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Background: Underrepresentation of racial and ethnic groups in clinical trials can limit generalizability of research findings and equitable access to treatment. This study evaluates racial and ethnic representation of youth in US-based interventional trials on childhood type 1 diabetes (T1D)., Methods: This cross-sectional study examined interventional trials of T1D conducted in the US and registered on ClinicalTrials.gov. Trials were included if completed as of June 6, 2023, began between years 2010 and 2022, and exclusively enrolled youth ≤19 years old. We assessed representation of racial and ethnic groups in T1D trials, estimated using the enrollment-prevalence difference (EPD)., Results: A total of 106 trials were eligible for inclusion. Of those eligible, 62 (58 %) trials reported participant race or ethnicity and were included in the analyses. Significant disparities in enrollment were observed for American Indian/Alaska Native, Asian/Pacific Islander, Black, and Hispanic youth compared to their respective contribution to disease burden among youth in the US. Disparities in trial enrollment were greatest for Black (EPD, -10.2; 95 % confidence interval [CI], -14.4 to -7.9) and Hispanic (EPD, -7.7; 95 % CI, -12.6 to -4.8) youth. EPDs of trials conducted prior to year 2017 did not differ significantly from those conducted as of year 2017., Conclusions: Historically marginalized racial and ethnic youth were underrepresented in T1D trials. Strategies to improve recruitment of these populations are needed to reduce inequities in diabetes treatment and outcomes., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Leukotriene-receptor antagonists (LTRA) and inhaled corticosteroids (ICS) are common controller medications for asthma, but limited studies examine their comparative risks on neuropsychiatric adverse events (NAEs) in patients with asthma., Objective: To investigate the comparative risks of LTRA versus ICS on 7 distinct categories of NAEs in patients with asthma at a nationwide level., Methods: We conducted a nationwide cohort study during 2010-2021. Incident NAEs and their clinical subgroups (eg, psychotic disorders, anxiety disorders, movement disorders, behavioral and emotional disorders, mood disorders, sleep-related disorders, and personality disorders) were assessed. Cox proportional hazards regressions were used to quantify the comparative risks., Results: There were 1,249,897 patients with asthma aged 6 to 64 years. Incidence rates for NAEs were 25.10 per 1000 person-years among patients treated with LTRA and 23.46 per 1000 person-years among those treated with ICS. The incidence rate difference was 1.64 (95% confidence interval [CI]: 0.30-2.98) per 1000 person-years. Positive associations of NAEs and 3 clinical subgroups were found in patients treated with LTRA compared with ICS (hazard ratios [HR]: 1.06 [95% CI: 1.00-1.12] for NAEs; HR: 1.88 [95% CI: 1.24-2.84] for psychotic disorders; HR: 1.10 [95% CI: 1.01-1.20] for anxiety disorders; and HR: 1.27 [95% CI: 1.02-1.58] for behavioral and emotional disorders), but not for movement disorders, mood disorders, sleep-related disorders, and personality disorders., Conclusions: This nationwide cohort study identified heightened risks, ranging from 6% to 88%, of NAEs and 3 clinical subgroups in patients with asthma treated with LTRA compared with ICS. These findings underscore the necessity for clinicians to communicate with patients regarding potential neuropsychiatric harms when prescribing LTRA., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Elective genomic testing (EGT) is increasingly available clinically. Limited real-world evidence exists about attitudes and knowledge of EGT recipients., Methods: After web-based education, patients who enrolled in an EGT program at a rural nonprofit health care system completed a survey that assessed attitudes, knowledge, and risk perceptions., Results: From August 2020 to April 2022, 5920 patients completed the survey and received testing. Patients most frequently cited interest in learning their personal disease risks as their primary motivation. Patients most often expected results to guide medication management (74.0%), prevent future disease (70.4%), and provide information about risks to offspring (65.4%). Patients were "very concerned" most frequently about the privacy of genetic information (19.8%) and how well testing predicted disease risks (18.0%). On average, patients answered 6.7 of 11 knowledge items correctly (61.3%). They more often rated their risks for colon and breast cancers as lower rather than higher than the average person but more often rated their risk for a heart attack as higher rather than lower than the average person (all P < .001)., Conclusion: Patients pursued EGT because of the utility expectations but often misunderstood the test's capabilities., Competing Interests: Conflict of Interest Robert C. Green, Kurt D. Christensen, Emilie S. Zoltick, Madison R. Hickingbotham, Jessica L. LeBlanc, and Lauren N. Galbraith were supported by a research grant from Sanford Health. Madison R. Hickingbotham, Madison R. Hickingbotham, Ann Chen Wu, Lauren N. Galbraith, and Jessica L. LeBlanc have been funded by National Center for Advancing Translational Sciences (NCATS), National Heart, Lung, and Blood Institute (NHLBI), and National Institute of Child Health and Human Development (NICHD). Ann Chen Wu has received grants from NICHD, NHLBI, and GlaxoSmithKline. Catherine Hajek is an employee of Helix OpCo. Christine Y. Lu undertook contract work with Illumina Inc outside the submitted work and has received research grants and contracts from National Human Genome Research Institute (NHGRI), NIMH, NICHD, National Cancer Institute, and Centers for Disease Control and Prevention. Emilie S. Zoltick has been funded by NIMHD. Hadley Stevens Smith has been funded by NHGRI and NICHD, has consulted for Illumina, Inc and received compensation, and has received compensation from Elsevier and the Eastern Society of Pediatric Research. Kurt D. Christensen has received research grants from NHGRI, NCATS, NHLBI, and NICHD. Lauren N. Galbraith is an employee of Pfizer, Inc. Robert C. Green has received compensation for advising the following companies: AIA, Allelica, Atria, Fabric, Genome Web, Genomic Life, Verily, and VinBigData; is cofounder of Genome Medical and Nurture Genomics; and has received research grants from NCATS, NHLBI, the Danaher Foundation, the Southcentral Foundation, GRAIL, and Beaumont Health. All other authors declare no conflicts of interest., (Copyright © 2024 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

CYP2C19 genotyping to guide antiplatelet therapy after patients develop acute coronary syndromes (ACS) or require percutaneous coronary interventions (PCIs) reduces the likelihood of major adverse cardiovascular events (MACE). Evidence about the impact of preemptive testing, where genotyping occurs while patients are healthy, is lacking. In patients initiating antiplatelet therapy for ACS or PCI, we compared medical records data from 67 patients who received CYP2C19 genotyping preemptively (results >7 days before need), against medical records data from 67 propensity score-matched patients who received early genotyping (results within 7 days of need). We also examined data from 140 patients who received late genotyping (results >7 days after need). We compared the impact of genotyping approaches on medication selections, specialty visits, MACE and bleeding events over 1 year. Patients with CYP2C19 loss-of-function alleles were less likely to be initiated on clopidogrel if they received preemptive rather than early or late genotyping (18.2%, 66.7%, and 73.2% respectively, p = 0.001). No differences were observed by genotyping approach in the number of specialty visits or likelihood of MACE or bleeding events (all p > 0.21). Preemptive genotyping had a strong impact on initial antiplatelet selection and a comparable impact on patient outcomes and healthcare utilization, compared to genotyping ordered after a need for antiplatelet therapy had been identified., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)

Background: The existing data on enrollment trends of historically underserved racial and ethnic children in clinical trials are limited., Objective: We sought to evaluate documentation and representation of race and ethnicity in pediatric asthma clinical trials in the United States., Methods: This is a cross-sectional study of United States-based interventional trials studying pediatric asthma that were completed between 2008 and 2022 and registered on ClinicalTrials.gov. Enrollment disparities were assessed by using the measure enrollment prevalence difference (EPD) (defined as the median difference between the proportion of participants enrolled and asthma prevalence in the US population by race and ethnicity)., Results: Of the 67 trials reviewed, 53 (79.2%) and 36 (53.7%) reported on race and ethnicity at ClinicalTrials.gov, respectively. Most participants were White (39.1%), Black (37.1%), or non-Hispanic (66.1%). Black, Hispanic, multiracial, and White children were enrolled in the expected proportions based on their contribution to asthma burden. However, American Indian or Alaska Native (AI/AN) (EPD = -1 [95% CI = -1 to -1]) and Asian children (EPD = -3 [95% CI = -3 to -3]) were underrepresented relative to disease burden in these respective groups. Fewer Black children were enrolled in drug or device trials (β = -0.80 [95% CI = -1.60 to -0.01]) than in other trials. Fewer Hispanic children were enrolled in early-phase than late-phase trials (β = -2.42 [95% CI = -3.66 to -1.19])., Conclusions: Enrollment in pediatric asthma trials conducted in the United States was commensurate with the demographics of children affected by asthma for most racial and ethnic groups, but American Indian or Alaska Native and Asian children were underrepresented. Concerted efforts are needed to promote inclusion of these underserved groups in future trials., Competing Interests: Supported by the 10.13039/100000133Agency for Healthcare Research and Quality (grant 2T32HS000063-30 [to A.T.G.]) and the 10.13039/100006545National Institute on Minority Health and Health Disparities (grant R21MD016984 [to M.O.]). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders were not involved in the design, analysis, or manuscript development. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (© 2024 The Author(s).)

Background: Asthma is routinely treated with inhaled corticosteroids (ICS). Asthma patients on ICS are at increased risk of adrenal suppression, a potentially serious effect of long-term glucocorticoid exposure; however, this relationship is poorly understood. Therefore, this study aims to identify metabolite biomarkers related to adrenal suppression in asthma patients taking ICS., Methods: A total of 571 urine metabolites from 200 children with asthma on ICS in the Pharmacogenetics of Adrenal Suppression with Inhaled Steroids (PASS) cohort were profiled. Samples were grouped by peak plasma cortisol measurement as adrenal sufficient (>350 nmol/L) or insufficient (≤350 nmol/L) (outcome). Regression and discriminant-based statistical models combined with network analyses were utilized to assess relationships between metabolites and the outcome. Finally, prioritized metabolites were validated using data from an ancillary study of the Childhood Asthma Management (CAMP) cohort with similar characteristics to PASS., Results: Ninety metabolites were significantly associated with adrenal suppression, of which 57 also could discriminate adrenal status. While 26 metabolites (primarily steroids) were present at lower levels in the adrenal insufficient patients, 14 were significantly elevated in this group; the top metabolite, mannitol/sorbitol, was previously associated with asthma exacerbations. Network analyses identified unique clusters of metabolites related to steroids, fatty acid oxidation, and nucleoside metabolism, respectively. Four metabolites including urocanic acid, acetylcarnitine, uracil, and sorbitol were validated in CAMP cohort for adrenal suppression., Conclusions: Urinary metabolites differ among asthma patients on ICS, by adrenal status. While steroid metabolites were reduced in patients with poor adrenal function, our findings also implicate previously unreported metabolites involved in amino acid, lipid, and nucleoside metabolism., (© 2024 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Background: Coronary artery calcium (CAC) is a marker of subclinical atherosclerosis and is a complex heritable trait with both genetic and environmental risk factors, including sex and smoking. Methods: We performed genome-wide association (GWA) analyses for CAC among all participants and stratified by sex in the COPDGene study ( n = 6144 participants of European ancestry and n = 2589 participants of African ancestry) with replication in the Diabetes Heart Study (DHS). We adjusted for age, sex, current smoking status, BMI, diabetes, self-reported high blood pressure, self-reported high cholesterol, and genetic ancestry (as summarized by principal components computed within each racial group). For the significant signals from the GWA analyses, we examined the single nucleotide polymorphism (SNP) by sex interactions, stratified by smoking status (current vs. former), and tested for a SNP by smoking status interaction on CAC. Results: We identified genome-wide significant associations for CAC in the chromosome 9p21 region [ CDKN2B-AS1 ] among all COPDGene participants ( p = 7.1 × 10 -14 ) and among males ( p = 1.0 × 10 -9 ), but the signal was not genome-wide significant among females ( p = 6.4 × 10 -6 ). For the sex stratified GWA analyses among females, the chromosome 6p24 region [ PHACTR1 ] had a genome-wide significant association ( p = 4.4 × 10 -8 ) with CAC, but this signal was not genome-wide significant among all COPDGene participants ( p = 1.7 × 10 -7 ) or males ( p = 0.03). There was a significant interaction for the SNP rs9349379 in PHACTR1 with sex ( p = 0.02), but the interaction was not significant for the SNP rs10757272 in CDKN2B-AS1 with sex ( p = 0.21). In addition, PHACTR1 had a stronger association with CAC among current smokers ( p = 6.2 × 10 -7 ) than former smokers ( p = 7.5 × 10 -3 ) and the SNP by smoking status interaction was marginally significant ( p = 0.03). CDKN2B-AS1 had a strong association with CAC among both former ( p = 7.7 × 10 -8 ) and current smokers ( p = 1.7 × 10 -7 ) and the SNP by smoking status interaction was not significant ( p = 0.40). Conclusions: Among current and former smokers of European ancestry in the COPDGene study, we identified a genome-wide significant association in the chromosome 6p24 region [ PHACTR1 ] with CAC among females, but not among males. This region had a significant SNP by sex and SNP by smoking interaction on CAC.

Background: Evidence on the comparative effectiveness of respiratory biologics remains sparse., Objective: We sought to evaluate the comparative effectiveness of omalizumab, mepolizumab, benralizumab, and dupilumab in a matched retrospective cohort of patients with asthma., Methods: We identified patients with asthma aged ≥18 years who were incident users of these biologics between November 1, 2018, and June 30, 2023, in administrative claims data from the Food and Drug Administration's Sentinel System and Merative MarketScan Commercial Database. We compared asthma-related exacerbations and hospitalizations in the 12 months since biologic prescription in pairwise comparisons of propensity score-matched cohorts. Covariates used in matching included age, sex, allergic comorbidities, baseline asthma medications use, and the Charlson Comorbidity Index. Incidence rate ratios (IRR) and 95% confidence intervals (CI) were estimated using negative binomial regression models., Results: A total of 893 patients on mepolizumab, 1300 on benralizumab, 1170 on omalizumab, and 1863 on dupilumab were identified. The average age was 55 years, and two-thirds of the participants were female. At baseline, over 80% of these individuals had an active prescription for an inhaled corticosteroid. Almost half of patients on dupilumab had concomitant nasal polyposis compared with 6% to 13% of patients on the other biologics. Covariates were balanced after matching. In matched analyses, dupilumab was associated with the lowest incidence of exacerbations over the follow-up period (vs dupilumab): mepolizumab (IRR: 1.36; 95% CI: 1.12, 1.64), omalizumab (IRR: 1.33; 95% CI: 1.13, 1.58), benralizumab (IRR: 1.19; 95% CI: 1.00, 1.41). For exacerbations leading to hospitalizations, benralizumab and mepolizumab were associated with the lowest incidence of hospitalizations, and the greatest difference was between mepolizumab versus dupilumab (IRR: 0.76; 95% CI: 0.56, 1.03)., Conclusions: Dupilumab was associated with the lowest incidence of overall exacerbations, and mepolizumab with the lowest incidence of asthma hospitalizations in this administrative claims-based cohort of individuals with asthma. Despite matching propensity scores, residual confounding, such as baseline eosinophil count, may explain some of these findings., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Depression is heritable, differs by sex, and has environmental risk factors such as cigarette smoking. However, the effect of single nucleotide polymorphisms (SNPs) on depression through cigarette smoking and the role of sex is unclear. In order to examine the association of SNPs with depression and smoking in the UK Biobank with replication in the COPDGene study, we used counterfactual-based mediation analysis to test the indirect or mediated effect of SNPs on broad depression through the log of pack-years of cigarette smoking, adjusting for age, sex, current smoking status, and genetic ancestry (via principal components). In secondary analyses, we adjusted for age, sex, current smoking status, genetic ancestry (via principal components), income, education, and living status (urban vs. rural). In addition, we examined sex-stratified mediation models and sex-moderated mediation models. For both analyses, we adjusted for age, current smoking status, and genetic ancestry (via principal components). In the UK Biobank, rs6424532 [ LOC105378800 ] had a statistically significant indirect effect on broad depression through the log of pack-years of cigarette smoking ( p = 4.0 × 10 -4 ) among all participants and a marginally significant indirect effect among females ( p = 0.02) and males ( p = 4.0 × 10 -3 ). Moreover, rs10501696 [ GRM5 ] had a marginally significant indirect effect on broad depression through the log of pack-years of cigarette smoking ( p = 0.01) among all participants and a significant indirect effect among females ( p = 2.2 × 10 -3 ). In the secondary analyses, the sex-moderated indirect effect was marginally significant for rs10501696 [ GRM5 ] on broad depression through the log of pack-years of cigarette smoking ( p = 0.01). In the COPDGene study, the effect of an SNP (rs10501696) in GRM5 on depressive symptoms and medication was mediated by log of pack-years ( p = 0.02); however, no SNPs had a sex-moderated mediated effect on depressive symptoms. In the UK Biobank, we found SNPs in two genes [ LOC105378800 , GRM5 ] with an indirect effect on broad depression through the log of pack-years of cigarette smoking. In addition, the indirect effect for GRM5 on broad depression through smoking may be moderated by sex. These results suggest that genetic regions associated with broad depression may be mediated by cigarette smoking and this relationship may be moderated by sex.

Purpose: To identify sociodemographic factors associated with the visual outcomes of retinoblastoma survivors., Methods: Retrospective cohort study using a US-based clinical data registry. All individuals < 18 years of age with a history of retinoblastoma in the Intelligent Research in Sight (IRIS®) Registry (1/1/2013-12/31/2020). The primary outcome was visual acuity below the threshold for legal blindness (20/200 or worse) in at least one eye. Multivariable logistic regression was used to evaluate the association between visual outcomes and age, sex, laterality, race, ethnicity, type of insurance, and geographic location., Results: This analysis included 1545 children with a history of retinoblastoma. The median length of follow-up was 4.1 years (IQR, 2.2-5.9 years) and the median age at most recent clinical visit was 12 years (IQR, 8-16 years). Retinoblastoma was unilateral in 54% of cases. Poor vision in at least one eye was identified in 78% of all children and poor vision in both eyes in 17% of those with bilateral disease. Poor visual outcomes were associated with unilateral diagnosis (OR, 1.55; 95% CI,1.13-2.12; p  = .007), Black race (OR, 2.03; 95% CI, 1.19-3.47; p  = .010), Hispanic ethnicity (OR, 1.65; 95% CI, 1.16-2.37; p  = .006), and non-private insurance (OR, 1.47; 95% CI, 1.02-2.10; p  = .037)., Conclusions: Poor visual outcomes appear to be more common among Black, Hispanic, and publicly insured children with a history of retinoblastoma, raising concerns regarding healthcare inequities. Primary care physicians should ensure that young children receive red reflex testing during routine visits and consider retinoblastoma in the differential diagnosis of abnormal eye exams.

Inhaled corticosteroids (ICS) are efficacious in the treatment of asthma, which affects more than 300 million people in the world. While genome-wide association studies have identified genes involved in differential treatment responses to ICS in asthma, few studies have evaluated the effects of combined rare and common variants on ICS response among children with asthma. Among children with asthma treated with ICS with whole exome sequencing (WES) data in the PrecisionLink Biobank (91 White and 20 Black children), we examined the effect and contribution of rare and common variants with hospitalizations or emergency department visits. For 12 regions previously associated with asthma and ICS response ( DPP10 , FBXL7 , NDFIP1 , TBXT , GLCCI1 , HDAC9 , TBXAS1, STAT6 , GSDMB/ORMDL3 , CRHR1 , GNGT2 , FCER2 ), we used the combined sum test for the sequence kernel association test (SKAT) adjusting for age, sex, and BMI and stratified by race. Validation was conducted in the Biorepository and Integrative Genomics (BIG) Initiative (83 White and 134 Black children). Using a Bonferroni threshold for the 12 regions tested (i.e., 0.05/12 = 0.004), GSDMB/ORMDL3 was significantly associated with ICS response for the combined effect of rare and common variants ( p -value = 0.003) among White children in the PrecisionLink Biobank and replicated in the BIG Initiative ( p -value = 0.02). Using WES data, the combined effect of rare and common variants for GSDMB/ORMDL3 was associated with ICS response among asthmatic children in the PrecisionLink Biobank and replicated in the BIG Initiative. This proof-of-concept study demonstrates the power of biobanks of pediatric real-life populations in asthma genomic investigations.

Background: Although inhaled corticosteroids (ICS) are the first-line therapy for patients with persistent asthma, many patients continue to have exacerbations. We developed machine learning models to predict the ICS response in patients with asthma., Methods: The subjects included asthma patients of European ancestry ( n = 1371; 448 children; 916 adults). A genome-wide association study was performed to identify the SNPs associated with ICS response. Using the SNPs identified, two machine learning models were developed to predict ICS response: (1) least absolute shrinkage and selection operator (LASSO) regression and (2) random forest., Results: The LASSO regression model achieved an AUC of 0.71 (95% CI 0.67-0.76; sensitivity: 0.57; specificity: 0.75) in an independent test cohort, and the random forest model achieved an AUC of 0.74 (95% CI 0.70-0.78; sensitivity: 0.70; specificity: 0.68). The genes contributing to the prediction of ICS response included those associated with ICS responses in asthma ( TPSAB1, FBXL16 ), asthma symptoms and severity ( ABCA7, CNN2, PTRN3, and BSG/CD147 ), airway remodeling ( ELANE, FSTL3 ), mucin production ( GAL3ST ), leukotriene synthesis ( GPX4 ), allergic asthma ( ZFPM1, SBNO2 ), and others., Conclusions: An accurate risk prediction of ICS response can be obtained using machine learning methods, with the potential to inform personalized treatment decisions. Further studies are needed to examine if the integration of richer phenotype data could improve risk prediction.

Asthma is a chronic respiratory disease with widespread prevalence that affects children, adolescents, and adults. Asthma morbidity and mortality can be exacerbated in the setting of housing insecurity. In this Grand Rounds Review article, we present a case and discuss the implications that housing insecurity has on asthma outcomes in the United States. We then highlight ways in which providers can advocate for patients with asthma and housing insecurity., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Asthma exacerbations reflect disease severity, affect morbidity and mortality, and may lead to declining lung function. Inflammatory endotypes ( e.g. T2-high (eosinophilic)) may play a key role in asthma exacerbations. We aimed to assess whether genetic susceptibility underlies asthma exacerbation risk and additionally tested for an interaction between genetic variants and eosinophilia on exacerbation risk., Methods: UK Biobank data were used to perform a genome-wide association study of individuals with asthma and at least one exacerbation compared to individuals with asthma and no history of exacerbations. Individuals with asthma were identified using self-reported data, hospitalisation data and general practitioner records. Exacerbations were identified as either asthma-related hospitalisation, general practitioner record of asthma exacerbation or an oral corticosteroid burst prescription. A logistic regression model adjusted for age, sex, smoking status and genetic ancestry via principal components was used to assess the association between genetic variants and asthma exacerbations. We sought replication for suggestive associations (p<5×10 -6 ) in the GERA cohort., Results: In the UK Biobank, we identified 11 604 cases and 37 890 controls. While no variants reached genome-wide significance (p<5×10 -8 ) in the primary analysis, 116 signals were suggestively significant (p<5×10 -6 ). In GERA, two single nucleotide polymorphisms (rs34643691 and rs149721630) replicated (p<0.05), representing signals near the NTRK3 and ABCA13 genes., Conclusions: Our study has identified reproducible associations with asthma exacerbations in the UK Biobank and GERA cohorts. Confirmation of these findings in different asthma subphenotypes in diverse ancestries and functional investigation will be required to understand their mechanisms of action and potentially inform therapeutic development., Competing Interests: Conflict of interest: M. Tobin received funding from Orion Pharma and GSK, outside the submitted work. Conflict of interest: L. Lahousse received consulting from AstraZeneca, and honoraria from IPSA vzw and Chiesi, all outside the submitted work; and is a leading member of the European and Belgian Respiratory Societies. Conflict of interest: A. Edris, K. Voorhies, A.C. Wu, S.M. Lutz, I. Hall, C. Iribarren and K. Fawcett declare no conflict of interest., (Copyright ©The authors 2024.)

Background: Asthma has a high healthcare burden globally, with up to 10% of the asthma population suffering from severe disease. Biologic agents are a newer class of asthma treatments for severe asthma, with good evidence for efficacy in clinical trials. Nevertheless, real-world studies of its impact on clinical outcomes are limited. Methods: This is an observational cohort study using administrative claims data. The study population consisted of patients aged ≥18 years who had a diagnosis of asthma and initiated mepolizumab after November 4, 2015 and had continuous medical and drug coverage in both the 365 days prior to and following mepolizumab initiation. In patients treated with mepolizumab, we described clinically significant asthma exacerbations by minimum continuous treatment thresholds following initiation of mepolizumab, medication switching patterns and chronic oral corticosteroid (≥28 days) use. Results: We identified 2,536 adults with asthma who initiated mepolizumab. There was an association toward reduction in severe asthma-related events over the first one year of exposure. We observed associations with reduced dispensings of oral corticosteroids over the first year after mepolizumab initiation. Very few patients switched to other biologics during the study period. Conclusions: Treatment with mepolizumab may be associated with fewer asthma-related events in the first year. Over the first one year after initiating mepolizumab, we found associations with decreased concomitant dispensings of oral corticosteroids and medium to high dose ICS/LABA. Additionally, most patients who initiated mepolizumab did not switch to other biologics.

Background: Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features., Objective: We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRS Asthma ) and spirometry (FEV 1 and FEV 1 /forced vital capacity; PRS spiro ) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO)., Methods: We developed and tested 2 asthma PRSs and applied the higher performing PRS Asthma and a previously published PRS spiro to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry., Results: In meta-analyses of 102,477 participants, the PRS Asthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRS spiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRS spiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRS spiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRS Asthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRS spiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRS Asthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRS spiro was associated with asthma exacerbations in White, LatinX, and East Asian participants., Conclusions: PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts., (Published by Elsevier Inc.)

Oral corticosteroids (OCS) are commonly prescribed for acute, self-limited conditions, despite studies demonstrating toxicity. Studies evaluating longitudinal OCS prescribing in the general population are scarce and do not compare use across countries. This study investigated and compared OCS prescription patterns from 2009 to 2018 in the general populations of the United States, Taiwan, and Denmark. This international population-based longitudinal cohort study used nationwide claims databases (United States: Optum Clinformatics Data Mart; de-identified; Taiwan: National Health Insurance Research Database; and Denmark: National Prescription and Patient Registries/Danish National Patient Registry) to evaluate OCS prescribing. We classified annual OCS duration as short-term (1-29 days), medium-term (30-89 days), or long-term (≥90 days). Longitudinal change in annual prevalence of OCS use and physician prescribing patterns were reported. Among 54,630,437 participants, average annual percentage of overall OCS use was 6.8% in the United States, 17.5% in Taiwan, and 2.2% in Denmark during 2009-2018. Prevalence of OCS prescribing increased at an average annual rate of 0.1%-0.17%, mainly driven by short-term prescribing to healthy adults. One-quarter to one-fifth of OCS prescribing was associated with a diagnosis of respiratory infection. Family practice and internal medicine physicians were among the highest OCS prescribers across countries and durations. Age- and sex-stratified trends mirrored unstratified trends. This study provides real-world evidence of an ongoing steady increase in OCS use in the general populations of the United States, Taiwan, and Denmark. This increase is largely driven by short-term OCS prescribing to healthy adults, a practice previously viewed as safe but recently shown to incur substantial population-level risk., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Importance: Untreated refractive error contributes to the racial, ethnic, and socioeconomic disparities in visual function of adolescent children in the US., Objective: To describe patterns in vision testing as a function of age among US adolescents and identify sociodemographic factors associated with vision testing., Design, Setting, and Participants: This cross-sectional study used data from the National Survey of Children's Health (2018-2019), a nationally representative survey of the noninstitutionalized US pediatric population. A total of 24 752 adolescent children (aged 12 to <18 years) were included. Data were analyzed from March 22 to August 11, 2023., Main Outcomes and Measures: The primary outcome was the caregiver report of vision testing within the last 12 months. Linear regression was used to describe the patterns in reported vision testing as a function of participant age. Logistic regression was used to describe the association of sociodemographic factors with the report of vision testing in each setting., Results: Among 24 752 adolescents, the median (IQR) age was 14 (13-16) years; 12 918 (weighted, 51%) were male. Vision testing in any setting within the previous year was reported by caregivers of 18 621 adolescents (weighted, 74%). Vision testing was reported to have occurred at an eye clinic in 13 323 participants (weighted, 51%), at a primary care clinic in 5230 participants (weighted, 22%), at a school in 2594 participants (weighted, 11%), and at a health center in 635 participants (weighted, 4%). The percentage of adolescents reported to have vision tested decreased with age (-1.3% per year; 95% CI, -2.5% to 0% per year) due to a decrease in testing in primary care and school settings. After adjusting for age and sex, there were lower odds of vision testing reported for adolescents who were uninsured vs insured (adjusted odds ratio [AOR], 0.81; 95% CI, 0.76-0.87), had caregivers with less than vs greater than high school education (AOR, 0.89; 95% CI, 0.84-0.95), and were from a family born outside vs inside the US (AOR, 0.90; 95% CI, 0.82-0.98)., Conclusions and Relevance: In this cross-sectional study, vision testing in adolescents decreased as a function of age due to fewer reported tests performed in primary care and school-based settings. Relative to children in socioeconomically advantaged families, those from disadvantaged families were less likely to report receiving vision testing in clinical settings. Efforts to expand the role of school-based vision testing for older adolescents from disadvantaged backgrounds may enable opportunities to address disparities in untreated refractive error.

The growing dependence on social media for health-related information boomed during the COVID-19 pandemic, posing unprecedented challenges in navigating the vast amounts of information available right at our fingertips. Social media had a major impact on clinical decision-making affecting individuals, communities, and societies at large. In this review, we discuss the role of social media in amplifying information and misinformation as well as factors contributing to its reliance and prevalence. We review how medical providers have been impacted by this changing landscape, useful communication strategies to employ with in-office patient encounters, and how we can be active players in using social media as a tool for health promotion, correcting misinformation, and preparing for future pandemics., (Copyright © 2023. Published by Elsevier Inc.)

Background: Antenatal corticosteroids are considered the standard of care for pregnant women at risk for preterm birth, but studies examining their potential risks are scarce. We aimed to estimate the associations of antenatal corticosteroids with three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding, in pregnant women., Methods: Of 2,157,321 pregnant women, 52,119 at 24 weeks 0/7 days to 36 weeks 6/7 days of gestation were included in this self-controlled case series study during the study period of 2009-2018. We estimated incidence rates of three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding. Conditional Poisson regression was used to calculate incidence rate ratios (IRRs) for comparing incidence rates of the adverse events in each post-treatment period compared to those during the baseline period among pregnant women exposed to a single course of antenatal corticosteroid treatment., Results: Among 52,119 eligible participants who received antenatal corticosteroid treatment, the estimated incidence rates per 1000 person-years were 0.76 (95% confidence interval (CI): 0.69-0.83) for sepsis, 0.31 (95% CI: 0.27-0.36) for heart failure, and 11.57 (95% CI: 11.27-11.87) for gastrointestinal bleeding. The IRRs at 5 ~ 60 days after administration of antenatal corticosteroids were 5.91 (95% CI: 3.10-11.30) for sepsis and 4.45 (95% CI: 2.63-7.55) for heart failure, and 1.26 (95% CI: 1.02-1.55) for gastrointestinal bleeding; and the IRRs for days 61 ~ 180 were 2.00 (95% CI: 1.01-3.96) for sepsis, 3.65 (95% CI: 2.14-6.22) for heart failure, and 1.81 (95% CI: 1.56-2.10) for gastrointestinal bleeding., Conclusions: This nationwide population-based study suggests that a single course of antenatal corticosteroids is significantly associated with a 1.3- to 5.9-fold increased risk of sepsis, heart failure, and gastrointestinal bleeding in pregnant women. Maternal health considerations, including recommendations for adverse event monitoring, should be included in future guidelines for antenatal corticosteroid treatment., (© 2023. The Author(s).)

Objective: To investigate the associations between exposure to antenatal corticosteroids and serious infection in children during the first three, six, and 12 months of life., Design: Nationwide cohort study., Setting: National Health Insurance Research Database, Birth Reporting Database, and Maternal and Child Health Database, 1 January 2008 to 31 December 2019, to identify all pregnant individuals and their offspring in Taiwan., Participants: 1 960 545 pairs of pregnant individuals and their singleton offspring. 45 232 children were exposed and 1 915 313 were not exposed to antenatal corticosteroids., Main Outcome Measures: Incidence rates were estimated for overall serious infection, sepsis, pneumonia, acute gastroenteritis, pyelonephritis, meningitis or encephalitis, cellulitis or soft tissue infection, septic arthritis or osteomyelitis, and endocarditis during the first three, six, and 12 months of life in children exposed versus those not exposed to antenatal corticosteroids. Cox proportional hazards models were performed to quantify adjusted hazard ratios with 95% confidence intervals for each study outcome., Results: The study cohort was 1 960 545 singleton children: 45 232 children were exposed to one course of antenatal corticosteroids and 1 915 313 children were not exposed to antenatal corticosteroids. The adjusted hazard ratios for overall serious infection, sepsis, pneumonia, and acute gastroenteritis among children exposed to antenatal corticosteroids were significantly higher than those not exposed to antenatal corticosteroids during the first six months of life (adjusted hazard ratio 1.32, 95% confidence interval 1.18 to 1.47, P<0.001, for overall serious infection; 1.74, 1.16 to 2.61, P=0.01, for sepsis; 1.39, 1.17 to 1.65, P<0.001, for pneumonia; and 1.35, 1.10 to 1.65, P<0.001, for acute gastroenteritis).Similarly, the adjusted hazard ratios for overall serious infection (P<0.001), sepsis (P=0.02), pneumonia (P<0.001), and acute gastroenteritis (P<0.001) were significantly higher from birth to 12 months of life. In the sibling matched cohort, the results were comparable with those observed in the whole cohort, with a significantly increased risk of sepsis in the first six (P=0.01) and 12 (P=0.04) months of life., Conclusions: This nationwide cohort study found that children exposed to one course of antenatal corticosteroids were significantly more likely to have an increased risk of serious infection during the first 12 months of life. These findings suggest that before starting treatment, the long term risks of rare but serious infection associated with antenatal corticosteroids should be carefully weighed against the benefits in the perinatal period., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: High-deductible health plans with health savings accounts (HDHP-HSAs) incentivize patients to use less health care, including necessary care. Preventive drug lists (PDLs) exempt high-value medications from the deductible, reducing out-of-pocket cost sharing; the associations of PDLs with health outcomes among patients with asthma is unknown., Objective: To evaluate the associations of a PDL for asthma medications on utilization, adverse outcomes, and patient spending for HDHP-HSA enrollees with asthma., Design, Setting, and Participants: This case-control study used matched groups of patients with asthma before and after an insurance design change using a national commercial health insurance claims data set from 2004-2017. Participants included patients aged 4 to 64 years enrolled for 1 year in an HDHP-HSA without a PDL in which asthma medications were subject to the deductible who then transitioned to an HDHP-HSA with a PDL that included asthma medications; these patients were compared with a matched weighted sample of patients with 2 years of continuous enrollment in an HDHP-HSA without a PDL. Models controlled for patient demographics and asthma severity and were stratified by neighborhood income. Analyses were conducted from October 2020 to June 2023., Exposures: Employer-mandated addition of a PDL that included asthma medications to an existing HDHP-HSA., Main Outcomes and Measures: Outcomes of interest were utilization of asthma medications on the PDL (controllers and albuterol), asthma exacerbations (oral steroid bursts and asthma-related emergency department use), and out-of-pocket spending (all and asthma-specific)., Results: A total of 12 174 participants (mean [SD] age, 36.9 [16.9] years; 6848 [56.25%] female) were included in analyses. Compared with no PDL, PDLs were associated with increased rates of 30-day fills per enrollee for any controller medication (change, 0.10 [95% CI, 0.03 to 0.17] fills per enrollee; 12.9% increase) and for combination inhaled corticosteroid long-acting β2-agonist (ICS-LABA) medications (change, 0.06 [95% CI, 0.01 to 0.10] fills per enrollee; 25.4% increase), and increased proportion of days covered with ICS-LABA (6.0% [0.7% to 11.3%] of days; 15.6% increase). Gaining a PDL was associated with decreased out-of-pocket spending on asthma care (change, -$34 [95% CI, -$47 to -$21] per enrollee; 28.4% difference), but there was no significant change in asthma exacerbations and no difference in results by income., Conclusions and Relevance: In this case-control study, reducing cost-sharing for asthma medications through a PDL was associated with increased adherence to controller medications, notably ICS-LABA medications used by patients with more severe asthma, but was not associated with improved clinical outcomes. These findings suggest that PDLs are a potential strategy to improve access and affordability of asthma care for patients in HDHP-HSAs.

Background: SLCO1B1 variants are known to be a strong predictor of statin-associated muscle symptoms (SAMS) risk with simvastatin. Methods: The authors conducted a retrospective chart review on 20,341 patients who had SLCO1B1 genotyping to quantify the uptake of clinical decision support (CDS) for genetic variants known to impact SAMS risk. Results: A total of 182 patients had 417 CDS alerts generated, and 150 of these patients (82.4%) received pharmacotherapy that did not increase risks for SAMS. Providers were more likely to cancel simvastatin orders in response to CDS alerts if genotyping had been done prior to the first simvastatin prescription than after (94.1% vs 28.5%, respectively; p < 0.001). Conclusion: CDS significantly reduces simvastatin prescribing at doses associated with SAMS.

Introduction: Older adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults., Methods: A genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases., Results: In 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six near PTCHD4 validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p<5 × 10 -5 were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci for CPED1 , CRADD and DST for the OCS burst outcome and GM2A , SNW1 , CACNA1C , DPH1 , and RPS10 for the asthma-related exacerbation outcome., Conclusions: Multiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, including PTCHD4 ., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Population newborn genetic screening for hypertrophic cardiomyopathy (HCM) is feasible, however its benefits, harms, and cost-effectiveness are uncertain., Methods: We developed a microsimulation model to simulate a US birth cohort of 3.7 million newborns. Those identified with pathogenic/likely pathogenic variants associated with increased risk of HCM underwent surveillance and recommended treatment, whereas in usual care, individuals with family histories of HCM underwent surveillance., Results: In a cohort of 3.7 million newborns, newborn genetic screening would reduce HCM-related deaths through age 20 years by 44 (95% uncertainty interval [UI] = 10-103) however increase the numbers of children undergoing surveillance by 8127 (95% UI = 6308-9664). Compared with usual care, newborn genetic screening costs $267,000 per life year saved (95% UI, $106,000 to $919,000 per life year saved)., Conclusion: Newborn genetic screening for HCM could prevent deaths but at a high cost and would require many healthy children to undergo surveillance. This study shows how modeling can provide insights into the tradeoffs between benefits and costs that will need to be considered as newborn genetic screening is more widely adopted., Competing Interests: Conflict of Interest K.D.C. received a grant from Sanford Health outside the submitted work. C.Y.L. undertook contract work with Illumina Inc outside the submitted work. All other authors report no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

The pursuit of activating the HDAC inhibitory template towards additional mechanisms spurred us to design dual modulators (Sig-1R agonist - HDAC inhibitor) via utilization of the core structural unit of donepezil (an FDA-approved anti-Alzheimer's agent) as a surface recognition part. Literature precedents coupled with our experience rendered us with several insights that led to the inclusion of chemically diverse linkers and hydroxamic acid (zinc-binding motif) as the other components of HDAC inhibitory pharmacophore. With this envisionment and clarity, donepezil-based HDAC inhibitory adducts were furnished and exhaustively explored for their anti-GBM efficacy. Resultantly, a magnificently potent HDAC inhibitor 10 [IC 50 (HDAC6) = 2.7 nM, IC 50 (HDAC2) = 0.71 μM] was pinpointed that was endowed with the ability to: i) exert cell growth inhibitory effects against Human U87MG GBM cells ii) cause death in TMZ-resistant GBM cells iii) induce subG1 arrest in GBM cells iv) prolong the survival of TMZ-resistant U87MG inoculated orthotopic mice (in-vivo studies) v) induce GBM cell apoptosis via binding to Sig-1R. Collectively, the results led to the identification of compound 10 as a tractable anti-GBM agent that deserves detailed investigation for the accomplishment of its candidature as a GBM therapeutic., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jing-Ping Liou reports financial support was provided by the Ministry of Science and Technology, Taiwan., (Copyright © 2022. Published by Elsevier Masson SAS.)

Telemedicine uptake in allergy/immunology was slow before the coronavirus disease 2019 pandemic, but has accelerated since. This review examines where telemedicine has been in allergy/immunology and where it is headed in the future. Focus is placed on patient, physician, and health care professional satisfaction with telemedicine, capacity to expand access to allergy/immunology care, cost considerations, the regulatory environment, and future applications of telemedicine including adherence monitoring, wearable biosensors, artificial intelligence, and machine learning addressed., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

One of the most compelling arguments for telemedicine is its potential to increase health care access by making care more affordable for patients and families, including those affected by asthma. This goal is critically important in the United States, where the high cost of asthma care is associated with nonadherence to preventive care regimens and suboptimal health outcomes. In this clinical commentary review, we draw from the literature and our own research to identify opportunities for and challenges to leveraging telemedicine to reduce the financial burden of asthma care. Our interviews with 42 families affected by asthma during the COVID-19 pandemic suggest that under favorable circumstances, telemedicine can meaningfully reduce costs, including those related to transportation and missed work, while offering high-quality care. However, families also identified ways in which telemedicine can increase costs. For example, some reported reduced access to support services and material resources such as medication samples, which they relied on to manage costs. In this way, our findings underscore the need for careful care coordination and communication in telemedicine. We conclude by discussing the 4Rs, a structured communication approach designed to support cost conversations, increase care coordination, and help families reduce asthma care cost burden., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Asthma is the most common chronic health condition among children in the United States. The adverse impacts of social determinants of health often manifest in unmet health-related social needs, potentially contributing to worse asthma outcomes. With the onset and rapid spread of coronavirus disease 2019 (COVID-19) and the identification of asthma as a potential risk factor for more severe disease, our asthma program quickly pivoted to a remote-access telemedicine asthma population management platform to best meet the needs of our most at-risk patients. Our practice provides care to a large proportion of Black and Latino/a/e children in urban areas insured by the State Medicaid Program and impacted by unmet social needs. As we pivoted to telemedicine, we consistently reached a greater number of patients and families than prepandemic and observed decreased emergency department visits and hospitalizations. About 1 in 5 families received resource touch points spanning categories of transportation, food and supplies, clothing, utilities, and rent. Overall, families reported positive experiences with telemedicine, including the ability to connect remotely with our social work and resource teams. Telemedicine may be an effective strategy for addressing both the medical and the social needs of children with asthma at risk for worse outcomes., (Copyright © 2022. Published by Elsevier Inc.)

The directionality of gene promoters-the ratio of protein-coding over divergent noncoding transcription-is highly variable. How promoter directionality is controlled remains poorly understood. Here, we show that the chromatin remodelling complex RSC and general regulatory factors (GRFs) dictate promoter directionality by attenuating divergent transcription relative to protein-coding transcription. At gene promoters that are highly directional, depletion of RSC leads to a relative increase in divergent noncoding transcription and thus to a decrease in promoter directionality. We find that RSC has a modest effect on nucleosome positioning upstream in promoters at the sites of divergent transcription. These promoters are also enriched for the binding of GRFs such as Reb1 and Abf1. Ectopic targeting of divergent transcription initiation sites with GRFs or the dCas9 DNA-binding protein suppresses divergent transcription. Our data suggest that RSC and GRFs play a pervasive role in limiting divergent transcription relative to coding direction transcription. We propose that any DNA-binding factor, when stably associated with cryptic transcription start sites, forms a barrier which represses divergent transcription, thereby promoting promoter directionality., (© 2022 Wu et al.)

Background: Bone stress injury (BSI) in youth runners is clinically important during times of skeletal growth and is not well studied., Objective: To evaluate the prevalence, anatomical distribution, and factors associated with running-related BSI in boy and girl middle school runners., Design: Retrospective cross-sectional study., Setting: Online survey distributed to middle school runners., Methods: Survey evaluated BSI history, age, grade, height, weight, eating behaviors, menstrual function, exercise training, and other health characteristics., Main Outcome Measurements: Prevalence and characteristics associated with history of BSI, stratified by cortical-rich (eg, tibia) and trabecular-rich (pelvis and femoral neck) locations., Participants: 2107 runners (n = 1250 boys, n = 857 girls), age 13.2 ± 0.9 years., Results: One hundred five (4.7%) runners reported a history of 132 BSIs, with higher prevalence in girls than boys (6.7% vs 3.8%, p = .004). The most common location was the tibia (n = 51). Most trabecular-rich BSIs (n = 16, 94% total) were sustained by girls (pelvis: n = 6; femoral neck: n = 6; sacrum: n = 4). In girls, consuming <3 daily meals (odds ratio [OR] = 18.5, 95% confidence interval [CI] = 7.3, 47.4), eating disorder (9.8, 95% CI = 2.0, 47.0), family history of osteoporosis (OR = 6.9, 95% CI = 2.6, 18.0), and age (OR = 1.6, 95% CI = 1.0, 2.6) were associated with BSI. In boys, family history of osteoporosis (OR = 3.2, 95% CI = 1.2, 8.4), prior non-BSI fracture (OR = 3.2, 95% CI = 1.6, 6.7), and running mileage (OR = 1.1, 95% CI = 1.0, 1.1) were associated with BSI. Participating in soccer or basketball ≥2 years was associated with lower odds of BSI for both sexes., Conclusion: Whereas family history of osteoporosis and prior fracture (non-BSI) were most strongly related to BSI in the youth runners, behaviors contributing to an energy deficit, such as eating disorder and consuming <3 meals daily, also emerged as independent factors associated with BSI. Although cross-sectional design limits determining causality, our findings suggest promoting optimal skeletal health through nutrition and participation in other sports including soccer and basketball may address factors associated with BSI in this population., (© 2021 American Academy of Physical Medicine and Rehabilitation.)