following the second dose were tested for SARS-CoV-2-specific antibodies, as well as CD4+ and CD8+ T-cell responses., Results: SOT recipients demonstrated lower mean anti-SARS-CoV-2 antibody levels compared to HCs after each dose, and only 21.6% achieved an antibody response after the second dose within the range of HC responses. Similarly, the percentage of responsive CD4+ and CD8+ T cells in SOT recipients was lower than in HCs. While most HCs showed notable humoral and cellular responses, responses were less concordant in SOT recipients, with some showing evidence of either humoral or cellular response, but not both., Conclusion: Humoral and cellular immune responses to the BNT162b2 vaccine are markedly reduced in SOT recipients as compared to HCs, suggesting that SOT recipients may benefit from more tailored regimens such as higher dose and/or additional vaccinations., (© 2021 Wiley Periodicals LLC.)

Objective: Guidance is needed on studying engagement and treatment effects in digital health interventions, including levels required for benefit. We evaluated multiple analytic approaches for understanding the association between engagement and clinical outcomes., Materials and Methods: We defined engagement as intervention participants' response rate to interactive text messages, and considered moderation, standard regression, mediation, and a modified instrumental variable (IV) analysis to investigate the relationship between engagement and clinical outcomes. We applied each approach to two randomized controlled trials featuring text message content in the intervention: REACH (Rapid Encouragement/Education and Communications for Health), which targeted diabetes, and VERB (Vanderbilt Emergency Room Bundle), which targeted hypertension., Results: In REACH, the treatment effect on hemoglobin A1c was estimated to be -0.73% (95% CI: [-1.29, -0.21]; P = 0.008), and in VERB, the treatment effect on systolic blood pressure was estimated to be -10.1 mmHg (95% CI: [-17.7, -2.8]; P = 0.007). Only the IV analyses suggested an effect of engagement on outcomes; the difference in treatment effects between engagers and non-engagers was -0.29% to -0.51% in the REACH study and -1.08 to -3.25 mmHg in the VERB study., Discussion: Standard regression and mediation have less power than a modified IV analysis, but the IV approach requires specification of assumptions. This is the first review of the strengths and limitations of various approaches to evaluating the impact of engagement on outcomes., Conclusions: Understanding the role of engagement in digital health interventions can help reveal when and how these interventions achieve desired outcomes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The rates of early-onset group B Streptococcus (GBS) disease (EOGBS) have declined since the implementation of universal screening and intrapartum antibiotic prophylaxis guidelines but late-onset (LOGBS) rates remain unchanged. Racial differences in GBS disease rates have been previously documented, with Black infants having higher rates of EOGBS and LOGBS, but it is not known if these have persisted. Therefore, we sought to determine the differences in EOGBS and LOGBS disease by race over the past decade in Tennessee., Methods: This study used active population-based and laboratory-based surveillance data for invasive GBS disease conducted through Active Bacterial Core surveillance in selected counties across Tennessee. We included infants younger than 90 days and who had invasive GBS disease between 2009 and 2018., Results: A total of 356 GBS cases were included, with 60% having LOGBS. EOGBS and LOGBS had decreasing temporal trends over the study period. Overall, there were no changes in temporal trend noted in the rates of EOGBS and LOGBS among White infants. However, Black infants had significantly decreasing EOGBS and LOGBS temporal trends (relative risk [95% confidence interval], .87 [.79, .96] [P = .007] and .90 [.84-.97] [P = .003], respectively)., Conclusions: Years after the successful implementation of the universal screening guidelines, our data revealed an overall decrease in LOGBS rates, primarily driven by changes among Black infants. More studies are needed to characterize the racial disparities in GBS rates, and factors driving them. Prevention measures such as vaccination are needed to have a further impact on disease rates., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections (ARIs) in hospitalized children. Although prematurity and underlying medical conditions are known risk factors, most of these children are healthy, and factors including RSV load and subgroups may contribute to severity. Therefore, we aimed to evaluate the role of RSV in ARI severity and determine factors associated with increased RSV-ARI severity in young children., Methods: Children aged <5 years with fever and/or ARI symptoms were recruited from the emergency department (ED) or inpatient settings at Vanderbilt Children's Hospital. Nasal and/or throat swabs were tested using quantitative reverse-transcription polymerase chain reaction for common respiratory viruses, including RSV. A severity score was calculated for RSV-positive children., Results: From November 2015 through July 2016, 898 participants were enrolled, and 681 (76%) had at least 1 virus detected, with 191 (28%) testing positive for RSV. RSV-positive children were more likely to be hospitalized, require intensive care unit admission, and receive oxygen compared with children positive for other viruses. Higher viral load, White race, younger age, and higher severity score were independently associated with hospitalization in RSV-positive children. No differences in disease severity were noted between RSV A and RSV B., Conclusions: RSV was associated with increased ARI severity in young children enrolled from the ED and inpatient settings, but no differences in disease severity were noted between RSV A and RSV B. These findings emphasize the need for antiviral therapy and/or preventive measures such as vaccines against RSV in young children., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Aims: Cribriform morphology, which includes intraductal carcinoma (IDCP) and invasive cribriform carcinoma, is an indicator of poor prognosis in prostate cancer. Phosphatase and tensin homologue (PTEN) loss is a predictor of adverse clinical outcomes. The association between PTEN expression and morphological patterns of prostate cancer is unclear., Methods and Results: We explored the association between PTEN expression by immunohistochemistry, Gleason pattern 4 morphologies, IDCP and biochemical recurrence (BCR) in 163 radical prostatectomy specimens. IDCP was delineated from invasive cribriform carcinoma by p63 positive immunohistochemical staining in basal cells. Combined invasive cribriform carcinoma and IDCP were associated with a higher cumulative incidence of BCR [hazard ratio (HR) = 5.06; 2.21, 11.6, P < 0.001]. When including PTEN loss in the analysis, invasive cribriform carcinoma remained predictive of BCR (HR = 3.72; 1.75, 7.94, P = 0.001), while PTEN loss within invasive cribriform carcinoma did not. Glomeruloid morphology was associated with lower odds of cancer stage pT3 and lower cumulative incidence of BCR (HR = 0.27; 0.088, 0.796, P = 0.018), while PTEN loss within glomeruloid morphology was associated with a higher cumulative incidence of BCR (HR = 4.07; 1.04, 15.9, P = 0.043)., Conclusions: PTEN loss within glomeruloid pattern was associated with BCR. The presence of any cribriform pattern was associated with BCR, despite PTEN loss not significantly associated with invasive cribriform carcinoma. We speculate that other drivers independent from PTEN loss may contribute to poor prognostic features in cribriform carcinoma., (© 2021 John Wiley & Sons Ltd.)

Background: Opioid analgesics are commonly prescribed to women after cesarean delivery. There is a growing effort to prescribe opioids judiciously; however, the risk of serious opioid-related events associated with specific prescribing patterns after cesarean delivery remains unclear., Objective: We examined the association between the dosage of the first opioid prescription filled after cesarean delivery and the risk of serious opioid-related events., Study Design: We identified opioid-naïve women with a cesarean delivery enrolled in Tennessee Medicaid (2007-2014). Pharmacy prescription fill data characterized opioids filled within 5 days after delivery. Patients were followed up from day 5 after delivery to the earliest of the following: serious opioid-related event (persistent opioid use, evidence of opioid use disorder [diagnosis or methadone or buprenorphine fill], overdose, or opioid-related death), non-opioid-related death, enrollment loss, or 365th day. We estimated the adjusted hazard ratios and 95% confidence intervals for the serious opioid-related event outcomes based on the dosage (morphine milligram equivalents) of the first filled opioid prescription, adjusting for baseline sociodemographic characteristics, delivery complications, multiple deliveries, comorbidities, and medication use. Secondary analyses examined the role of commonly prescribed opioid strengths and quantities., Results: The overall incidence rate of serious opioid-related events among women after cesarean delivery was 3.0 per 100 person-years. Compared with women who did not fill an opioid prescription, the rate of serious opioid-related events was higher among women who filled an opioid prescription, although only significantly higher among women who filled a total dosage of ≥100 morphine milligram equivalents (97.1% of opioid prescriptions). In the secondary analyses, women with a low prescribed daily opioid dosage and women with a low prescribed number of oxycodone (5 mg) tablets (<10 tablets) were not at increased risk of serious opioid-related events compared with women who did not fill an opioid prescription., Conclusion: Opioid-naïve women who filled a postpartum opioid prescription at commonly prescribed doses after cesarean delivery had an increased risk of serious opioid-related events compared to women who did not fill a postpartum opioid prescription. Low opioid doses were not associated with a significant increase in the risk of serious opioid-related events., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Norovirus is a leading cause of epidemic acute gastroenteritis (AGE), with most outbreaks occurring during winter. The majority of outbreaks are caused by GII.4 noroviruses; however, data to support whether this is true for sporadic medically attended AGE are limited. Therefore, we sought to compare the clinical characteristics and seasonality of GII.4 vs non-GII.4 viruses., Methods: Children aged 15 days -17 years with AGE symptoms were recruited from the outpatient, emergency department, and inpatient settings at Vanderbilt Children's Hospital, Davidson County, Nashville, Tennessee, from December 2012 -November 2015. Stool specimens were tested using qRT-PCR for GI and GII noroviruses and subsequently genotyped by sequencing a partial region of the capsid gene., Results: A total of 3705 patients were enrolled, and stool specimens were collected and tested from 2885 (78%) enrollees. Overall, 636 (22%) samples were norovirus-positive, of which 567 (89%) were GII. Of the 460 (81%) genotyped GII-positive samples, 233 (51%) were typed as GII.4 and 227 (49%) as non-GII.4. Compared with children with non-GII.4 infections, children with GII.4 infections were younger, more likely to have diarrhea, and more likely to receive oral rehydration fluids. Norovirus was detected year-round and peaked during winter., Conclusions: Approximately 40% of sporadic pediatric norovirus AGE cases were caused by GII.4 norovirus. Children infected with GII.4 had more severe symptoms that required more medical care. Seasonal variations were noticed among different genotypes. These data highlight the importance of continuous norovirus surveillance and provide important information on which strains pediatric norovirus vaccines should protect against., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

Importance: Medicaid work requirements seek to promote health and personal responsibility but can also jeopardize health care access. Physicians have a central function in assisting patients with exemption requests, but it is unclear how their role affects patient welfare, professionalism, and the ethical and legal justification of programs., Objective: To understand the degree of variability in physician response to assist patients with depression in receiving a Medicaid work requirement exemption., Design Setting and Participants: We conducted a mailed survey experiment among practicing primary care physicians in the first 4 approved states (Arkansas, Kentucky, Indiana, New Hampshire) in July and October of 2019. We report response, cooperation, refusal, and contact rates in line with American Association for Public Opinion Research (AAPOR) standards., Exposures: In each state, we used an experimental factorial design to randomize recipients to 1 of 4 patient clinical scenarios., Main Outcomes and Measures: The primary outcome was the indicator of willingness to assist a patient reporting depression with an exemption., Results: We received 715 responses (overall AAPOR response rate: 21%; cooperation rate: 84%; refusal rate: 4%; contact rate: 25%). Respondents' mean (SD) age was 54 (12) years; mean (SD) time since graduation, 26 (12) years; 435 (61%) identified as male; 177 as Democrat (25%); 156 as Republican (22%); 197 as Independent/other (28%); and 185 as declined/unknown (26%); the mean (SD) share of Medicaid patients was 29% (21%). We found that 97 of 387 physicians (25%) would offer assistance even when state policy would not support an exemption, and 170 of 315 (54%) would not offer assistance when regulations would require this. Moreover, 49 of 245 respondents (20%) who deemed an exemption appropriate indicated that they would not assist. State, administrative effort, political affiliation, and perceived appropriateness were statistically associated with the odds of assisting with an exemption., Conclusions and Relevance: In this survey study of primary care physicians, we found substantial variation regarding willingness to assist patients qualifying for a work requirement exemption where none should exist. Insofar as work requirements are implemented again, it is critical to proactively identify measures to ensure that patients qualifying for exemptions are not put at risk due to either the burdensomeness of exemption procedures, or physicians' political or personal views., Competing Interests: Conflict of Interest Disclosures: Drs Schmidt, Spieker, Szymczak, Grande reported grants from the Robert Wood Johnson Foundation’s Research in Transforming Health and Health Care Systems program (Grant # 76037) during the conduct of the study. No other disclosures were reported., (Copyright 2021 Schmidt H et al. JAMA Health Forum.)

Objectives: Nonpharmaceutical interventions against coronavirus disease 2019 likely have a role in decreasing viral acute respiratory illnesses (ARIs). We aimed to assess the frequency of respiratory syncytial virus (RSV) and influenza ARIs before and during the coronavirus disease 2019 pandemic., Methods: This study was a prospective, multicenter, population-based ARI surveillance, including children seen in the emergency departments and inpatient settings in 7 US cities for ARI. Respiratory samples were collected and evaluated by molecular testing. Generalized linear mixed-effects models were used to evaluate the association between community mitigation and number of eligible and proportion of RSV and influenza cases., Results: Overall, 45 759 children were eligible; 25 415 were enrolled and tested; 25% and 14% were RSV-positive and influenza-positive, respectively. In 2020, we noted a decrease in eligible and enrolled ARI subjects after community mitigation measures were introduced, with no RSV or influenza detection from April 5, 2020, to April 30, 2020. Compared with 2016-2019, there was an average of 10.6 fewer eligible ARI cases per week per site and 63.9% and 45.8% lower odds of patients testing positive for RSV and influenza, respectively, during the 2020 community mitigation period. In all sites except Seattle, the proportions of positive tests for RSV and influenza in the 2020 community mitigation period were lower than predicted., Conclusions: Between March and April 2020, rapid declines in ARI cases and the proportions of RSV and influenza in children were consistently noted across 7 US cities, which could be attributable to community mitigation measures against severe acute respiratory syndrome coronavirus 2., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Schuster receives support from Merck; Dr Williams is on boards for Quidel and GlaxoSmithKline; Dr Harrison’s institution receives support from GlaxoSmithKline, Merck, and Pfizer; Dr Englund is a consultant for Sanofi Pasteur and Meissa Vaccines and receives institutional research support from AstraZeneca, GlaxoSmithKline, Pfizer, and Novavax; Dr Halasa has grant funding from Sanofi and Quidel and received an honorarium from an educational grant from Genentech; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2021 by the American Academy of Pediatrics.)