BACKGROUND: Preterm children with their aberrant gut microbiota and susceptibility to infections and inflammation constitute a considerable target group for probiotic therapy to generate the age-appropriate healthy microbiota. METHODS: 68 preterm neonates were randomized into five intervention groups: Beginning from the median age of 3 days, 13 children received Lactobacillus rhamnosus GG (LGG) directly orally, and 17 via the lactating mother. 14 children received LGG with Bifidobacterium lactis Bb-12 (Bb12) orally, and 10 via the lactating mother. 14 children received placebo. The children's faecal microbiota was assessed at the age of 7 days by 16S rRNA gene sequencing. RESULTS: The gut microbiota compositions of the children directly receiving the probiotic combination (LGG + Bb12) were significantly different from those of the children receiving the other intervention modes or placebo (p = 0.0012; PERMANOVA), the distinction being due to an increase in the relative abundance of Bifidobacterium animalis (P < 0.00010; ANCOM-BC), and the order Lactobacillales (P = 0.020; ANCOM-BC). CONCLUSION: The connection between aberrant primary gut microbiota and a heightened risk of infectious and non-communicable diseases invites effective microbiota modulation. We show that the direct, early, and brief probiotic intervention of LGG + Bb12 109 CFU each, is sufficient to modulate the gut microbiota of the preterm neonate. IMPACT: Preterm children have a higher risk of several health problems partly due to their aberrant gut microbiota. More research is needed to find a safe probiotic intervention to modify the gut microbiota of preterm children. The maternal administration route via breast milk might be safer for the newborn. In our study, the early and direct administration of the probiotic combination Lactobacillus rhamnosus GG with Bifidobacterium lactis Bb-12 increased the proportion of bifidobacteria in the preterm children's gut at the age of 7 days, but the maternal administration route was not as effective.

BACKGROUND: Our objective was to examine heterogeneity in the effect of therapeutic hypothermia by sex in infants with moderate or severe neonatal encephalopathy. METHODS: We conducted a post hoc analysis of the Induced Hypothermia trial, which included infants born at gestational ages ≥36 weeks, admitted at ≤6 postnatal hours with evidence of severe acidosis or perinatal complications and moderate or severe neonatal encephalopathy. Multivariate modified Poisson regression models were used to compare the treatment effect of whole-body hypothermia versus control, with an evaluation of interaction by sex, on the primary outcome of death or moderate or severe disability at 18-22 months of corrected age. RESULTS: A total of 101 infants (51 male, 50 female) were randomly assigned to hypothermia treatment and 104 infants (64 male, 40 female) to control. The primary outcome occurred in 45% of the hypothermia group and 63% of the control group (RR 0.73; 95% CI 0.56, 0.94). There was no significant difference (interaction P = 0.50) in the treatment effect of hypothermia on the primary outcome between females (RR 0.79; 95% CI 0.54, 1.17) compared to males (RR 0.63; 95% CI 0.44, 0.91). CONCLUSION: We found no evidence that sex influences the treatment effect of hypothermia in infants with moderate or severe neonatal encephalopathy. IMPACT: Preclinical evidence suggests a differential effect in response to cooling treatment of hypoxic-ischemic injury between males and females. We found no evidence of heterogeneity in the treatment effect of whole-body hypothermia by sex in this post hoc subgroup analysis of infants with moderate or severe neonatal encephalopathy from the National Institute of Child Health and Human Development Neonatal Research Network Induced Hypothermia trial.

BACKGROUND: Illness severity scores predict mortality following pediatric critical illness. Given declining PICU mortality, we assessed the ability of the Pediatric Risk of Mortality-III (PRISM) and Pediatric Logistic Organ Dysfunction-2 (PELOD) scores to predict morbidity outcomes. METHODS: Among 359 survivors <18 years in the Life After Pediatric Sepsis Evaluation multicenter prospective cohort study, we assessed functional morbidity at hospital discharge (Functional Status Scale increase ≥3 points from baseline) and health-related quality of life (HRQL; Pediatric Quality of Life Inventory or Functional Status II-R) deterioration >25% from baseline at 1, 3, 6, and 12 months post-admission. We determined discrimination of admission PRISM and admission, maximum, and cumulative 28-day PELOD with functional and HRQL morbidity at each timepoint. RESULTS: Cumulative PELOD provided the best discrimination of discharge functional morbidity (area under the receive operating characteristics curve [AUROC] 0.81, 95% CI 0.76-0.87) and 3-month HRQL deterioration (AUROC 0.71, 95% CI 0.61-0.81). Prediction was inferior for admission PRISM and PELOD and for 6- and 12-month HRQL assessments. CONCLUSIONS: Illness severity scores have a good prediction of early functional morbidity but a more limited ability to predict longer-term HRQL. Identification of factors beyond illness severity that contribute to HRQL outcomes may offer opportunities for intervention to improve outcomes. IMPACT: Illness severity scores are commonly used for mortality prediction and risk stratification in pediatric critical care research, quality improvement, and resource allocation algorithms. Prediction of morbidity rather than mortality may be beneficial given declining pediatric intensive care unit mortality. The PRISM and PELOD scores have moderate to good ability to predict new functional morbidity at hospital discharge following pediatric septic shock but limited ability to predict health-related quality of life outcomes in the year following PICU admission. Further research is needed to identify additional factors beyond illness severity that may impact post-discharge health-related quality of life.

BACKGROUND: Clinical translation of the extracorporeal artificial placenta (AP) is impeded by the high risk for intracranial hemorrhage in extremely premature newborns. The Nitric Oxide Surface Anticoagulation (NOSA) system is a novel non-thrombogenic extracorporeal circuit. This study aims to test the NOSA system in the AP without systemic anticoagulation. METHODS: Ten extremely premature lambs were delivered and connected to the AP. For the NOSA group, the circuit was coated with DBHD-N2O2/argatroban, 100 ppm nitric oxide was blended into the sweep gas, and no systemic anticoagulation was given. For the Heparin control group, a non-coated circuit was used and systemic anticoagulation was administered. RESULTS: Animals survived 6.8 ± 0.6 days with normal hemodynamics and gas exchange. Neither group had any hemorrhagic or thrombotic complications. ACT (194 ± 53 vs. 261 ± 86 s; p < 0.001) and aPTT (39 ± 7 vs. 69 ± 23 s; p < 0.001) were significantly lower in the NOSA group than the Heparin group. Platelet and leukocyte activation did not differ significantly from baseline in the NOSA group. Methemoglobin was 3.2 ± 1.1% in the NOSA group compared to 1.6 ± 0.6% in the Heparin group (p < 0.001). CONCLUSIONS: The AP with the NOSA system successfully supported extremely premature lambs for 7 days without significant bleeding or thrombosis. IMPACT: The Nitric Oxide Surface Anticoagulation (NOSA) system provides effective circuit-based anticoagulation in a fetal sheep model of the extracorporeal artificial placenta (AP) for 7 days. The NOSA system is the first non-thrombogenic circuit to consistently obviate the need for systemic anticoagulation in an extracorporeal circuit for up to 7 days. The NOSA system may allow the AP to be implemented clinically without systemic anticoagulation, thus greatly reducing the intracranial hemorrhage risk for extremely low gestational age newborns. The NOSA system could potentially be applied to any form of extracorporeal life support to reduce or avoid systemic anticoagulation.

Anthropogenic climate change-driven primarily by the combustion of fossil fuels that form greenhouse gases-has numerous consequences that impact health, including extreme weather events of accelerating frequency and intensity (e.g., wildfires, thunderstorms, droughts, and heat waves), mental health sequelae of displacement from these events, and the increase in aeroallergens and other pollutants. Children are especially vulnerable to climate-related exposures given that they are still developing, encounter higher exposures compared to adults, and are at risk of losing many healthy future years of life. In order to better meet the needs of generations of children born into a world affected by climate change, medical trainees must develop their knowledge of the relationships between climate change and children's health-with a focus on applying that information in clinical practice. This review provides an overview of salient climate change and children's health topics that medical school and pediatric residency training curricula should cover. In addition, it highlights the strengths and limitations of existing medical school and residency climate change and pediatric health curricula. IMPACT: Provides insight into the current climate change and pediatric health curricular opportunities for medical trainees in North America at both the medical school and residency levels. Condenses climate change and pediatric health material relevant to trainees to help readers optimize curricula at their institutions.

BACKGROUND: The main pathophysiologic characteristic of chronic respiratory disease following extremely premature birth is arrested alveolar growth, which translates to a smaller alveolar surface area (SA). We aimed to use non-invasive measurements to estimate the SA in extremely preterm infants. METHODS: Paired measurements of the fraction of inspired oxygen and transcutaneous oxygen saturation were used to calculate the ventilation/perfusion ratio, which was translated to SA using Fick's law of diffusion. The SA was then adjusted using volumetric capnography. RESULTS: Thirty infants with a median (range) gestational age of 26.3 (22.9-27.9) weeks were studied. The median (range) adjusted SA was 647.9 (316.4-902.7) cm2. The adjusted SA was lower in the infants who required home oxygen [637.7 (323.5-837.5) cm2] compared to those who did not [799.1 (444.2-902.7) cm2, p = 0.016]. In predicting the need for supplemental home oxygen, the adjusted SA had an area under the receiver operator characteristic curve of 0.815 (p = 0.017). An adjusted SA ≥688.6 cm2 had 86% sensitivity and 77% specificity in predicting the need for supplemental home oxygen. CONCLUSIONS: The alveolar surface area can be estimated non-invasively in extremely preterm infants. The adjusted alveolar surface area has the potential to predict the subsequent need for discharge home on supplemental oxygen. IMPACT: We describe a novel biomarker of respiratory disease following extremely preterm birth. The adjusted alveolar surface area index was derived by non-invasive measurements of the ventilation/perfusion ratio and adjusted by concurrent measurements of volumetric capnography. The adjusted alveolar surface area was markedly reduced in extremely preterm infants studied at 7 days of life and could predict the need for discharge home on supplemental oxygen. This method could be used at the bedside to estimate the alveolar surface area and provide an index of the severity of lung disease, and assist in monitoring, clinical management and prognosis.

BACKGROUND: Preterm birth and multiple gestation are independently associated with adverse neurodevelopmental outcomes. The objective of this study was to describe risks of screening positive for attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and anxiety in preterm-born twin children by zygosity (monozygotic, dizygotic) and birth order (first-born, second-born). METHODS: Caregivers of 349 preterm-born twin pairs (42% monozygotic) aged 3-18 years reported child behavioral outcomes on Strengths and Weaknesses of ADHD Symptoms and Normal Behavior; Social Responsiveness Scale, Second Edition; and Preschool Anxiety Scale or Screen for Child Anxiety and Related Emotional Disorders. RESULTS: Concordance for behavioral outcomes in twin pairs ranged from 80.06 to 89.31% for ADHD, 61.01 to 84.23% for ASD, and 64.76 to 73.35% for anxiety. Monozygotic twins had a greater risk than dizygotic of screening positive for inattention (risk ratio = 2.91, 95% CI = 1.48-5.72) and social anxiety (1.79, 1.23-2.61). Relative to first-born, second-born twins had a greater risk of screening positive for hyperactivity/impulsivity (1.51, 1.06-2.16); overall ASD (2.38, 1.62-3.49); difficulties with social awareness (2.68, 1.94-3.71), social cognition (4.45, 3.06-6.46), and social communication (2.36, 1.56-3.57); restricted/repetitive behavior (1.91, 1.30-2.81); overall anxiety (1.34, 1.10-1.64); generalized anxiety (1.34, 1.11-1.60); and social anxiety (1.32, 1.06-1.64). CONCLUSION: The current findings emphasize considering zygosity and birth order in preterm and multiple birth outcomes research, and highlight clinical implications for discharge planning, neurodevelopmental surveillance, and facilitating parenting and family support. IMPACT: Zygosity and birth order are important determinants of behavioral and socioemotional outcomes in preterm-born twins. Among 349 preterm-born twin pairs aged 3-18 years (42% monozygotic), 61-89% demonstrated concordance for behavioral and socioemotional outcomes. Monozygosity had greater risks than dizygosity for positive screening of inattention and social anxiety. Second-born twins had greater risks than first-born for hyperactivity/impulsivity, social difficulties (awareness, cognition, communication), restricted/repetitive behavior, and anxiety (generalized, social). These findings have implications for discharge planning, neurodevelopmental surveillance, and facilitating parenting and family support.