BACKGROUND:Our aim was to describe the possible association between early, routinely measured serum laboratory parameters and in-hospital mortality in neonates with neonatal encephalopathy (NE), treated with hypothermia. METHODS:This retrospective exploratory cohort study analyzed the results of 19 routinely measured laboratory parameters taken at 6 h of postnatal life from neonates with NE. The primary outcome was defined as in-hospital mortality. RESULTS:A total of 441 neonates were analyzed, the rate of in-hospital mortality was 12.5%. Multivariable logistic regression analysis (adjusted for 5 min Apgar, initial base excess and Thompson score) showed that for every 1 mmol/L increase in serum phosphate level, the odds of death increased by 8.43-fold (95% CI 3.33-21.39; p = 0.001). ROC analysis demonstrated that a serum phosphate level above 2.58 mmol/L (a threshold remaining within the normal range) provided strong discriminatory potential for in-hospital mortality within this cohort (AUC 0.90; sensitivity 80%, specificity 89%). Among survivors, neurodevelopmental impairment (using the Bayley-II test) was not associated with the initial serum phosphate level. CONCLUSION:Our results suggest that early serum phosphate may be a potential biomarker in the future and may additionally be used to determine the severity and short-term prognosis of neonates with NE. IMPACT:Increased serum phosphate level at six hours of postnatal age was associated with higher odds of in-hospital mortality in infants with neonatal encephalopathy. Unlike for mortality prediction, phosphate was not a significant predictor of neurodevelopmental outcomes. Early serum phosphate may be a potential biomarker in the future and may additionally be used to determine the severity and short-term prognosis of neonates with neonatal encephalopathy.
BACKGROUND:Post-inflammatory wheezing (PIW) is a highly prevalent recurrent respiratory disease in children after acute pulmonary infection, characterized by persistent airway inflammatory imbalance. Azithromycin (AZM) exerts independent immunomodulatory functions beyond its antibacterial activity and can effectively improve pediatric PIW. However, it remains unclear whether AZM participates in the repair of PIW by regulating SET domain containing 1B (SETD1B)-mediated histone H3K4me3 methylation and modulating alveolar macrophage polarization. METHODS:A total of 239 children with severe pneumonia were enrolled and divided into non-wheeze and PIW groups. Children with PIW received either routine symptomatic treatment or AZM intervention at a dose of 10 mg/kg/day for 5 consecutive days. Clinical prognoses, BALF cellular composition, inflammatory cytokine levels, and the expression of SETD1B and H3K4me3 were compared between groups. A lipopolysaccharide (LPS)-induced inflammatory model of rat alveolar macrophages, treated with the SETD1B-specific inhibitor WDR5-0103, was constructed to validate the core regulatory pathway. RESULTS:Children with PIW exhibited abnormal BALF cellular composition, upregulated pro-inflammatory factor IL-6, downregulated anti-inflammatory factor IL-10, and significantly increased expression of SETD1B and H3K4me3. AZM treatment effectively shortened wheezing duration and hospital stay and reduced medical costs. Furthermore, no significant differences in clinical efficacy were observed between mycoplasma-positive and mycoplasma-negative children treated with AZM, confirming that the therapeutic effect of AZM is independent of its anti-mycoplasma activity. In vitro, LPS induced SETD1B/H3K4me3 hypermethylation, inflammatory cytokine disturbance, and M1-type macrophage polarization. Either AZM or WDR5-0103 alone significantly reversed these LPS-induced abnormalities, and no additional synergistic efficacy was observed in the combined intervention group. CONCLUSIONS:AZM ameliorates PIW in children mainly through immunomodulation rather than antibacterial effects. It inhibits SETD1B-mediated H3K4me3 hypermethylation, corrects the imbalance of alveolar M1/M2 macrophage polarization, restores IL-6/IL-10 inflammatory homeostasis, and ultimately alleviates airway inflammatory injury and wheezing symptoms in children. IMPACT:Azithromycin (AZM) alleviates the release of inflammatory factors by regulating the H3K4me3 modification, thereby reducing post-inflammatory wheezing; The addition of new indications to the clinical application of AZM; Currently, there is no effective treatment for post-inflammatory wheezing. Although AZM is a common antimicrobial agent, this study demonstrates that it can alleviate non-specific inflammation in alveolar macrophages. Thus, AZM represents a promising therapeutic strategy.
BACKGROUND:Gut microbiota imbalances may contribute to obesity, yet whether dietary interventions can modulate the microbiota and improve metabolic health in pediatrics has not been thoroughly reviewed. This systematic review and meta-analysis explores the impact of dietary interventions on the gut microbiota of children and adolescents with overweight or obesity, and its association with cardiometabolic improvements. METHODS:A systematic search of clinical trials in Pubmed, Cochrane and EMBASE was conducted following PRISMA guidelines (PROSPERO n°CRD42024505494). Risk of bias was assessed with RoB2 and ROBINS, for randomized and non-randomized intervention studies. RESULTS:Overall, 60 articles were assessed for full-text eligibility, 8 were included, and 4 provided alpha-diversity data for meta-analysis. A total of 200 participants were included (6-16 years). Six studies implemented calorie-restricted diets, one a low free-sugar diet, and one CHILD-1 diet. The meta-analysis revealed a significant increase in Chao1 (48.76 [95%CI 1.81; 95.70]; I2 = 86.8%, p < 0.001) following a balanced calorie-restricted dietary intervention. Although there was heterogeneity in taxa-level changes, several butyrate-producing genera (Clostridium XVIa, Coprococcus, Roseburia, Faecalibacterium, Blautia, Butyricimonas) increased following dietary intervention. CONCLUSIONS:Balanced dietary interventions with calorie-restriction adequate for pediatric age could increase gut microbiota richness and butyrate-producing bacteria abundance. Future trials should clarify diet-driven gut microbiota changes in childhood obesity and related metabolic changes. IMPACT:Balanced calorie restriction diet may increase gut microbiota richness in childhood obesity Butyrate-producer expansion needs long-term dietary intervention Gaps in linking microbiota-metabolism interplay in pediatric obesity.
BACKGROUND:Albumin infusion is commonly used in preterm infants following intestinal resection, but the optimal treatment duration remains unclear. METHODS:This two-center retrospective cohort study included 102 preterm infants who underwent intestinal resection in China between 2018 and 2024. Infants were classified as receiving short-course (≤5 days, n = 69) or long-course (>5 days, n = 33) albumin therapy. The primary outcome was 90-day all-cause mortality. Multivariable regression analyses modeled treatment duration as a continuous variable and adjusted for measured covariates; sensitivity and subgroup analyses were performed. RESULTS:No statistically significant differences were observed in measured baseline characteristics between the groups. Crude 90-day mortality was numerically higher in the long-course group than in the short-course group (15.2% vs. 4.3%). When treatment duration was modeled continuously, the adjusted odds ratio for mortality was 1.36 per additional treatment day (95% CI, 0.98-1.97; P = 0.063). No statistically significant differences were detected in secondary outcomes or analyses using alternative duration thresholds. CONCLUSIONS:Among preterm infants undergoing intestinal resection, no statistically significant differences in mortality or major postoperative outcomes were detected between treatment groups. However, clinician-determined treatment duration and residual confounding by indication preclude conclusions regarding equivalence or the clinical benefit of prolonged therapy. IMPACT:No statistically significant differences in mortality or major postoperative outcomes were detected between short-course (≤5 days) and long-course (>5 days) albumin therapy in preterm infants undergoing intestinal resection. Albumin treatment duration was determined by clinical status, and substantial residual confounding by indication cannot be excluded. These exploratory findings do not establish equivalence between treatment strategies and cannot determine whether prolonged albumin therapy provides clinical benefit.
BACKGROUND:Body mass index (BMI) is widely used to assess pediatric obesity but does not fully capture adiposity-related organ dysfunction. The Clinical Framework of Obesity 2025 (CFO-2025), proposed by The Lancet Diabetes & Endocrinology Commission, offers a complementary clinical approach. OBJECTIVE:To evaluate pediatric obesity classification using Centers for Disease Control and Prevention BMI (CDC-BMI) criteria and the CFO-2025, and to describe organ-system involvement in clinical obesity. METHODS:This cross-sectional study analyzed 220 patients aged 4-16 years from a pediatric obesity clinic in northeastern Mexico. Obesity was classified using CDC-BMI criteria and the CFO-2025 with pediatric adaptations. Under the CFO-2025, patients were categorized as having preclinical or clinical obesity based on organ-system involvement. Concordance was assessed using Cohen's kappa. RESULTS:Obesity prevalence was 80% by CDC-BMI criteria and 95% by the CFO-2025, with fair concordance (κ = 0.321; p < 0.001). Clinical obesity was identified in 83.2% of patients, including those classified as having normal weight or overweight by CDC-BMI; metabolic (73.2%) and cardiovascular (59%) systems were most frequently affected. CONCLUSIONS:Applied alongside BMI, the CFO-2025 identified additional multisystem involvement. Although not yet validated in children, it may support a more comprehensive clinical assessment of pediatric obesity. IMPACT:In the Pediatric Obesity Clinic at a referral hospital in northeastern Mexico, the Clinical Framework of Obesity 2025 (CFO-2025) classified a higher proportion of children as having obesity compared with the CDC-BMI criteria, with only fair concordance between systems. We provide preliminary pediatric evidence that the CFO-2025 identifies multisystem involvement, including metabolic and cardiovascular abnormalities, even among children categorized as normal weight or overweight by BMI. Although the CFO-2025 has not yet been validated in pediatric populations, integrating BMI with the CFO-2025 may support a more structured and comprehensive assessment of obesity-related organ involvement in children.
Environmental exposures are major determinants of child health, particularly during critical developmental windows extending from preconception through childhood. The exposome framework provides a comprehensive and dynamic approach to studying the totality of environmental exposures and their biological consequences across the life course, moving beyond traditional single-pollutant approaches. Here, we summarize current exposure-assessment tools, including questionnaires, biomarkers, sensors, geospatial indicators, and large-scale databases. It also highlights advances in longitudinal cohort studies, multi-omics integration, and analytical methods designed to address complex exposure mixtures and critical windows of susceptibility. Recent exposome studies have improved our understanding of how chemical, physical, climatic, built-environment, and social exposures interact to influence child health and development. Large exposome cohorts have demonstrated the feasibility of integrating environmental, biological, and social data while identifying pathways linking early-life exposure to child-health outcomes. Ongoing developments in exposure assessment, harmonization, causal inference, and multi-omics integration are accelerating the translation of exposome research into prevention, clinical practice, and public health. Because many environmental determinants of health act during early development, pediatricians should play a central role in translating exposome evidence into prevention, clinical practice, and public-health action. IMPACT QUESTION: WHAT DOES THIS REVIEW ADD TO THE EXISTING LITERATURE?: This review provides a pediatric-focused overview of exposome research, emphasizing critical windows from preconception through early life and their implications for lifelong health It integrates recent advances in exposome assessment, longitudinal cohort studies, multi-omics approaches, and analytical methods, while highlighting current methodological and translational challenges. It highlights the central role of pediatricians in translating exposome research into prevention, clinical practice, and public-health actions by identifying modifiable environmental, biological, and social determinants of child health.
Bronchopulmonary dysplasia (BPD) is the most common chronic pulmonary complication of extreme prematurity in infants, now understood as a disorder of disrupted lung development rather than acute injury alone. Conventional clinical and functional criteria fail to capture the full heterogeneity of outcomes or the persistence of pulmonary morbidity into adulthood. Epigenetic mechanisms-including DNA methylation, histone modifications, and non-coding RNAs-provide a unifying biological framework linking perinatal exposures to long-term lung dysfunction. In the preterm lung, hyperoxia, inflammation, infection, pharmacologic interventions, and microbiome alterations durably influence gene expression without changing the DNA sequence, contributing to impaired alveolarization, pulmonary vascular growth, antioxidant defenses, immune regulation, and cellular senescence. Hyperoxia, specifically, has been associated with lasting epigenetic changes in redox-sensitive pathways, angiogenic signaling, and cell cycle control, while inflammatory stimuli may establish epigenetic "memory" that is consistent with the persistence of chronic inflammation and defective repair. Collectively, these processes support a model in which epigenetically programmed lung phenotypes may emerge, characterized by reduced pulmonary reserve, accelerated lung aging, and heightened vulnerability to respiratory disease across the lifespan. Although evidence for transgenerational inheritance in humans is limited, inherited susceptibility remains plausible, but unproven. Framing BPD as a disorder of biological memory emphasizes the need for epigenetic biomarkers, longitudinal cohort studies, and targeted preventive or therapeutic strategies to improve lifelong outcomes in survivors. IMPACT: This review reframes Bronchopulmonary Dysplasia as a disorder of developmental programming and biological memory, integrating hyperoxia, inflammation, and pharmacologic exposures within a DOHaD-based epigenetic framework to explain long-term pulmonary and systemic heterogeneity. It synthesizes experimental, translational, and clinical evidence-including redox epigenetics, trained immunity, sex-specific responses, and lung-brain-immune interactions-supporting a model in which early-life exposures shape lifelong respiratory and extra-pulmonary outcomes, while acknowledging that some mechanisms remain unproven. It identifies key translational priorities, including validation of epigenetic biomarkers, longitudinal multi-omics studies, and cautious development of epigenetic therapies, while emphasizing current methodological limitations and remaining evidence gaps.
Impact The publication of a commentary provides an opportunity to increase the visibility of a manuscript published in the journal by highlighting a research phenomenon with significant potential.
BACKGROUND:To determine whether chorioamnionitis-exposure in extremely preterm infants was associated with higher transepidermal water loss (TEWL) and to explore whether this relationship varied by gestational age, placental histopathology and illness severity. METHODS:In this prospective single-centre cohort study, infants ≤27+6 weeks' gestational age underwent closed-chamber TEWL measurement on days 1, 3 and 14 in humidified incubators utilizing standardized methodology. Infants were classified according to placental histopathology and inflammation severity. Interactions assessed included gestational and postnatal age, and illness acuity. RESULTS:Thirty-seven infants were included, 13 of which had histological chorioamnionitis. Chorioamnionitis was associated with higher day-one TEWL; however, this was no longer significant after gestational adjustment (p = 0.152). A significant gestation-by-chorioamnionitis interaction was confined to the most immature infants (p = 0.017). In this cohort, higher TEWL was associated with a placental inflammatory response and postnatal instability. Adjusted TEWL declined from days 1 to 14, with the greatest between-group difference on day-one. CONCLUSION:In this exploratory cohort, the association between histological chorioamnionitis and early TEWL was modified by gestational age, with higher TEWL observed among the most immature exposed infants. These hypothesis-generating findings suggest that fetal inflammation and early physiological instability may both contribute to impaired barrier adaptation. IMPACT:Chorioamnionitis-exposure and epidermal immaturity are frequent hallmarks of extreme prematurity. Although several morbidities have been attributed to chorioamnionitis, a skin component remains unclear. We report a gestation-dependent association between chorioamnionitis and skin integrity, most evident in infants at or below approximately 25 weeks' gestational age. A fetal inflammatory response may contribute to both elevated transepidermal water loss and postnatal instability, suggesting these may contribute alongside immaturity to impaired barrier function in the most preterm infants. Our findings suggest extremely preterm infants exposed to intrauterine inflammation may be uniquely vulnerable to fluid imbalance or skin injury owing to compromised barrier integrity.
BACKGROUND:This study aimed to assess disseminated intravascular coagulation (DIC) incidence and its correlation with pediatric intensive care unit mortality across various scoring systems to identify the most effective diagnostic approach for different subgroups of critically ill children. METHODS:This observational cohort study compared five established diagnostic criteria for DIC: the International Society on Thrombosis and Hemostasis overt DIC criteria (DIC-ISTH 2021 and 2025criteria), sepsis-induced coagulopathy criteria (SIC-ISTH and SIC-China criteria) and the Chinese DIC Scoring System. RESULTS:This study of 2015 critically ill children revealed substantial variation in DIC incidence rates across diagnostic criteria, with SIC-ISTH consistently identifying the highest proportion of cases. There was excellent agreement between the 2021 and 2025 DIC-ISTH criteria and near-perfect agreement between the SIC-ISTH and SIC-China criteria, with consistent results across all subgroups. In patients with sepsis, SIC criteria exhibited higher area under the curve (AUC) and sensitivity than DIC criteria. Among patients with hematologic malignancies, mortality rates and sensitivity for mortality discrimination were comparable between SIC and DIC criteria. CONCLUSIONS:DIC incidence varies significantly depending on diagnostic criteria and clinical subgroup. SIC criteria provide the most reliable for early detection of DIC. A combination of the SIC-ISTH and DIC-ISTH (2001) criteria is recommended for screening overt-DIC in critically ill pediatric patients. IMPACT:1. Disseminated intravascular coagulation is a life-threatening condition in pediatric critical care, strongly correlating with multiorgan dysfunction and mortality. 2. No single definition has proven superior, and a universal consensus on the most appropriate diagnostic criteria for pediatric patients remains lacking. 3. This study addresses a critical gap in pediatric critical care by systematically evaluating five established DIC diagnostic criteria in a heterogeneous PICU cohort, including sepsis and hematologic malignancy subgroups. 4. Our key findings directly align with your journal's focus on evidence-based approaches to pediatric research.
BACKGROUND:Prematurity is associated with a high risk of abnormal neurodevelopment, inflicting life-long neurocognitive consequences with major public health importance. This calls for early biomarkers of functional brain development to serve as indicators of the effect of environmental enrichment in neonatal intensive care units (NICU). METHODS:Here, we studied whether the previously found functional brain network effects of Family Nurture Intervention (FNI) are replicated in an independent trial, and when these effects arise in early brain development. We compared networks in infants following FNI treatment to infants receiving standard NICU care (SC) and to term-born healthy controls (HC). RESULTS:We found that the prior network results, i.e. decrease in the strength of phase-based networks of FNI infants, replicated fully within the same site and partially at an external validation site. Moreover, longitudinal tracking of cortical networks disclosed an early divergence of trajectories between FNI and SC groups during the preterm period, resulting in no detectable difference in the functional networks of FNI and HC infants at term age, while the corresponding networks of SC infants showed significant difference. CONCLUSION:The findings together support the idea that FNI may modulate early developmental trajectories of cortical networks and mitigate effects of prematurity. IMPACT:Previously reported brain network effects of Family Nurture Intervention (FNI) replicated fully in an independent trial within the same site and partially at an external validation site. Developmental analysis revealed that FNI lead infants to a different trajectory of brain development compared to infants receiving standard care, resulting in no detectable difference in their functional networks compared to healthy term-born counterparts at term age. The findings together support the idea that FNI may modulate early developmental trajectories of cortical networks and mitigate the effects of prematurity. FNI provides an accessible and cost-effective intervention with potentially substantial global impact.
BACKGROUND:Antimicrobial resistance increasingly complicates empirical treatment of pediatric Helicobacter pylori (H. pylori) infection. We examined resistance patterns and the relationship of molecular and culture-based results to treatment and eradication outcomes. METHODS:We retrospectively studied children who underwent clinically indicated endoscopy with paired polymerase chain reaction (PCR) and culture testing between October 2022 and October 2024. Resistance-associated variants were identified by PCR and Sanger sequencing. Culture-positive isolates underwent antimicrobial susceptibility testing, which informed treatment selection. Eradication was assessed by carbon-13 urea breath testing. RESULTS:Of 145 children, 128 (88.3%) were PCR positive and 92 were culture positive. Phenotypic resistance to clarithromycin (CLA), metronidazole (MTZ), and levofloxacin (LVX) was 82.6%, 81.5%, and 29.3%, respectively; 72.8% of isolates were resistant to at least two antibiotics. Molecular prediction of CLA nonsusceptibility had 98.8% sensitivity, 90.9% specificity, and 97.8% accuracy; corresponding values for LVX were 90.9%, 97.7%, and 95.5%. Eradication was achieved in 86 of 97 treated children (88.7%), and 80 of 84 treated culture-positive children received phenotypically concordant regimens. CONCLUSION:CLA and MTZ resistance and multidrug resistance were frequent. Molecular analysis of 23S rRNA and gyrA complemented culture-based susceptibility testing in treatment selection. IMPACT:Clarithromycin and metronidazole resistance exceeded 80%, and nearly three quarters of the pediatric H. pylori isolates were resistant to at least two antibiotics, substantially limiting empirical treatment options. Molecular analysis of 23S rRNA and gyrA closely reflected phenotypic clarithromycin and levofloxacin nonsusceptibility, whereas molecular findings for other antibiotics were less readily interpretable. By linking molecular and culture-based resistance results with the regimens prescribed and subsequent eradication outcomes, this study shows how the two approaches can complement each other in routine pediatric care.
IgA vasculitis (IgAV) is the most common pediatric small-vessel vasculitis, while central nervous system involvement remains rare and mechanistically unclear. In this commentary, we discuss a recent study investigating whether gut microbiota alterations may be associated with neurological involvement in IgAV through gut–brain axis interactions. Using fecal microbiota transplantation from children with IgAV with or without neurological involvement into specific pathogen-free mice, the authors reported electroencephalographic abnormalities exclusively in mice receiving microbiota from neurologically affected donors. The study further identified enrichment of Anaeroplasma, alterations in short-chain fatty acids including increased caproic acid, and changes in systemic cytokines such as IL-17A and IL-1α. We highlight the potential relevance of integrating microbiome, metabolome, and immune profiling in a functional experimental framework to move beyond associative microbiome studies. However, limitations including small donor numbers, lack of paired human multi-omics validation, and incomplete mechanistic resolution of neurophysiological changes constrain causal interpretation. We propose that these findings should be viewed as hypothesis-generating and emphasize the need for larger human cohorts and mechanistic validation using gnotobiotic models. Overall, this study provides a conceptual framework linking gut microbial alterations to neurological manifestations in IgAV and opens new avenues for future research into subtype-specific disease mechanisms.
