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.

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.

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.

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.

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.

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.

BackgroundNeurodevelopmental impairment remains common in neonatal hypoxic-ischemic encephalopathy (HIE) despite treatment with the standard of care, therapeutic hypothermia (TH). The complement response activates at reperfusion and is known to exacerbate neuroinflammation and injury, though its full role and interaction with hypothermia are incompletely defined. We hypothesized that modulating the complement response could improve structural and functional outcomes in HIE, and tested a novel complement therapy (CT), consisting of C3a peptides and the C5a-receptor antagonist PMX205, as both a stand-alone treatment and as an adjuvant to TH. MethodsWistar rat pups were randomized to the following treatment groups: Sham (uninjured control), NT (uninjured, normothermia/not treated control), or injured and treated with either TH, CT, or CT+TH. At term-equivalence, mild-moderate hypoxic-ischemic injury was induced by Vannuccis method. To capture the short and long-term effects of the treatments, cohorts were harvested 3 or 66-72 days post-injury, respectively. Cerebral injury was measured by quantifying levels of inflammatory markers and cerebral tissue loss, and functional outcomes were assessed in a series of behavioral tests. The data were stratified to detect sexual dimorphisms. ResultsCT and TH treatments demonstrated test and sex-dependent differences in improvement compared to untreated, injured rats. In male rats, TH treatment worsened long-term hippocampal and thalamic brain injury and functional measures of ataxia and attention. CT-treatment worsened long-term thalamic loss in females. Combining the two treatments (CT+TH) demonstrated additive improvement in both sexes, including short and long-term cortical loss and ataxia. ConclusionsComplement modulation enhances the neuroprotective effects of TH after neonatal hypoxic-ischemic injury, with sex-specific effects on inflammation and behavior. Combining complement modulation with the standard of care often demonstrated synergistic improvement in both sexes, supporting complement-targeted therapy as a promising adjunct to hypothermia in neonatal HIE. Graphical abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/717097v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1025d1forg.highwire.dtl.DTLVardef@2fa4e5org.highwire.dtl.DTLVardef@1f2c1c4org.highwire.dtl.DTLVardef@8f3410_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender. Saadat, A. (2026) https://BioRender.com/siwm825.

Neonates requiring intensive care are at increased risk for long-term neuropsychiatric disorders. However, clinical adoption of risk prediction models remains limited when their performance lacks adequate interpretability for informed clinical decision-making. Here, we investigated whether longitudinal neonatal electronic health record (EHR) data from the first 90 days of life can support clinically meaningful interpretation of long-term risk signals for major neuropsychiatric diagnoses by age seven. In a retrospective register-based cohort of 17,655 at-risk children from an academic medical center, of whom 8.0\% (1,420) received a major neuropsychiatric diagnosis during follow-up, we applied a time-aware transformer model (Self-supervised Transformer for Time-Series; STraTS) and thoroughly evaluated its predictions using three complementary interpretability approaches: perturbation-based variable importance, value-dependent effect analysis, and leave-one-out (LOO) feature attribution. STraTS achieved the highest area under the precision--recall curve (AUPRC 0.171 {+/-} 0.022), compared with Random Forest (0.166 {+/-} 0.008), logistic regression (0.151 {+/-} 0.007), and XGBoost (0.128 {+/-} 0.010). Across interpretability methods, five predictors were consistently identified: birth weight, gender, Apgar score at 1 minute, umbilical serum thyroid stimulating hormone (uS-TSH), and treatment time in hospital. Indicators of early clinical severity, including chromosomal abnormalities and neonatal cerebral-status disturbances, showed the largest risk-increasing effects. Furthermore, the model's learned vector representations of subject-specific EHR sequences formed clinically coherent latent embeddings that reflect population heterogeneity along established perinatal risk dimensions. These findings demonstrate that combining multiple complementary interpretability methods yields stable, clinically plausible risk signals while revealing limitations that would remain undetected by any single approach, highlighting the importance of careful interpretability analysis of deep learning-based risk predictions.

Hypoxic-ischemic encephalopathy (HIE) is a neonatal brain injury in which a definitive diagnosis within the first 6 hours of life is essential for initiating therapeutic hypothermia and improving neurological outcomes. However, early clinical evaluation and currently available biomarkers lack quantitative specificity during this narrow therapeutic window. We are providing insights into how rapid disturbances in systemic metabolites that regulate cerebral energy metabolism, neurotransmitter cycling, redox balance, and membrane integrity generate a definitive biochemical signature of HIE immediately after birth. We performed quantitative blood-based 1H NMR metabolomics on collected blood samples within [~]1 hour of birth from 81 neonates (HIE, n = 42; non-HIE, n = 39), under optimized handling conditions to preserve metabolic integrity. Metabolite analysis revealed a distinct HIE-associated profile characterized by elevated lactate, alanine, succinate, glutamate, taurine, glycine, choline, and pyroglutamate, alongside significant depletion of glucose and glutamine compared with non-HIE controls (p < 0.05). These coordinated metabolic shifts reflect impaired mitochondrial respiration, enhanced anaerobic glycolysis, excitotoxic amino acid accumulation, altered membrane phospholipid turnover, and oxidative stress. Multivariate analysis demonstrated clear separation between groups (PLS-DA accuracy = 0.83, R{superscript 2}Y = 0.46, Q{superscript 2} = 0.82), with glutamine, lactate, glutamate, and pyroglutamate as key discriminators. Pathway enrichment highlighted perturbations in glycolysis, the glucose-alanine cycle, glutamate-glutamine metabolism, Warburg effect like metabolic reprogramming, and redox homeostasis. Integration into supervised machine-learning models (Random Forest, XGBoost, SVM, KNN) achieved strong diagnostic performance (AUC = 0.97 {+/-} 0.03; sensitivity {approx} 87%). Collectively, this minimally invasive NMR-to-machine-learning framework enables early, mechanistically grounded risk stratification of neonatal HIE within the therapeutic window.

Objective Cerebral palsy (CP) affects approximately 1 million Americans and 18 million individuals worldwide, yet contemporary US epidemiologic data remains limited. We aimed to use Cerebral Palsy Research Network (CPRN) clinical registry to describe demographics and clinical characteristics of individuals with CP across the US and determine associations with gross motor function and genetic etiology. Methods Registry subjects were included if they had clinician-confirmed CP and prospectively entered data for Gross Motor Function Classification System (GMFCS) Level, gestational age, genetic etiology, CP distribution, and tone/movement types. Logistic regression was used to determine which of these variables plus race, sex, ethnicity, and age were associated with GMFCS level and genetic etiology. Results A total of 9,756 children and adults with CP from 22 CPRN sites met inclusion criteria. Participants were predominantly White (73.0%), male (57.3%), non-Hispanic (87.8%), and younger than 18 years (73.7%). Most were classified as GMFCS levels I-III (55.6%), born preterm (52.8%), had spasticity (83.8%), and had quadriplegia (41.9%); 12.2% were identified as having a genetic etiology. Tone/movement types, CP distribution, and gestational age were significantly associated with both GMFCS level and genetic etiology (p<0.001). Compared to White individuals, Black individuals were more likely to have greater gross motor impairment (p<0.001). Conclusion In this large US cohort, clinical and demographic factors, including race, were associated with gross motor function and genetic etiology in CP. These findings highlight persistent disparities and demonstrate the value of a national clinical registry for informing prognostication, quality improvement efforts, and targeted genetic testing strategies.

Severe neonatal hyperbilirubinaemia represents a considerable cause of mortality and long term-morbidity in neonates born in low resource settings. Early identification of risk factors, such as glucose-6-phosphate dehydrogenase (G6PD) status, has the potential to prevent severe hyperbilirubinaemia and improve the clinical outcomes. The primary aim of the study was to assess equivalency of cord blood and neonatal capillary blood for diagnosis of G6PD deficiency using the quantitative point-of-care "STANDARD G6PDTM" test (SD Biosensor, Korea). Additional secondary aims were to compare the "STANDARD G6PDTM" with gold standard spectrophotometry and to analyse changes in G6PD activity in the first 4 months of life. A total of 75 neonates born in Shoklo Malaria Research Unit (SMRU) clinics were selected based on their G6PD status assessed through routine cord blood screening using the "STANDARD G6PDTM" test. Using activity thresholds established before in this setting, 25 G6PD deficient, 25 G6PD intermediate and 25 G6PD normal neonates were identified and re-tested on capillary blood collected within 24 hours of life and at day 7. They were also followed-up at 1 and 4 months of age to study haematologic and G6PD activity changes over time. The results showed that the "STANDARD G6PDTM" can be used reliably up to one week of life for testing neonates using the same thresholds established in cord blood. Performance of the point-of-care test as compared to the gold standard spectrophotometry remained excellent at all sampling time-points. Nevertheless, G6PD activity assessed longitudinally in the same participants decreased over time, both at 1 month of age and at 4 months of age, and interpretation of results in female infants with intermediate activity might require different thresholds. The study demonstrated that the "STANDARD G6PDTM" can effectively support clinical care in neonates and infants in populations with prevalent G6PD deficiency at the primary care level and especially in low-resource settings.

OBJECTIVE This study investigates the long-term impacts of childhood exposure to voiding cystourethrogram (VCUG), a diagnostic procedure for vesicoureteral reflux. Primary outcomes include long-term health outcomes, mental health disorders, healthcare avoidance, and participation in risky behaviors compared to a control group. METHODS A 9-month retrospective cohort study was conducted with adults who received most of their medical care in the U.S. Respondents self-reported health metrics, behaviors, and outcomes via a 20-minute survey. Respondents were divided into two groups: those who remembered undergoing at least one VCUG in childhood (VCUG group), and those who did not (control group). RESULTS Of 334 respondents, 204 (61%) were in the VCUG group (mean age: 29, 70% female) and 130 (39%) were controls (mean age: 34, 70% female). Notable findings include: 47% of VCUG respondents were diagnosed with depression compared to 27% of controls. 15% of female-born VCUG respondents reported they would never visit a gynecologist compared to 2% of controls. 34% of VCUG respondents smoked regularly compared to 5% of controls, and 11% of VCUG respondents regularly missed work compared to 1% of controls. These findings highlight the need for further research and clinical consideration of VCUG's long-term consequences. CONCLUSIONS This study suggests that the effects of childhood VCUG extend into adulthood. Our findings underscore the need to reassess informed consent protocols and consider full-scale studies to minimize bias.

Rationale: Sepsis is a life-threatening syndrome causing significant morbidity and mortality especially in the aging population. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition of clonal expansion of hematopoietic stem cells harboring somatic mutations associated with increased incidence of chronic illness and all-cause mortality. Objective: Evaluate the association of pre-illness CHIP with mortality and morbidity in patients admitted to the ICU with sepsis. Methods: We performed a retrospective study using a de-identified electronic health record linked with a DNA biorepository. We identified adult patients with sepsis who had DNA collected prior to ICU admission. We tested the association between CHIP status, determined from whole-genome sequencing, and ICU mortality, organ support-free days, and long-term survival adjusting for age, sex, race and Sequential Organ Failure Assessment (SOFA) score on ICU admission. Measurements and Main Results: Pre-illness CHIP was associated with increased sepsis mortality (OR = 1.54, 95% CI 1.13 to 2.07, P = 0.005) and fewer days alive and free of organ support (-1.7 days, 95% CI -3.2 to -0.2, P = 0.028) after adjusting for age, sex, race, and SOFA score. In sepsis survivors, CHIP was also associated with increased long-term mortality after discharge (HR 1.40, 95% CI 1.01 to 1.93, P = 0.041). Conclusions: Pre-illness CHIP was independently associated with increased mortality and morbidity in critically-ill adults with sepsis. These findings suggest that CHIP is a risk factor for sepsis severity. Elucidating the mechanism underlying this association could uncover new therapeutic interventions for sepsis.

ObjectiveTo establish a fetal lamb model of complex gastroschisis and characterize the impact on the intestines over time. Summary Background DataGastroschisis is a congenital abdominal wall defect and in its complex form is associated with serious morbidity. Robust large-animal models may help understanding are lacking. MethodsAt gestational day 75, gastroschisis was induced by creating a 1-cm abdominal wall defect reinforced by a silicone ring. Fetuses were assessed either at term or at mid-gestation (13-21 days post-induction). The primary outcome was complex gastroschisis occurrence, defined by bowel stenosis, atresia, volvulus, perforation or necrosis; otherwise classified as simple. At mid-gestation, occurrence was compared between early (13-16 days) and late (17-21 days) intervals. Secondary outcomes included prenatal ultrasound findings, in vivo bowel motility and morphology, ex-vivo bowel contractility, amniotic fluid composition, and histology across complex, simple, and normal groups. ResultsGastroschisis was induced in 32 fetuses. At term (n=14), all survivors (7/14; 50%) had complex gastroschisis, with impaired bowel motility, altered enteric neural contractile responses and smooth muscle remodeling. At mid-gestation (n=18), complex gastroschisis occurred more frequently in the late than in the early group (71% vs. 11%; p=0.035). Mid-gestation gastroschisis fetuses showed greater intra-abdominal bowel dilatation on ultrasound and higher amniotic fluid digestive enzyme levels compared with non-operated littermates, with the greatest dilation observed in complex gastroschisis. ConclusionsThis model consistently reproduces complex gastroschisis in term survivors. After induction, complex gastroschisis occurrence increases with disease duration and is accompanied by structural and functional bowel changes.

Background/ObjectivesIndividuals with Down syndrome (DS) are at increased risk of obesity and metabolic comorbidities, yet the mechanisms underlying these conditions remain unclear. Here we investigated how DS-associated genetic condition interacts with diet and metabolic pathways in the Dp(16)1Yey mouse model of DS. MethodsUntargeted plasma metabolomics was performed in Dp(16)1Yey and control mice, subjected to either control or high-fat diet (HFD). Raw data were processed, and features were annotated. Statistical analyses were conducted in R, and pathway analysis was performed with MetaboAnalyst v5.0. Fecal microbiome was obtained using 16SrRNAseq and analyzed using phyloseq in R. ResultsDiet exerted the strongest effect on mice plasma metabolome, followed by sex and genotype. Seventy-five diet-responsive metabolites were enriched in amino acid and nucleotide metabolism. Genotype-driven changes affected 34 metabolites, notably impacting amino acid and taurine-hypotaurine metabolism. Fifty-six sex-associated metabolites highlighted disruptions in aromatic amino acid biosynthesis and pyrimidine metabolism. A significant Diet*Genotype interaction was observed for five metabolites, including a marked reduction in the microbiota-derived metabolite 3-indolepropionic acid (IPA) in Dp(16)1Yey mice on HFD. Both genotype and diet exerted pronounced effects on fecal microbiome with selective depletion of the IPA-producing Clostridia in Dp1Yey mice under HFD. ConclusionSegmental trisomy in Dp(16)1Yey mice modulates the host metabolic response to dietary fat, partly through microbiota-derived metabolites such as IPA. These findings highlight the importance of genotype, diet, and microbiome interactions in shaping metabolic disease risk in DS and point toward microbiota-targeted dietary interventions.

Background: Acute necrotizing encephalopathy (ANE) is a rare and severe neurologic complication of viral infection in children, thought to result from a hyperacute cytokine storm causing blood-brain barrier disruption and central nervous system injury. Despite characteristic clinical and radiologic features, ANE remains poorly understood at the molecular level, with no validated biomarkers or targeted therapies. We aimed to determine whether genetic predisposition to ANE due to RANBP2 variants is associated with a distinct immunologic signature. Methods: We conducted a prospective biological study of familial ANE (ANE1, NCT06731790). We included 23 heterozygous carriers of the RANBP2 c.1754C>T (p.Thr585Met) variant from 10 families, and 28 noncarriers (median age, 40 years [range, 4-72]). Soluble immune mediators, transcriptomic analyses, multiparameter flow cytometry, and cellular imaging were analysed in peripheral blood mononuclear cells (PBMCs) and monocytes. Baseline and resiquimod stimulated immune responses were analysed within the same statistical model, with genetic status as the primary predictor. Findings: The RANBP2 Thr585Met mutation was associated with a dysregulated inflammatory phenotype characterized by reduced basal mediator production and exaggerated TNF- responses following stimulation (estimated difference, +2,098 pg/mL; 95% CI, 1,121 to 3,076; P=0.0001). Transcriptomic and flow cytometry analyses showed broad reprogramming of myeloid cells with enrichment of CXCR3-high CD14-high subsets. Expansion of these populations was associated with increased long-term disease burden. The RANBP2 variant was the only independent factor associated this inflammatory phenotype. Interpretation: RANBP2-associated ANE is characterised by a distinct immunological signature that can inform disease stratification and support the development of targeted immunotherapeutic approaches.

Background: Placental function is associated with congenital heart defects (CHD), frequently presenting with malperfusion lesions and small-for-gestational-age size. However, placental villous vasculature in the setting of CHD is understudied. This study evaluated differences in placental, neonatal, and maternal outcomes among maternal/infant dyads with versus without CHD. Methods: We conducted a gestational age- and fetal sex-matched retrospective case control study using specimens prospectively collected by a local biobank. Neonatal outcomes included birthweight, placental weight, and their ratio (placental efficiency). We estimated the proportion of placental villous tissue comprised of fetal vascular endothelial cells (%FVE) using anti-CD34 immunohistochemistry and a pixel count algorithm. Placental weight multiplied by %FVE estimated the grams of placental tissue comprised of villous vasculature (placental vascular index). Maternal outcomes included hypertensive disorders of pregnancy and gestational diabetes. We compared cases and controls using linear and logistic regression adjusted for maternal smoking and cold ischemia time. Stratified analyses examined associations by preterm birth status. Results: Dyads (n=34 with CHD, n=34 without CHD) had maternal age of 29.4 +/- 4.9 years and were 35.6 +/- 4.0 gestational weeks at delivery. Groups had similar placental, neonatal, and maternal parameters. Among preterm neonates, we observed small-to-moderate effect sizes indicating lower placental weight, %FVE, and placental vascular index, and higher placental efficiency, in CHD cases. Among term neonates, moderate effect sizes suggested lower birthweight, placental weight, and placental vascular index in CHD cases. Conclusions: Though differences between groups were not significant, moderate effect sizes suggested that placental vascularization was lower among preterm neonates with CHD.