Pediatric Research

Premature very low birth weight (VLBW) infants have high rates of mortality and morbidity from sepsis, necrotizing enterocolitis, and respiratory failure requiring intubation and mechanical ventilation. Earlier detection of cardiorespiratory deterioration using vital signs from continuous physiological monitoring may lead to more timely interventions and improved outcomes. To further this research area, we present PreMo, a publicly available dataset of continuous heart rate and oxygen saturation, demographics, clinical events, and outcomes for 3,829 VLBW patients from four Neonatal Intensive Care Units (NICUs) in the United States. The PreMo dataset consists of a collection of parquet files, RO-Crate metadata, and sample usage code scripts hosted on the University of Virginia LibraData Dataverse website.

Background: Extrauterine growth restriction (EUGR) is a common and clinically significant complication among preterm infants, contributing to adverse neurodevelopmental and metabolic outcomes. Early and individualized risk prediction remains challenging. This study aimed to develop and validate an interpretable machine learning model for early prediction of EUGR using routinely available clinical variables, and to implement a user-friendly web-based calculator for clinical use. Methods: We retrospectively analyzed 1,431 preterm infants admitted within 24 hours after birth to our hospital between May 2020 and March 2025. Infants from the Yangpu campus (n=863) formed the training set, and those from the Huangpu campus (n=568) formed the validation set. Early clinical variables available within 48-72 hours were screened using the Boruta algorithm. Logistic regression, XGBoost, random forest, decision tree, and support vector machine models were developed and compared. Model performance was evaluated using area under the curve (AUC), accuracy, sensitivity, specificity, F1 score, and Brier score. SHapley Additive exPlanations (SHAP) were applied to assess global and individual feature contributions, nonlinear effects, and interactions. A web-based calculator was constructed based on the optimal model. Results: Nine variables were identified as important predictors: birth weight, small for gestational age status, gestational age, breastfeeding, multiple gestation, neonatal respiratory distress syndrome, patent ductus arteriosus, maternal hypertension, and maternal group B Streptococcus infection. Among the five models, XGBoost achieved the best performance in the validation set (AUC 0.922, accuracy 0.849, Brier score 0.108). SHAP analysis showed that low birth weight, small for gestational age, maternal group B Streptococcus infection, and patent ductus arteriosus were major risk factors, while breastfeeding was protective. Notable nonlinear and interactive effects were observed, particularly between birth weight and gestational age and between breastfeeding and patent ductus arteriosus. The web-based calculator provides real-time individualized risk estimation and visualized interpretation. Conclusions: An interpretable XGBoost-based model and web calculator were successfully developed and validated for early prediction of EUGR in preterm infants. This tool may support clinicians in identifying high-risk infants and guiding individualized nutritional and clinical management.

BackgroundNeonatal jaundice management increasingly relies on transcutaneous bilirubinometry (TcB), yet discrepancies with serum bilirubin (TSB) have limited its clinical reliability. This study introduces Skin Residual Bilirubin Volume (SRBV) as a physiologically grounded framework to enhance TcB interpretation. ObjectiveTo evaluate SRBV as an explanation for TcB-TSB discordance and assess whether incorporating SRBV improves the interpretability and reliability of TcB measurements during diagnosis, phototherapy, and recovery. MethodsTcB readings (MBj20) were calibrated against laboratory TSB in non-jaundiced neonates (TSB <3 mg/dL). Neonates undergoing phototherapy were monitored using paired TcB measurements before and after treatment breaks (TBL-out and TBL-return). TSB was measured before treatment, at mid-treatment, and prior to discharge. Patterns of TcB-TSB disparity and an observed reproducible Recovery Value Flip (RVP) phenomenon were analysed. ResultsAcross 102 neonates, TBL consistently equalled or exceeded TSB, supporting the additive SRBV model. Early in phototherapy, TBL-return > TBL-out, indicating persistent cutaneous bilirubin. A reproducible RVP occurred mid-treatment, after which TBL-return < TBL-out coincided with sustained bilirubin decline. Fractional SRBV contribution increased with baseline bilirubin and persisted into recovery, demonstrating dynamic, patient-specific cutaneous bilirubin retention. ConclusionSRBV provides a biologically plausible explanation for TcB-TSB discordance and dynamic TcB behaviour. Incorporating SRBV into TcB interpretation enables physiologically informed monitoring, improving safety and reliability in laboratory-limited neonatal settings. Significance StatementTranscutaneous bilirubinometry is widely used but limited by disagreement with serum bilirubin. This study introduces SRBV as a physiological explanation for TcB variability and proposes an SRBV-adjusted framework that transforms TcB measurements into actionable, non-invasive clinical guidance.

BackgroundPatent ductus arteriosus (PDA) is a common and potentially serious cardiovascular condition in preterm infants, particularly those with low gestational age and birth weight. Its management remains controversial due to variability in screening, diagnostic criteria, and treatment strategies. This study aimed to evaluate risk factors, outcomes, and management strategies for PDA in preterm infants, and to identify predictors of clinical and echocardiographic response to therapy. MethodsWe conducted a retrospective cohort study over a 4-year period (2016-2019) in the neonatal intensive care unit (NICU) of a tertiary care center. All consecutive preterm infants admitted during the study period were eligible. Infants with echocardiographically confirmed PDA who received pharmacological treatment with intravenous paracetamol or ibuprofen were included in the analysis. Missing data were minimal and handled using available-case analysis. Statistical analyses included descriptive statistics, Pearsons chi-square test, and multivariable logistic regression. ResultsAmong 2154 preterm infants admitted to the NICU, 60 were diagnosed with PDA (incidence : 2.8%). The mean gestational age was 29 {+/-} 2.6 weeks, and the median birth weight was 1200 g. Respiratory distress occurred in 95% of cases, mainly due to hyaline membrane disease (86.7%). PDA was symptomatic in 80% of infants. First-line treatment resulted in clinical improvement in 77% and ductal closure in 83.3% of cases, most within 3 days. Predictors of successful closure included gestational age [&ge;] 28 weeks (OR = 5.9; 95% CI : 1.7-20.2) and antenatal corticosteroid exposure (OR = 1.2; 95% CI : 1.0-1.6). Overall mortality was 35% and was significantly higher in infants < 28 weeks (OR = 5.0; 95% CI : 2.4-10.3). Clinical improvement (OR = 3.7) and echocardiographic closure (OR = 4.5) after first-line treatment were associated with reduced mortality. ConclusionsPDA in preterm infants is associated with substantial morbidity and mortality, particularly in those born before 28 weeks of gestation. Early diagnosis, antenatal corticosteroid exposure, and timely pharmacological treatment may improve outcomes. Systematic echocardiographic screening in high-risk neonates should be considered.

BackgroundChildren with tracheostomies experience frequent and recurrent acute respiratory infections (ARIs). While cultured respiratory pathogens can inform ARI diagnosis, it is unknown if their presence in the airway affects future ARI risk. ObjectiveTo identify predictors of frequent (3+) ARIs within 36 months of tracheostomy. MethodsWe conducted a single-center, retrospective cohort study of children with tracheostomies placed between 2010-2016. Medical records were reviewed for each encounter in which a respiratory culture was obtained over the 3 years post-tracheostomy. ARIs were defined using encounter ICD-9/10 codes. Logistic and Poisson regression were used to model the association between clinical and microbiologic predictor variables with having frequent (3+) ARIs and the total number of ARIs per child. Mediation analysis using stepwise regression models further evaluated the role of P. aeruginosa. ResultsAmong 436 children, 631 diagnosed ARIs occurred within 36 months of tracheostomy; 20.2% of children had 3+ ARIs. Pseudomonas aeruginosa was isolated in 25% of children and was more common among those with 3+ ARIs compared with 0-2 ARIs (56.8% vs 20.7%, p<0.001). Those with early P. aeruginosa isolation were more likely to have 3+ ARIs (aOR 3.38, 95% CI 1.97-5.81), and this relationship persisted when analyzing ARIs and P. aeruginosa counts. Identification of P. aeruginosa partially mediated the relationship of ventilator dependence with ARI frequency. ConclusionIsolation of P. aeruginosa, particularly early and repeated isolation, is associated with frequent ARIs in the 3 years after tracheostomy and is an important partial mediator. Findings may inform risk stratification and targeted treatment strategies.

Objective: To describe the clinical characteristics of term neonates with neonatal bacterial meningitis (NBM) and explore the association between different pathogens and imaging complications, providing clinical evidence for early identification and individualized management. Methods: A retrospective study was conducted on 531 term neonates diagnosed with NBM admitted to the Capital Institute of Pediatrics from 2013 to 2025. Demographics, clinical manifestations, laboratory parameters, etiological results, imaging complications and treatment measures were collected. Patients were divided into favorable/adverse discharge outcome groups and pathogen-positive/negative groups. Statistical analyses were performed using appropriate tests, and Cramers V coefficient was used to analyze the association between pathogens and imaging complications. Results: (1) The most common clinical manifestations were abnormal body temperature (79.85%), altered consciousness (55.18%) and jaundice (46.52%). CSF/blood culture was positive in 133 cases (25.05%), with Escherichia coli (27.07%), group B streptococcus (17.29%) and Staphylococcus species (16.54%) as predominant pathogens. The overall incidence of imaging complications was 22.22%, mainly hydrocephalus (5.84%), subdural effusion (4.90%) and encephalomalacia (2.64%). (2) Adverse discharge outcomes occurred in 107 cases (20.15%). Compared with the favorable group, the adverse group had higher incidences of convulsions, altered consciousness, anterior fontanelle bulging, abnormal muscle tone and primitive reflexes (all P<0.001), more obvious laboratory abnormalities (higher CRP, CSF leukocytes and protein, lower CSF glucose, all P<0.05), higher culture positive rates and greater need for adjuvant therapy (all P<0.001). (3) Pathogen-positive patients had higher imaging complication rates. Gram-negative infections were associated with higher hydrocephalus and subdural effusion rates, while Gram-positive infections had higher brain abscess risk. Specifically, Escherichia coli correlated with hydrocephalus and subdural effusion; group B streptococcus with cerebral infarction and encephalomalacia; LM with intracranial hemorrhage and brain abscess; negative cultures correlated with no imaging complications (all P<0.05). Conclusion: Term NBM neonates have non-specific manifestations, mainly abnormal body temperature and altered consciousness. Predominant pathogens are Escherichia coli, group B streptococcus and Staphylococcus species, with hydrocephalus and subdural effusion as common imaging complications. Adverse outcomes are associated with severe symptoms, obvious laboratory abnormalities and higher pathogen positivity. Specific pathogens correlate with distinct imaging complications.

ImportanceCurrent guidelines from the World Health Organization, Centers for Disease Control and Prevention, and Academy of Breastfeeding Medicine recommend discarding all milk remaining in bottles immediately after infant feeding. However, these recommendations lack supporting microbiological evidence from studies of actual infant feeding, imposing substantial financial and emotional burden on the 78 million families worldwide who bottle-feed their infants. ObjectiveTo determine (1) the financial, emotional, and time burden associated with bottle feeding and parental milk disposal practices, and (2) bacterial growth in leftover human milk and formula under different storage conditions. Design(1) Cross-sectional online survey (January 2023-February 2024) and (2) prospective microbiological cohort study. Setting(1) Online survey, (2) infants recruited in Hannover, Germany Participants(1) Survey respondents (n=1056; 99% mothers) and (2) healthy, full-term, bottle-fed infants (n=44; 17 humanmilk, 27 formula) aged 0-12 months. Main Outcomes and MeasuresParental burden scores, milk disposal frequency, and bacterial colony-forming units (CFU)/ml in milk samples before feeding, immediately after feeding, and at 4, 8, and 24 hours post-feeding at 4{degrees}C and 20{degrees}C. ResultsAmong surveyed parents, 46% discarded leftover milk daily, yet 84% reported they would keep milk longer if deemed safe. In microbiological testing, median bacterial burden in humanmilk increased from 4200 CFU/ml (range 300-350,000) pre-feeding to 24,600 CFU/ml (range 1900-29,004,400) post-feeding, but showed no significant further increase at 4 hours (p=0.82) or 8 hours (p=0.64) when stored at either 4{degrees}C or 20{degrees}C. Formula showed similar stability: median CFU/ml increased from 0 (range 0-10,700) to 11,700 (range 1900-630,000) post-feeding, with no significant change at 4 hours (p=0.91) or 8 hours (p=0.73) at either temperature. Significant bacterial growth occurred only after 24 hours at 20{degrees}C (p<0.001). Conclusions and RelevanceBacterial burden in leftover infant milk remained stable below concerning thresholds for 8 hours when refrigerated and 4-8 hours at room temperature, challenging current guidelines that mandate immediate disposal. Evidence-based guideline revision could reduce financial burden and milk waste for families around the globe without compromising infant safety. Key PointsO_ST_ABSQuestionC_ST_ABSHow long is it safe to offer leftover milk in a bottle to an infant that has previously drunk from it? FindingsThe number of bacteria in leftover human milk or formula did not significantly increase from 0 to 8h post-feeding in milk bottles sampled from 44 infants, regardless of whether the milk was kept at room temperature or refrigerated. MeaningLeftover milk may be safely reoffered beyond the limits of the current guidelines.

Background. Brain development is altered in neonates with congenital heart disease (CHD). However, development in the perioperative period remains incompletely understood. Purpose. This study used Structural Covariance Component (SCC) analysis to identify brain regions showing spatial patterns of coordinated expansion and contraction that differ between neonates with CHD after cardiac intervention and healthy controls, as well as pre-to postoperative changes and effects of perioperative risk factors. Study type. Prospective. Population. The cohort included 41 neonates with CHD who underwent cardiac surgery or catheterization and 359 healthy neonates. Field strength and sequence. 3 Tesla T2-weighted turbo-spin-echo sequence. Assessment: Brain MRI were motion-corrected and reconstructed using an established neonatal algorithm. Jacobian determinants calculated from non-linear registration of MRI to a neonatal template were input into an Independent Component Analysis to identify SCCs (N=40). SCC weightings were extracted, reflecting the degree to which the pattern of covariance is expressed in each neonate. Statistical tests. Postoperative SCC weightings were compared to healthy neonates using a general linear model or robust regression. Pre- and postoperative SCC weightings were compared using a linear mixed effect model. Pre- to postoperative differences were calculated and associations with age at surgery, cardiopulmonary bypass duration, and postoperative paediatric intensive care unit stay were assessed using partial spearman's rank correlation. Analyses were adjusted for covariates and corrected for multiple comparisons using False Discovery Rate. Results. 16/40 SCCs showed significant differences between neonates with CHD after surgery and controls, including white matter, cortical- and deep grey matter, brainstem, and CSF regions, with seven also showing significant perioperative change. A further nine SCCs only showed significant perioperative change. Perioperative risk factors were not associated with perioperative change. Data conclusion. This data-driven approach highlights region-specific postoperative alterations and perioperative changes in brain morphology of neonates with CHD. Evidence level. 1. Technical Efficacy. Stage 3.

Objectives. To compare the efficacy and safety of invasive sacral neuromodulation (SNM) and noninvasive enteral neuromodulation (ENM) in children with refractory gastrointestinal motility disorders (GMD). Materials and Methods. This prospective interventional trial enrolled pediatric patients with GMD between 2019 and 2024 at a single tertiary referral center. Children with inflammatory bowel disease or mechanical causes of GMD were excluded. Participants received either SNM via an implanted device or ENM via surface electrodes. Stimulation was delivered at 14 Hz, 210 s pulse width, with individualized intensity (median 1.0 mA for SNM; 6.0 mA for ENM). Primary outcomes were abdominal pain, fecal incontinence, defecation frequency, and stool consistency. Treatment success was defined as clinically significant improvement in at least two of these four domains. Quality of life was assessed at baseline and 12 weeks. Safety outcomes were monitored over a 12-month follow-up. Results. Of 70 eligible patients, 48 completed the study (18 SNM; 30 ENM). Diagnoses included Hirschsprung disease, functional constipation, and congenital neuronal malformations. Severe comorbidities were more frequent in the SNM group (45%) than the ENM group (3%; P = .0018). Treatment success was observed in 80% of ENM and 83% of SNM patients (P = 1.00). No significant differences were found between groups for individual outcomes. No major complications occurred. Minor adverse events were comparable (ENM 27% vs SNM 17%; P = .50). Conclusions. Both SNM and ENM are effective and safe options for treating pediatric GMD and may be considered within a multimodal therapeutic approach.

Background and ObjectivesRecurrent acute otitis media (rAOM; defined as [&ge;]3 AOM episodes in 6 months or [&ge;]4 episodes in 12 months) affects 10-15% of children in the United States and is a leading cause of healthcare utilization and antibiotic prescriptions. Prospective identification of children at risk of rAOM could help target interventions and identify new risk factors to guide preventive approaches. We therefore sought to develop predictive models to identify children at risk of rAOM using electronic health records (EHR) data. MethodsWe extracted retrospective EHR data for children who were born at Duke University Health System (DUHS) hospitals between January 1, 2014, and June 30, 2022, and who had at least one AOM episode during the study period. We used LASSO to build predictive models for development of rAOM at each episode and identified factors associated with rAOM. ResultsWe identified 6,566 children who met the study criteria, including 1,634 (24.8%) who met criteria for rAOM. A model using only data available at the first AOM episode had an area under the curve (AUC) of 0.75 (0.73, 0.77) and an Area Under the Precision Recall Curve (AUPRC) of 0.41 (95% CI 0.37, 0.46), indicating moderate discriminative ability. At the time of the first AOM episode, features associated with subsequent rAOM development included age, number of prior antibiotic prescriptions, and diagnosis of gastroesophageal reflux disease (GERD). Further, children who developed rAOM were more likely to experience treatment failure than children who did not meet rAOM criteria across all episodes. ConclusionsOur findings indicate that clinical exposures and patient characteristics documented in the EHR distinguish children who are at risk of developing rAOM. Such models could be deployed within EHR systems to identify children who would benefit from early evaluation by an otolaryngologist and audiologist.

ObjectivesTo develop and validate pediatric adaptations of the Venous Excess Ultrasound Score (P-VExUS) for noninvasive estimation of central venous pressure (CVP) in critically ill children. DesignProspective observational study. SettingPICU of a tertiary-care teaching hospital. PatientsFifty-six mechanically ventilated children (median age 7.4 months, median weight 6.0 kg) with central venous catheters. InterventionsNone. Measurements and Main ResultsVenous Doppler ultrasonography of the inferior vena cava, hepatic, portal, and intrarenal veins was performed at the bedside. Two P-VExUS models were tested: (1) a categorical grading system (0-III) and (2) a semiquantitative point-based score (0-7). Both models showed significant associations with CVP. For predicting elevated CVP (>12 mmHg), model 1 achieved an AUROC of 0.74 (95% CI 0.61-0.85) with 45% sensitivity and 98% specificity, while model 2 demonstrated superior accuracy with an AUROC of 0.94 (95% CI 0.84-0.98), sensitivity 82%, and specificity 91% (p < 0.001). For detecting low CVP (<7 mmHg), model 2 also outperformed model 1 (AUROC 0.80 vs. 0.69, p = 0.02). Among individual venous Doppler components, intrarenal veins had the highest discriminative ability (AUROC 0.92), followed by hepatic (0.89) and portal (0.80) veins. ConclusionsTwo pediatric-specific P-VExUS models were feasible and accurate for estimating CVP in critically ill children. The point-based model (model 2) demonstrated superior diagnostic performance, supporting its potential as a noninvasive tool to assess venous congestion at the bedside. Research in ContextO_LIVenous congestion, reflected by elevated central venous pressure (CVP), is associated with adverse outcomes in critically ill children, including mortality and renal dysfunction. C_LIO_LIThe Venous Excess Ultrasound Score (VExUS) is validated in adults, but pediatric-specific adaptations and cutoff values remain poorly defined. C_LIO_LIThere is a need for noninvasive, bedside tools to estimate CVP in children and guide fluid management in the PICU. C_LI What This Study MeansO_LIThis study validates pediatric-specific adaptations of the Venous Excess Ultrasound Score (P-VExUS) for estimating CVP in critically ill children. C_LIO_LIThe semiquantitative point-based model provided more consistent and accurate discrimination of venous congestion compared with categorical grading. C_LIO_LIThese findings highlight the feasibility and potential clinical utility of venous Doppler ultrasonography as a noninvasive bedside tool in the PICU. C_LI

Dysglycemia is a critical metabolic disturbance associated with mortality in acutely ill children, yet its burden may be underrecognized in low-income settings due to reliance on single point-of-care measurements. Using continuous glucose monitoring (CGM), we aimed to characterize glucose patterns in acutely ill children of different anthropometric status. MethodsChildren aged 2-23 months admitted with acute illness were prospectively recruited from two hospitals in Bangladesh and Malawi. Clinical data were collected, and interstitial glucose was monitored for 48 hours using the Dexcom G4 Platinum system. Glucose excursions and variability were analyzed and associated with anthropometric status. ResultsOf 93 enrolled children, 88 had sufficient CGM data: 21 not wasted (NW), 22 moderately wasted (MW), and 45 with severe malnutrition (SAM; 29 severe wasting [SW], 16 edematous malnutrition [EM]). Low-glucose excursions were detected in 8 (38%) children with NW, 11 (50%) with MW, 12 (41%) with SW, and 10 (63%) with EM. While not confirmed hypoglycemia, these low-glucose excursions were longer and more frequently below severe thresholds in children with EM. Hyperglycemic excursions occurred in 31% of children and were longer in children with SAM compared to NW (median 41 vs. 23 min, p<0.0001). Overall, 35% of children maintained euglycemic profiles, while others exhibited marked glucose variability. ConclusionCGM revealed frequent glucose instability among acutely ill children, with patterns varying across anthropometric groups. When interpreted cautiously, CGM may serve as a research tool to detect dysglycemia and assess response to therapeutic or nutritional interventions in critically ill children in low-resource settings.

ObjectiveTo compare intrathalamic morphometry in infants born preterm, with congenital heart disease (CHD) and typical controls and investigate associations with neurodevelopmental outcomes. Methods592 infants underwent T2-weighted brain MRI: 107 CHD [gestational age at birth (GA) [&ge;]37.00 weeks], 126 preterm (GA 23.00-36.86), 359 controls (GA [&ge;]37.00). We used data-driven structural covariance analysis to derive 8 components of coordinated expansion and contraction within the thalamus. Permutation testing was used to test associations between intrathalamic morphometry and group (control, CHD, preterm birth <32 weeks GA), GA in infants born preterm and controls, cerebral oxygen delivery (CDO2) in infants with CHD, and neurodevelopmental outcomes at 18-24 months. ResultsPreterm infants born <32 weeks GA differed from infants with CHD and controls in 6 components encompassing most of the thalamus. Infants with CHD differed from controls in 2 components containing medial, ventricle-bordering and some anterior and ventrolateral thalamic areas. GA was associated with 7 components covering most of the thalamus, excepting the left posterior thalamus. CDO2 was not associated with intrathalamic morphometry. Right posterior thalamus morphometry was associated with motor scores in preterm infants born <32 weeks, but not in controls or infants with CHD. InterpretationPreterm infants born <32.00 weeks showed widespread morphometric changes across the thalamus, with alterations in the right posterior thalamus associated with motor outcomes at 18 months. Thalamic alterations in CHD were less widespread, confined to medial, ventrolateral, and ventricle-bordering tissues, which were not related to CDO2. Together, these findings suggest distinct thalamic phenotypes in prematurity and CHD.

BackgroundAnti-seizure medications (ASMs) are widely used in neonatal intensive care, but there is limited evidence for their safety and long-term outcomes. Phenobarbital is the only ASM generally recommended for use in neonates, but it has been linked with adverse effects in infants. Other anti-seizure medications, such as fosphenytoin, levetiracetam, and midazolam are used off-label in this population. MethodsWe performed a retrospective observational study of 18,548 infants in intensive care at an academic medical center, examining links between neonatal ASM exposure and neurological outcomes over the follow-up period of median 4{middle dot}5 years (IQR 1{middle dot}6 - 9{middle dot}2 years). The real-world clinical data included comprehensive maternal, perinatal, and medication data. The outcomes of interest were cerebral palsy, epilepsy, intellectual disability, and visual impairment. Multivariable cause-specific Cox models were used to estimate hazard ratios (HRs) for phenobarbital, levetiracetam, midazolam, and fosphenytoin exposure. Models were adjusted for major perinatal confounders, including gestational age, birth weight, mode of delivery, intraventricular hemorrhage, hypoxic-ischemic encephalopathy, and stroke. FindingsExposure to the median cumulative dose of phenobarbital was associated with increased HR for epilepsy (HR 1{middle dot}35; 95% CI, 1{middle dot}11-1{middle dot}62, p = 0{middle dot}002) visual impairment (HR 1{middle dot}20; 95% CI, 0{middle dot}99-1{middle dot}45, p = 0{middle dot}06), and intellectual disability (HR 1{middle dot}18; 95% CI, 0{middle dot}99-1{middle dot}41, p = 0{middle dot}06). In contrast, levetiracetam was associated with smaller risk increases for cerebral palsy (HR 1{middle dot}13; 95% CI, 1{middle dot}03-1{middle dot}23, p = 0{middle dot}006, epilepsy (HR 1{middle dot}14; 95% CI 1{middle dot}05-1{middle dot}24, p = 0{middle dot}002 and visual impairment (HR 1{middle dot}18; 95% CI 1{middle dot}11-1{middle dot}26, p <0{middle dot}0001). Midazolam exposure was associated with slightly increased risk of intellectual disability (HR 1{middle dot}09, 95% CI, 1{middle dot}02- 1{middle dot}16). Results for fosphenytoin were statistically not significant. We did not find evidence of a dose-dependent effect of phenobarbital, but increased maximum phenobarbital blood concentration were associated with elevated hazard ratios for cerebral palsy (HR 1{middle dot}48; 95% CI, 1{middle dot}07-2{middle dot}06, p = 0{middle dot}02 for 50 {micro}mol/l increase) and epilepsy (HR 1{middle dot}64; 95% CI, 1{middle dot}14-2{middle dot}35, p = 0{middle dot}007 for 50 {micro}mol/l increase). InterpretationThe results align with previous findings linking phenobarbital to neurodevelopmental harm and emphasize the need for its cautious use in neonates. Levetiracetam had more favorable safety profile. These findings highlight the potential of real-world data to inform evidence-based neonatal pharmacotherapy when randomized trials are impractical. FundingThe Foundation for Pediatric Research (Finland), the Association of Friends of the University Childrens Hospitals (Lastenklinikoiden Kummit ry), and internal institutional funding.

RationaleBronchopulmonary dysplasia (BPD), the lung disease associated with premature birth, is a significant health problem, often with long-term respiratory consequences. Recent research has highlighted the potential role of the lung and gut microbiome in the development and progression of BPD, yet it is unclear what aspects of the microbiome may contribute to BPD susceptibility. ObjectivesTo comprehensively characterize the lung and gut microbiomes of preterm infants and identify shared microbial taxa that are associated with BPD development. MethodsTracheal aspirate and stool samples were collected from 39 premature infants over the first month of life. To assess the taxonomic microbial composition of the lung and gut, samples were analyzed using shotgun metagenomic sequencing. BPD classification was determined using the National Institute of Child Health and Human Development severity-based definition at 36 weeks postmenstrual age. Measurements and Main ResultsMicrobial communities of the lung and gut were significantly different between infants who went on to develop BPD and those who did not, with an enrichment of skin-associated microbial genera such as Staphylococcus, Corynebacterium, and Cutibacterium in infants who developed BPD. Specifically, Staphylococcus epidermidis was enriched in premature infants who developed BPD and was the most prominent species shared between lung and gut communities. Temporal changes in gut microbial communities co-occurred with feeding practices and antibiotic exposure, suggesting an influence of external factors on microbiome composition. ConclusionsOur findings provide evidence that certain microbial colonization patterns among premature infants are closely associated with the pathogenesis and progression of BPD.

Objectives: Acute gastroenteritis is a leading cause of pediatric emergency department (ED) visits. While ondansetron reduces vomiting, intravenous rehydration, and hospital admissions, its efficacy when initiated at triage remains unclear. We aimed to evaluate whether triage nurse-initiated administration of ondansetron in children with suspected gastroenteritis reduces the proportion of patients requiring observation following initial physician assessment. Methods: We conducted a randomized, double-blind, placebo-controlled trial in a tertiary pediatric ED in Canada. Children aged 6 months to 17 years presenting with morae than 3 episodes of vomiting in the preceding 24 hours (including 1 within 2 hours of arrival), were eligible. At triage, we randomized participants to receive liquid ondansetron or a color- and taste-matched placebo. The primary outcome was the proportion of patients requiring observation after the first physician evaluation. Secondary outcomes included post-intervention vomiting, ED length of stay, patient comfort, and 48-hour return visits. The trial was registered at ClinicalTrials.gov (NCT03052361). Results: Recruitment was stopped prematurely due to the COVID-19 pandemic. Ninety-one participants were randomized to ondansetron (n= 44) or placebo (n= 47). Overall, 40 patients (45%) were discharged immediately after the initial physician assessment, with no difference between the ondansetron and placebo groups (44% vs. 45%; absolute difference -1%, 95% CI: -20% to 19%). No significant differences were observed in all secondary outcomes. Conclusion: In this trial, triage nurse-initiated ondansetron administration did not reduce the need for ED observation in children with presumed gastroenteritis. While being underpowered, this study could inform researchers planning larger clinical trials.

BackgroundThe influence of genetic and environmental factors, especially during early development, is critical in the pathogenesis of autism. Maternal autoantibodies that recognize specific fetal brain proteins can be strong predictors of autism risk. These antibodies cross the placenta and bind to their target antigens, which play critical roles in neurodevelopment, thereby increasing autism risk. This etiologically defined subtype is now referred to as Maternal Autoantibody-Related Autism (MARA). The newly developed MAR-AutismTM test is an indirect multi-ELISA assay designed to detect specific combinations of these maternal antibodies, which strongly predicts increased autism risk. ObjectiveTranslation of the indirect ELISA assays for the eight relevant antibodies (LDH-A, LDH-B, GDA, STIP1, CRMP1, CRMP2, NSE and YBOX) from an academic laboratory to a clinical development laboratory for optimization and determination of the analytical performance of the individual antibody assays. MethodsFeasibility assays were transferred from the academic laboratory and their performance confirmed prior to optimization of all steps from target protein production to preliminary threshold determination. Validation to rigorous standards was conducted. The ELISAs are qualitative assays using an internal continuous response and a cutoff to define positivity and negativity for each analyte. Analytical performance metrics of linearity, sensitivity, specificity, precision, and stability were determined by standard testing methodologies. ResultsThe optimized ELISAs all performed at acceptable standards for analytical performance. All of the assays except one were demonstrated to be linear upon dilution with buffer and with non-reactive plasma, however, recovery was overestimated with buffer diluent. The precision profile results demonstrated that the Lower Limit of Quantification (LOQ) was greater than the Limit of Detection (LOD) and below the preliminary thresholds determined from a general population cohort distribution. Precision studies showed coefficients of variation less than 15% with two minor exceptions. Common interfering substances, apart from whole human IgG, did not affect assay performance. The microtiter assay plates were stable for at least 6 months without significant drift. ConclusionOverall, the individual antibody assays demonstrated high sensitivity, specificity, and robustness sufficient to enable extension to clinical validation. These assays enable evaluation of specific antibody combinations that were previously reported to strongly and specifically correlate with autism risk, particularly in settings of suspected diagnosis or in families with an older sibling with a confirmed autism diagnosis.

Background: Preterm births contribute to approximately 35% of neonatal deaths globally, with an estimated 13.4 million infants born prematurely each year. Despite this substantial burden, limited evidence exists on time to discharge and its determinants among preterm neonates admitted to Neonatal Intensive Care Units (NICUs), particularly in rural Ugandan settings. This study aimed to investigate time to discharge and associated factors among preterm neonates admitted to Kiwoko Hospital in Nakaseke District, Uganda. Methods: A retrospective cohort study was conducted using secondary data from Kiwoko Hospital on preterm neonates admitted to the Neonatal Intensive Care Unit (NICU) between 2020 and 2021 (n = 847). The cumulative incidence function was used to estimate the probability of discharge within 28 days of admission, accounting for competing events. A Fine and Gray sub-distribution hazard regression model was fitted to identify factors associated with time to discharge. Results: Of the 847 preterm admissions, 70.1% were discharged alive within 28 days. The median time to discharge was 14 days. The cumulative incidence of discharge by 28 days was 68%, accounting for competing events. During follow-up, 165 neonates did not complete the 28-day period, including 88 deaths. Factors significantly associated with time to discharge included place of delivery (SHR: 0.62; 95% CI: 0.53-0.73; p<0.001), maternal residence in other districts (SHR: 0.69; 95% CI: 0.48-0.99; p=0.044), extreme preterm (SHR: 0.05; 95% CI: 0.03-0.09; p<0.001), very preterm (SHR: 0.18; 95% CI: 0.14-0.25; p<0.001), moderate preterm (SHR: 0.59; 95% CI: 0.46-0.76; p<0.001), triplet births (SHR: 0.40; 95% CI: 0.23-0.68; p=0.001), 2-4 ANC visits (SHR: 0.70; 95% CI: 0.56-0.87; p=0.002), <=1 ANC visit (SHR: 0.64; 95% CI: 0.49-0.85; p=0.002), respiratory distress syndrome (SHR: 0.64; 95% CI: 0.48-0.74; p<0.001), and birth trauma (SHR: 2.62; 95% CI: 1.60-4.29; p<0.001). Conclusions: Respiratory distress syndrome, fewer antenatal care visits, out-of-district residence, and higher degrees of prematurity were associated with prolonged time to discharge among preterm neonates. Strengthening antenatal care utilization and improving access to quality neonatal care in underserved areas may enhance discharge outcomes.

BackgroundNeonatal global hypoxic-ischemic cerebral injury is a leading cause of infant mortality and lifelong disability. Current rodent models do not replicate neonatal global cerebral ischemia (nGCI) and reperfusion injury. Here, we developed and characterized a rodent model of cardiac arrest and cardiopulmonary reperfusion (CA/CPR) to induce nGCI, producing acute systemic ischemia, mild neuronal injury, white matter alterations, and motor and memory deficits. MethodsRat pups underwent CA/CPR or sham procedure on postnatal day 9-11. CA/CPR in rat pups was performed under anesthesia while intubated. Asystole was induced with intravenous (IV) KCl and maintained for 10-14 minutes. Resuscitation included oxygen ventilation, chest compressions, and IV epinephrine. ResultsTwelve minutes of asystole provided an optimal balance between survival and systemic injury. Behavioral testing on postoperative day (POD) 7 revealed memory impairments. Despite the absence of overt neuronal death in the hippocampus or cerebellum, we observed evidence of glial activation and white matter alterations. ConclusionThis novel rodent model of nGCI addresses limitations in existing models while offering clinically relevant features to support future mechanistic and translational research. ImpactO_LIThis study validates cardiac arrest and cardiopulmonary resuscitation (CA/CPR) as a novel model for neonatal global cerebral ischemia (nGCI), complementing existing rodent models of unilateral and permanent injury by enabling investigation of both global ischemia and reperfusion injury. C_LIO_LInGCI results in memory impairment in the absence of overt neuronal cell death. Functional deficits are associated with neuroinflammatory responses in the hippocampus, white matter, and cerebellum. C_LIO_LINeonatal CA/CPR induces global cerebral ischemia which uniquely allows investigation of hindbrain structures, such as cerebellum, which are typically spared in existing rodent models of neonatal hypoxia-ischemia. C_LI

BackgroundNeurogenic bowel is a major cause of morbidity in patients affected by neural tube defects (NTDs) such as spina bifida, but the underlying reasons for bowel dysfunction are unknown. An absolute requirement for gastrointestinal (GI) motility is the enteric nervous system (ENS) located within the walls of the GI tract. Enteric neurons coalesce into circumferential stripes throughout embryonic and early postnatal development, and this gradual organization of the ENS into enteric neuronal stripes correlates with the emergence of neurogenic GI motility. We hypothesized that NTDs are associated with changes in ENS organization that correlate with specific GI motility defects. MethodsWe used prenatal valproic acid (VPA) exposure as a model for NTDs in embryonic mice. We used immunohistochemistry, high resolution confocal imaging, and ex vivo motility assays to assess enteric neuronal stripes and gastrointestinal motility in embryos with a VPA-induced neural tube defect. Key resultsGI tracts from embryos with a VPA-induced NTD contain blood. Structurally, the enteric neuronal stripes are thinner with a narrower interstripe distance, leading to an increased number of stripes. Functionally, GI motility is abnormal, with increased contraction frequency and increased length of contractile segments. Conclusions and inferencesENS organization and GI motility are disrupted in mouse embryos with a VPA-induced NTD. This has important implications for our understanding of neurogenic bowel in central nervous system diseases such as spina bifida. Key Points- VPA exposure is a reliable model of neural tube defects with variable intralitter susceptibility - Embryos with a VPA-induced neural tube defect have blood in the amniotic sac and within the lumen of the gastrointestinal tract - Enteric nervous system organization is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, with thinner enteric neuronal stripes and narrower interstripe distance - Ex vivo gastrointestinal motility is abnormal in the duodenum and jejunum of embryos with a VPA-induced neural tube defect, including increased contraction frequency and increased length of the contractile segment