Pediatrics

Importance: Nirsevimab, a monoclonal antibody against RSV, was implemented in France in September 2023. Recently, rare resistance-associated substitutions were described in RSV but the effectiveness according to lineages remains unclear. Objective: We aimed to estimate the effectiveness of nirsevimab against hospitalization for RSV bronchiolitis according to RSV lineages. Design: We conducted a multicenter test-negative case-control study from October 15, 2023 to March 15, 2025. Setting: This study was based on data from three national multicentric prospective studies. The 12 participating centers were secondary or tertiary hospital with a pediatric department located in France. Participants: We included all children younger than 12 months who were hospitalized for RSV bronchiolitis in one of the participating centers in France during the two first RSV epidemic seasons following the implementation of nirsevimab (from October 15, 2023 to February 29, 2024, and from October 10, 2024 to March 15, 2025). Main outcomes and measures: The main outcome of the study was the RSV test result of bronchiolitis cases. RSV whole-genome sequencing was performed using a tiled amplicon approach covering the complete viral genome, as previously described in the POLYRES studies. We estimated the effectiveness of nirsevimab by a multivariable logistic regression model adjusted for potential confounders. We estimated the adjusted risk of immunization failure for each lineage by calculating relative odds ratio to a reference lineage. A range of sensitivity analyses were conducted. Results: We included 3019 infants with bronchiolitis among which 2273 had a positive RSV test (case patients) and 746 had a negative RSV test (control patients). Overall, 373/2273 (16.4%) case patients were immunized by nirsevimab versus 423/746 (56.7%) control patients. The adjusted effectiveness of nirsevimab against hospitalization for bronchiolitis was 88.4% (95% CI, 84.5-91.4) with RSV-B and 79.4% (95% CI, 73.7-83.8) with RSV-A. The risk of immunization failure was 3.2-fold (95% CI 1.8-5.7) higher for lineages derived from A.D.3 than for lineages derived from B.D.4.1. Conclusion and relevance: In this multicentric case-control study, we observed that nirsevimab effectiveness was variable across RSV lineages, with a lower effectiveness against A.D.3 lineages compare to others. Further surveillance is needed to confirm these findings and assess their implication on RSV lineages epidemiology as nirsevimab use expands.

Objective: To compare healthcare access among U.S. children with attention-deficit/hyperactivity disorder (ADHD) only, autism only, and co-occurring ADHD-autism, and to identify social inequities associated with unmet care using recent nationally representative data. Methods: We analyzed combined 2023-2024 National Survey of Childrens Health data for 13,576 children aged 3-17 years with current ADHD and/or autism. Six healthcare-access outcomes were examined: forgone healthcare, unmet mental health care, no medical home, coverage gap or inadequate insurance, unmet specialist care, and unmet care coordination. Survey-weighted modified Poisson regression estimated adjusted prevalence ratios (aPRs) and 95 percent confidence intervals (CIs). Six multiply imputed poverty measures were combined using Rubins rules. Sensitivity models additionally adjusted for functional difficulty. Results: Compared with ADHD only, co-occurring ADHD-autism was associated with higher prevalence of forgone healthcare (aPR, 1.73; 95 percent CI, 1.38-2.16), no medical home (1.11; 1.02-1.20), inadequate or discontinuous insurance (1.14; 1.03-1.28), unmet specialist care (1.49; 1.14-1.94), and unmet care coordination (1.15; 1.04-1.28). Autism only was associated with unmet mental health care (1.49; 1.13-1.97) and care coordination (1.13; 1.02-1.25). Food insufficiency, housing instability, and non-supportive neighborhood conditions were consistently associated with poorer access. After adjustment for functional difficulty, associations remained for co-occurring ADHD-autism with forgone and specialist care and for autism only with unmet mental health care. Conclusions: Healthcare access inequities differed by neurodevelopmental diagnostic group and social context. Pediatric systems should strengthen care coordination, specialty and mental health access, insurance continuity, family navigation, and responses to food and housing hardship. Keywords: attention-deficit/hyperactivity disorder; autism spectrum disorder; healthcare access; health disparities; social determinants of health

Background: Pertussis has resurged in the post-COVID-19 era, yet diagnostic delay remains a barrier to timely treatment and transmission interruption, particularly among adults. Methods: Retrospective observational cohort study of 787 patients with confirmed pertussis from January 2016 through March 2026 across two South Carolina health systems. Electronic health record data from the 60 days preceding confirmation were used to characterize diagnostic timing (same-day vs. delayed), delay duration, and respiratory pathogen testing patterns including pertussis test modality. Results: Adults accounted for 48.4% of cases (median age 16 years [IQR 4-52]; 61.6% female). Same-day diagnosis was highest among children aged 1-4 years (75.4%) and lowest among adults aged 50 and older (approximately 50%). Among the 305 patients (38.8%) with delayed diagnosis, median delay ranged from 7-12 days in children to 22.5-26.5 days in adults aged 50 and older. Delay did not vary significantly by COVID-19 period, race, ethnicity, or insurance type. Testing breadth was greater in inpatient and emergency settings than outpatient. Pertussis testing was predominantly PCR-based in children but serologic in adults, potentially reflecting later clinical presentation relative to illness onset; however, the near-absence of PCR testing in older adults may contribute to missed diagnoses during the early illness window when PCR sensitivity is highest. Conclusions: Older adults experienced markedly delayed pertussis diagnoses compared with children. Earlier consideration of pertussis in adults with prolonged cough, including PCR testing early in illness before serologic conversion, may reduce diagnostic delay and facilitate timelier treatment and contact tracing.

PurposeTo examine the association between BMI-for-age z-score (BAZ) and BMI status with refractive error prevalence, incidence, subtypes, and quantitative refraction in Vietnamese schoolchildren. MethodsWe retrospectively analyzed body mass index and refractive error data from annual school health checks in three Vietnamese cities, 2022 to 2024. The main analysis set was restricted to children age 6 and older (49,415 examinations, 31,522 children). Refractive error subtypes and quantitative refraction came from a Hanoi autorefractor sub-cohort (13,059 examinations). We used sex-stratified Poisson models with generalized estimating equations, adjusted for age, city, and year, plus linear mixed models for quantitative outcomes. ResultsAny refractive error followed a U shaped curve across BAZ in both sexes, significant in girls (prevalence ratio 1.01 per 1-SD BAZ, p = 0.027) but not boys (p = 0.099). Obesity was associated with higher any refractive error prevalence in girls (adjusted prevalence ratio 1.05, p = 0.017). Astigmatism was associated with BAZ in both sexes (p < 0.001), anisometropia in boys only (p < 0.001), with no association for myopia or hyperopia. Spherical equivalent shifted slightly toward hyperopia, not myopia, with higher BAZ. A supplementary check over 1 to 2 years found no evidence that prior BAZ predicted new refractive error onset (prevalence ratio 1.02, p > 0.6 in both sexes), and the nonlinear pattern did not reappear. ConclusionsAdiposity relates cross-sectionally to refractive error in a nonlinear, sex specific way concentrated in astigmatism and anisometropia rather than myopia, though this did not hold up short term.

Purpose Children with suspected rare genetic disorders often remain undiagnosed after exome, gene panel, or chromosomal microarray testing. We sought to define recurrent missed-diagnosis mechanisms and evaluate an integrated clinical-genomic reanalysis framework. Methods We studied 75 participants with rare or striking pediatric-onset phenotypes who remained undiagnosed after prior genetic testing. Trio genome sequencing evaluated SNVs, indels and copy-number variants. RNA sequencing was performed in 63 participants to assess aberrant expression and splicing, with targeted follow-up assays used selectively for prioritized variants. Clinician-genome scientist review integrated longitudinal phenotyping, physician input, and inheritance. Unresolved cases underwent research-level candidate prioritization. Results Clinically reportable findings were returned in 9, including two with multilocus findings: 5 explained the primary phenotype and 4, while not fully explanatory, were clinically relevant and informing surveillance, management, or family follow-up. Previously missed findings reflected technical limitations, including deep intronic splice-altering variants supported by transcriptome analysis and a genomic deletion, and interpretive limitations related to incomplete phenotype integration or narrowly scoped prior testing. Research-level analysis prioritized six candidate genes, including biallelic ACHE variants with reduced enzymatic activity. Conclusion Integrated clinical-genomic reanalysis framework identified diagnostic gaps, recovered care-informing findings, and prioritized candidate genes for rare disease discovery.

BackgroundCOVID-19 pandemic modified trends of infant bronchiolitis, leading cause of emergency room (ER) attendance in infants in high income countries, primarily due to Respiratory Syncytial Virus. Understanding recent pandemic-related epidemiological shifts could inform affordable prevention efforts to improve sustainability and coverage of prophylactic treatments beyond maternal vaccines and infant monoclonal antibodies. MethodsWe estimated incidence rates (IR) of bronchiolitis ER presentations in 0-6month olds in 2012-2023 in a region-wide cohort of almost 1 million births using administrative health data from Lombardy, Italy. To assess potential contributors, we investigated direct and indirect COVID-19-related factors, including disease severity, shape of the epidemic peak, parental health seeking behaviour and vaccine coverage. We estimated COVID-19 maternal vaccination associations using mothers-infants data linkages and multivariable-adjusted logistic regression. FindingsCompared to pre-pandemic levels, IRs doubled in 2021-2023 (from 2 to [&ge;] 4/100 person-time). The surge could not be explained by changes in infant age at ER visit, clinical severity or in the shape of the epidemic peak. Adjusted models showed little support for a role of infant routine or maternal COVID-19 vaccination on bronchiolitis episodes (respectively hazard ratio 1.09, 95%CI: 0.98-1.22 and odds ratio 0.91, 95%CI: 0.76-1.09). InterpretationThe post-pandemic increase in infant bronchiolitis is likely driven by multiple epidemiological changes rather than a single factor. As maternal RSV vaccination and infant RSV monoclonal antibodies are introduced and scale up, identifying these mechanisms will be critical to maximise their public health impact, inform complementary prevention strategies, and improve preparedness for future RSV epidemics.

Objective: to estimate reconsultation risk and trajectories after a new episode of musculoskeletal pain in children and young people (CYP), and to determine routinely recorded prognostic factors associated with reconsultation. Design: Population based retrospective cohort study. Setting: Clinical Practice Research Datalink (CPRD) Aurum, 2005-2021. Participants: CYP aged 8-18 years consulting primary care for a new musculoskeletal pain episode (no musculoskeletal consultation in prior 12-months). Main Outcome Measures: Musculoskeletal pain reconsultation within 12-months, and 3-year musculoskeletal reconsultation trajectories derived using latent class growth analysis. Prognostic factors selected from a literature search and two-year symptom histories (sample prevalence >1%) were examined using regression models (conditional logistic; multinomial). Results: Among 313,830 CYP with >12 months' follow-up, 32% reconsulted for musculoskeletal pain within 12 months. Among 240,384 CYP with >3 years' follow-up, three trajectories were observed: single episode (62%), early reconsultation (18%), and persistent reconsultation (20%). Older age; female gender; hip, knee, multisite and back pain on index; previous headache; previous abdominal pain; and analgesic prescribing were associated with higher reconsultation risk. Asian or Black ethnicity, and residing in more deprived areas, were associated with lower recorded reconsultation. Conclusion: Most CYP had no further recorded consultation, but 38% followed early or persistent reconsultation trajectories. Routinely recorded prognostic factors, particularly index pain side and prior pain/symptom history, may differentiate groups who could benefit from proactive follow-up. Lower recorded reconsultation among Asian and Black individuals, and living in more deprived areas, should not imply lower need and warrants equity-sensitive monitoring of access, health-seeking, and coding.

Background: Gender-affirming medical care (GAMC) for children and adolescents in Australia has become increasingly politicized, despite care being provided in accordance with latest evidence-based international guidelines. Critics of GAMC claim that current assessment and deliberation processes are insufficient, and that too many young people are accessing medical interventions, no longer identifying as trans, and expressing treatment regret. These claims have led to widespread bans on the provision of paediatric GAMC, despite growing evidence regarding harms caused by such bans. Aim: This study sought to describe the care journeys of the young people attending Australia's largest paediatric gender service, with a focus on reporting the rates at which young people commenced medical interventions, re-identified with their birth-assigned sex, and expressed regret about their treatment. Methods: The Royal Children's Hospital Gender Service (RCHGS) is a statewide service that provides individualised multidisciplinary care to trans and gender diverse young people in Victoria, Australia. An initial extended triage appointment explores the needs and goals of the young person and their family. Some proceed to receive individualised multidisciplinary care (MDC) at RCHGS which can include psychosocial assessment and management, family support, and medical interventions including pubertal suppression (PS) and gender-affirming hormonal therapy (GAHT). We undertook a retrospective file audit of all patients who had attended at least one RCHGS appointment and been discharged between 1/1/2017-31/12/2024. For each person, key data were extracted from their electronic medical record and recorded in REDCap. Results: 1,391 patients were discharged over the 8-year study period and many different care trajectories were observed. 814 (58.5%) did not access ongoing MDC. Of the remaining 577, 353 (25.4% of total cohort) started a medical intervention ((PS: n=64/1391 (4.6%); estradiol: n=97/1391 (7.0%); testosterone: n=244/1391 (17.5%)). For those who started these medical interventions, the median duration and number of sessions from first appointment until commencement of medications was 530 (IQR: 371-693) days and 9 (IQR: 7-13) sessions. 346 of these patients (98.0%) had data on gender identity at discharge and subsequent care pathways. 7 (2.0%) re-identified with their birth-registered sex and stopped treatment: 4 did so after commencing PS (4/61=6.6% of those starting PS), 2 did so after commencing testosterone, and 1 did so after commencing estradiol (3/341=0.9% of those starting GAHT). Just one of these patients, who had been on estradiol for 1 month, expressed treatment regret given concerns about initial breast budding and future fertility. Conclusion: This study highlights varied trajectories of those referred to paediatric gender services, directly challenges claims used to justify restrictions on paediatric GAMC and underscores the importance of a person-centred approach to care.

Background: Vitamin D modulates innate and adaptive immunity and has been investigated for preventing pediatric respiratory infections. Objective: To assess the effects of vitamin D supplementation on respiratory tract infections (RTIs), including upper RTIs, lower RTIs/recurrent pneumonia, and hospitalization/clinical severity in children and adolescents. Methods: Systematic review and random-effects meta-analysis of 16 publications, of which 13 contributed to quantitative synthesis. Twenty-four effect estimates were pooled, eight per outcome. The odds ratio (OR) was analyzed on its natural logarithmic scale (logOR), using restricted maximum likelihood (REML) estimation and Knapp-Hartung (KH) adjusted inference. Where necessary, risk ratios (RRs), hazard ratios (HRs), and incidence rate ratios (IRRs) were approximated on the logOR scale. Results: For respiratory infection/upper RTI, pooled logOR was -0.284 (KH-adjusted 95% confidence interval [CI]: -0.678 to 0.110; OR 0.753; p = 0.132; I2 = 97.2%). For lower RTI/recurrent pneumonia, logOR was -0.445 (95% CI: -0.987 to 0.097; OR 0.641; p = 0.093; I2 = 89.5%). For hospitalization/clinical severity, logOR was -0.609 (95% CI: -1.134 to -0.083; OR 0.544; p = 0.029; I2 = 78.3%). Conclusions: Pooled estimates favored supplementation in direction for all three groups, although confidence intervals included the null for the first two. Heterogeneity was substantial, and the results are limited by approximations among effect measures, clinically diverse endpoints, and potentially correlated effects from individual studies.

Background: Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of neurodegenerative disorders characterized by progressive lower-extremity weakness and spasticity, with or without additional neurological symptoms. Objectives: To characterize the molecular genetic spectrum, inheritance patterns, molecular finding rate, and clinical characteristics of HSP within a multicenter Canadian cohort. Methods: We investigated 671 patients from 423 families who met clinical criteria for HSP identified through the Canadian HSP (CanHSP) registry from 7 medical centers across Canada. Patients were evaluated using known HSP and HSP mimic gene panels, whereas unsolved and more recent patients underwent whole-exome sequencing (WES). 435 individuals underwent gene-panel testing and 485 underwent WES. Copy-number variants (CNVs) were assessed using ExomeDepth, and candidate CNVs using multiplex ligation-dependent probe amplification (MLPA). Results: Molecular findings were identified in 426 of 671 individuals (63.5%): 351 (52.3%) had HSP-associated findings, 70 (10.4%) HSP-mimicking disorders, and five (0.7%) other molecular findings; 245 (36.5%) remained unresolved. Candidate variants were found in 80 relevant genes, 36 of which were HSP-associated genes. The most frequently implicated genes were SPAST (22.5%), SPG7 (5.7%), ATL1 (5.2%), SPG11 (3.6%), and SPG8 (3.3%). Phenotypically, SPAST, ATL1, and SPG8 w[zg1.1]ere predominantly associated with pure HSP, whereas SPG7 and SPG11 more often showed complicated phenotypes, with prominent cerebellar involvement in SPG7 and cognitive and developmental features in SPG11. Conclusion: Patients in CanHSP present with genetic and phenotypic heterogeneity. Reanalysis and complementary approaches, including whole-genome, RNA, and long-read sequencing, may increase diagnostic yield.

Background: The relationship between recent viral infection and subsequent susceptibility to, or protection against, other viruses remains unclear, particularly across ages and symptom status. Methods: A prospective cohort study enrolled participants aged 6 months to 49 years in Washington and Oregon, USA, 2022-2024. Weekly nasal swabs were tested for SARS-CoV-2, respiratory syncytial virus (RSV), and influenza A/B; additional swabs were collected during symptomatic illness and were also tested for parainfluenza (PIV) 1-4, endemic human coronaviruses (hCOV), adenovirus, human metapneumovirus, human rhinovirus (hRV), and enteroviruses. Proportional hazards regression models were used to characterize associations between incident symptomatic infection (illness) and history of recent illness due to other viruses (within 1-7, 8-14, 15-30, 31-60, 61-90, 91-180 days), adjusted for geographic region, age, sex, daycare/school/work attendance, household size, and number of children in the household. For SARS-CoV-2, influenza, and RSV, these analyses were repeated to study incidence of infection (including asymptomatic cases). Findings: Of 3,560 participants, 2,969 (83%) had [&ge;]1 illness over 4,299 person-years. Adjusted hazard ratios (aHRs) in the short term ([&le;]2 weeks) after an illness were predominantly below 1, indicating that recent viral illness was often associated with lower risk of subsequent illness with other viruses. Across age groups, recent hRV illness was associated with lower risk of hCOV, PIV, and RSV illness (aHRs 0.07-0.27). SARS-CoV-2 illness was associated with a higher short-term risk of adenovirus and PIV illness (aHRs 3.20-3.33). In children aged 6 months-4 years, recent influenza illness was associated with higher short-term risk of SARS-CoV-2 illness. Including asymptomatic infections generally attenuated these associations. Interpretation: Some viral illnesses may alter short-term susceptibility to subsequent viral illnesses. Interactions may differ by age and symptom status. Funding: US Centers for Disease Control and Prevention; Washington State Department of Health.

Importance: In the US, Human papillomavirus (HPV) related cancers cause significant morbidity and mortality, yet HPV vaccine is underutilized. Vaccination is recommended routinely at age 11-12 years but can be given at 9 years. There is controversy about whether earlier introduction would increase completion of the HPV series before by age 13 years or whether it might decrease rates of delivery of other routinely recommended vaccines at 11-12-years [quadrivalent meningococcal conjugate (MenACWY) vaccine, and tetanus-diptheria-acellular pertussis (Tdap) vaccine]. Objective: To determine whether introduction of the HPV vaccine at ages 9-10 versus 11-12 years, results in earlier median age of series completion (primary outcome) and higher rates of initiation and completion by age 13 years. We also examined the effect of earlier introduction of HPV on rates of Tdap and MenACWY initiation and completion by age 13 years. Design: Two-arm cluster-randomized trial involving 31 pediatric practices in Colorado and California between 10/2021-4/2026. Practices were randomized using covariate constrained randomization within each state to Intervention (introduction of HPV vaccination at ages 9-10) or Control (introduction at ages 11-12). Both study groups received similar annual training about best practices for HPV vaccination with recommended initiation age as the only difference. Results: Age at HPV series completion was substantially earlier in the Intervention group (median 12.2 v. 13.3 years; adjusted hazard ratio [aHR] 2.37; 95% CI 1.94-2.89). Key secondary outcomes were also improved in the intervention group: age at series initiation (median 11.0 v. 11.8 years; aHR 2.19; 95% CI 1.84-2.62), series completion by 13 years (61.6% v. 45.1%; RR 1.37; 95% CI 1.04-1.74), and vaccine initiation by age 13 years (77.1% v. 67.0%; RR 1.15; 95% CI 1.00-1.33). The intervention group was more likely to receive Tdap (aHR 1.47;95%CI 1.13, 1.92) during the trial; receipt of both vaccines by age 13 years did not differ. Conclusions: Earlier introduction of HPV vaccination resulted in earlier age of series completion, and more adolescents initiating and completing the series by age 13 without decreasing rates of other routinely recommended vaccines. Our findings support a preferential recommendation at 9-10 years. Trial registration number: NCT04722822 ClinicalTrial.gov

Background and Objectives: Influenza vaccination has a strong safety record and is effective in reducing pediatric influenza-associated morbidity and mortality. However, pediatric vaccination coverage (VC) has declined since the 2019/20 influenza season in the United States. We estimated the impact of increased vaccine protection (through increased VC and/or vaccine effectiveness [VE]) on pediatric influenza-associated burden during the 2022/23-2024/25 seasons. Methods: We used a compartmental model and laboratory-confirmed influenza-associated hospitalization, VC, and VE data among children 6 months-17 years to estimate influenza burden from 2022/23-2024/25 (the 'baseline' scenario) and the impact of vaccination. We simulated scenarios that (1) increased VC by five percentage points; (2) increased VE by five percentage points; (3) increased VC and VE by five percentage points; and (4) increased VC to levels achieved in 2019/20 (the season with the highest pediatric VC to date). We estimated the difference in hospitalizations and deaths between each scenario and the baseline scenario. Results: Among children 6 months-17 years, an estimated 120,000 influenza-associated hospitalizations and 1,650 deaths occurred across all seasons at baseline. Increasing VC to 2019/20 levels had the greatest estimated impact, reducing hospitalizations by 8,670 (7.2%) and deaths by 130 (7.9%). Increasing both VC and VE by five percentage points reduced hospitalizations by 6.6% and deaths by 6.7%, whereas increasing VC or VE by five percentage points reduced hospitalizations by 3.1% and deaths by 3.2%. Conclusions: Increasing pediatric influenza vaccination coverage back to 2019/20 levels was estimated to significantly reduce pediatric influenza-associated morbidity and mortality.

Objective: To identify factors associated with predischarge morbidity and mortality among small for gestational age infants. Study Design: We conducted a retrospective single-center cohort study of small for gestational age infants admitted to a level IV neonatal intensive care unit. We determined the association of clinical characteristics, congenital anomalies, and genetic disorders with the primary outcome of predischarge morbidity or mortality and characterized morbidity and mortality across congenital anomaly subgroups. Results: Among 293 small for gestational age infants, 18 (6.1%) had a genetic disorder and 103 (35.2%) had a major congenital anomaly, with congenital heart disease (CHD) representing the largest subgroup. The primary outcome of morbidity or mortality occurred in 93 infants (31.7%); 74 infants (25.3%) experienced morbidity and 19 (6.5%) died. CHD (adjusted odds ratio [aOR]: 16.5, 95% CI 6.44-45.7) and multiple congenital anomalies (aOR: 17.8, 95% CI 4.64-71.1) were found to be strongly associated with morbidity or mortality, after accounting for sex, maternal race, and intubation > 7 days. Statistically significant associations were also found with the presence of musculoskeletal anomalies as well as genetic disorders in infants without congenital anomalies, though in limited sample sizes. CHD was the largest contributor to morbidity, whereas multiple congenital anomalies accounted for the greatest proportion of mortality. Infants with abdominal wall defects and central nervous system anomalies experienced no morbidity or mortality. Conclusion: Congenital heart disease and multiple congenital anomalies were strongly associated with morbidity and mortality among SGA infants, whereas the degree of SGA alone was not. These findings suggest that risk is not explained by the degree of SGA alone and may be more strongly associated with congenital disease and other underlying factors.

Background: Common variable immunodeficiency is frequently underrecognized due to its heterogeneous clinical presentation, resulting in diagnostic delays that increase disease-related complications, with each year of delay increasing mortality risk by 4% for the most common inborn error of immunity. Objective: In individuals with established common variable immunodeficiency, we sought to recognize patterns in patient diagnostic trajectories to identify opportunities for interventions to reduce time to diagnosis. Methods: We analyzed retrospective electronic health records data from 139 individuals with physician-confirmed common variable immunodeficiency across five academic health systems representing >10million patients. We evaluated diagnosing specialties and international classification of disease code trajectories in the two years prior to and at common variable immunodeficiency confirmation. Additionally, we construct specialty-specific prediction on a 1:50 case: control cohort using a gradient boosting algorithm. Results: The leading diagnoses at common variable immunodeficiency determination were respiratory (35% of individuals), and individuals with respiratory symptoms were more likely to be diagnosed by Allergy / Immunology than by other specialties (odds ratio 2.9, standard error 0.35, p-value 1.9x10-3) and had a higher frequency of visits to pulmonary disease in the two years prior to diagnosis. Individuals with neoplasms were 50% more likely than other patients (OR 2.0, SE 0.29, p-value 0.02) to receive a diagnosis at each visit, reducing their diagnostic delay by up to a year. We find that a larger ratio of number of specialties visited to the total number of visits is significantly correlated with an increased time to diagnosis. A trajectory-informed specialty-specific prediction improved detection with an area under the precision-recall curve of fifty times the value expected under the null. Conclusions: Individuals referred to Allergy / Immunology have shorter time to diagnosis, and a specialty-specific prediction could improve detection of common variable immunodeficiency. Clinical Implications: Overall, we find that phenotype-specialty interactions may inform targeted interventions to improve common variable immunodeficiency recognition across specialties, reducing diagnostic odyssey and disease-related complications.

Background: Rapid genome sequencing (rGS) is a first-tier test in the neonatal intensive care unit (NICU). Implementation strategies to scale rGS for clinical care may change clinician roles. We analyzed the NICU rGS workflow to understand challenges rGS poses for clinical roles and responsibilities. Methods: The study took a qualitative approach to understanding the rGS workflow in Level III and Level IV NICUs. The five workflow phases studied included: i) identification of a patient with a suspected genetic disorder, ii) subspecialist consultation, iii) test selection and ordering, iv) return of results, and v) disclosure. Data were collected via job task journals, interviews, and workflow diagram construction with clinicians involved in rGS. Analysis included participant-guided workflow diagram refinement, qualitative thematic analysis, and identification of rGS workflow challenges. Results: We documented issues related to decision-making authority and scope of responsibility for clinicians, with the majority relating to complexities of subspecialist consultations. Issues included differences in: criteria for triggering consultations, expectations of consulted subspecialists' roles, test selection preferences, and responsibility for documenting clinical interpretations and disclosure. Conclusion: Subspecialist consultations in clinical rGS involved significant role ambiguity and communication challenges, requiring intentional implementation efforts to ensure clear clinical roles and responsibilities.

Background: More than five years after the COVID-19 outbreak, the infection by the SARS-CoV-2 virus should still be considered as a global threat with highly heterogeneous clinical outcomes from asymptomatic to fatal depending on existing genetic and phenotypic inter-individual and inter-population variability. Our objective is to identify risk loci associated with COVID-19 in an admixed Latin American population. Methods: We performed a genome-wide association study in the framework of the Chilean C19-GenoNet team, analyzing a cohort of 3,417 individuals recruited from the northernmost to the southernmost regions of the country, who presented variations in the severity of their COVID-19 clinical manifestations. Results: Our investigation replicated the extensively reported association of several variants at the 3p21.31 locus with COVID-19 severity and found a suggestive association for a variant within the FOXP4 gene at 6p21.1 with COVID-19 hospitalization. Both associations appear to be shared with other populations. Importantly, our study identified three previously unreported loci associated with COVID-19 severity or hospitalization at 7q21.11, 16p13.12 and 6p25.3, and one additional locus at 4p13 associated with SARS-CoV-2 positivity, a proxy for infection susceptibility. Conclusions: these new risk loci may represent population-specific effects in Chilean and, potentially, other Latin American admixed groups. Our study highlights the importance of expanding efforts to study underrepresented and genetically different populations, which may provide new clues on the genetic basis of human diseases and may help to anticipate global responses to emerging viral infections and future pandemics.

Background: Half of US children are prescribed an antibiotic by age 2. Maternal education and socio-economic factors influence prescribing but the role of other factors, such as age of solid food introduction is unknown. Objectives: We assessed risk factors for time to first antibiotic use between birth to age 2 to identify modifiable drivers of antibiotic use. Methods: We analyzed interviews from mothers of 1032 children participating in the mother-child Center for Oral Health Research in Appalachia cohort 2 between 2011 and 2017. The cohort enrolled healthy, English-speaking, pregnant White women > 18 years with singleton pregnancies. We used time-to-event analyses and a Cox Proportional Hazards model to describe and estimate hazard ratios (HRs) for time to first antibiotic. Results: By age 2, 78% of children received at least one antibiotic (median age at first antibiotic: 12.5 months). Over half (58%) of antibiotics prescribed were for ear infections. After adjustment for household income and birth quarter as fixed variables, time of solid food introduction (aHR: 4.75; 95% CI: 3.19, 7.07), time of first ear infection (aHR: 3.28; 95% CI: 2.58,4.17), and time of first illness (aHR: 4.60; 95% CI: 3.32,6.36) were significantly associated with time of first antibiotic use. Conclusions: Earlier time of solid food introduction was associated with earlier antibiotic use. Childhood illnesses, especially ear infections, also strongly influence antibiotic initiation. These modifiable factors offer targets to reduce unnecessary early antibiotic use.

Background: Genetic conditions are common in congenital heart disease (CHD) and affect care, but are often missed or diagnosed late. We asked whether routine clinical data can shortlist the most likely genetic conditions. Methods: Retrospective single-center cohort of children with CHD and an echocardiogram who had either a confirmed genetic diagnosis or negative cytogenetic testing and CHD gene sequencing. Echocardiogram images and serial medical record data were added as model inputs in the order they become clinically available. Class balanced logistic regression (LR) and a multimodal deep learning fusion network were fitted to the same inputs at each step. The primary metric was balanced top-3 accuracy (correct diagnosis among the top three, averaged across conditions), with bootstrap intervals. Results: The cohort included 1,720 children (988 with common CHD-associated genetic conditions, 231 rare diagnoses, 501 negative testing). Using only inputs generated at the echocardiogram visit, LR reached a balanced top-3 accuracy 0.758 (chance 0.429). Serial records, radiology notes and ICD-10 codes, raised this to 0.809. Multimodal fusion performed similarly at each stage. With a genetic condition withheld from training, the fusion embedding placed affected children nearest to others sharing a gene group in 0.37 of cases versus 0.10 without the embedding (+0.268 [95% CI +0.242, +0.295]). Conclusions: Routine clinical data available at first echocardiogram can help identify likely genetic diagnoses, and later coded inputs ceiling. Multimodal fusion added no accuracy over LR, but places children sharing a genetic cause near one another, making nearest-neighbor retrieval informative for undiagnosed children.

BACKGROUND: Adverse consequences of neonatal hyperbilirubinemia disproportionately affect babies in low- and middle-income countries. Laboratory measurement of total serum bilirubin is limited in low-resource settings, necessitating simpler alternatives. Our study aimed to evaluate the diagnostic accuracy of visual inspection of jaundice via the World Health Organization Integrated Management of Childhood Illnesses algorithm compared to transcutaneous bilirubinometry for the identification of hyperbilirubinemia in community settings. METHODS: Hyperbilirubinemia was assessed by visual inspection for jaundice and transcutaneous bilirubinometry at 0-72 hours, 3-5 days, and 5-14 days postnatal in the PRISMA prospective cohort study in six sites in Asia and Africa. We assessed sensitivity, specificity, and positive and negative percent agreement. RESULTS: We analyzed data from 14,331 infants, including 1,852 preterm infants. 15% had hyperbilirubinemia, as defined by transcutaneous bilirubin values and the NICE nomograms, at 3-5 days postnatal. Visual inspection had a sensitivity of 16%, specificity of 96%, positive percent agreement of 56%, and negative percent agreement of 86% at 3-5 days postnatal age, pooled across all sites and gestational ages, versus transcutaneous bilirubin defined by NICE nomograms. CONCLUSION: The poor sensitivity of visual inspection underscores an urgent need for accurate, affordable screening tools to improve screening for hyperbilirubinemia.