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Objective: To characterize the demographic and clinical features of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) syndromes and identify admission variables predictive of disease severity.Study Design: We conducted a multicenter, retrospective, and prospective study of pediatric patients hospitalized with acute SARS-CoV-2 infections and multisystem inflammatory syndrome in children (MIS-C) at 8 sites in New York, New Jersey, and Connecticut.Results: We identified 281 hospitalized patients with SARS-CoV-2 infections and divided them into 3 groups based on clinical features. Overall, 143 (51%) had respiratory disease, 69 (25%) had MIS-C, and 69 (25%) had other manifestations including gastrointestinal illness or fever. Patients with MIS-C were more likely to identify as non-Hispanic black compared with patients with respiratory disease (35% vs 18%, P = .02). Seven patients (2%) died and 114 (41%) were admitted to the intensive care unit. In multivariable analyses, obesity (OR 3.39, 95% CI 1.26-9.10, P = .02) and hypoxia on admission (OR 4.01; 95% CI 1.14-14.15; P = .03) were predictive of severe respiratory disease. Lower absolute lymphocyte count (OR 8.33 per unit decrease in 109 cells/L, 95% CI 2.32-33.33, P = .001) and greater C-reactive protein (OR 1.06 per unit increase in mg/dL, 95% CI 1.01-1.12, P = .017) were predictive of severe MIS-C. Race/ethnicity or socioeconomic status were not predictive of disease severity.Conclusions: We identified variables at the time of hospitalization that may help predict the development of severe SARS-CoV-2 disease manifestations in children and youth. These variables may have implications for future prognostic tools that inform hospital admission and clinical management. [ABSTRACT FROM AUTHOR]

Prior work has examined associations between cardiometabolic pregnancy complications and autism spectrum disorder (ASD) but not how these complications may relate to social communication traits more broadly. We addressed this question within the Environmental Influences on Child Health Outcomes program, with 6,778 participants from 40 cohorts conducted from 1998–2021 with information on ASD-related traits via the Social Responsiveness Scale. Four metabolic pregnancy complications were examined individually, and combined, in association with Social Responsiveness Scale scores, using crude and adjusted linear regression as well as quantile regression analyses. We also examined associations stratified by ASD diagnosis, and potential mediation by preterm birth and low birth weight, and modification by child sex and enriched risk of ASD. Increases in ASD-related traits were associated with obesity (β = 4.64, 95% confidence interval: 3.27, 6.01) and gestational diabetes (β = 5.21, 95% confidence interval: 2.41, 8.02), specifically, but not with hypertension or preeclampsia. Results among children without ASD were similar to main analyses, but weaker among ASD cases. There was not strong evidence for mediation or modification. Results suggest that common cardiometabolic pregnancy complications may influence child ASD-related traits, not only above a diagnostic threshold relevant to ASD but also across the population. [ABSTRACT FROM AUTHOR]

We examined the effect of maternal smoking on plasma and urinary levels of vitamin E isoforms in preterm infants. Maternal smoking during pregnancy decreased infant plasma alpha- and gamma-tocopherol concentrations at 1 week and 4 weeks, with 45% of infants of smokers deficient in alpha-tocopherol at 1 month after birth. [ABSTRACT FROM AUTHOR]

Objective: n -3 fatty acid consumption during pregnancy is recommended for optimal pregnancy outcomes and offspring health. We examined characteristics associated with self-reported fish or n -3 supplement intake. Design: Pooled pregnancy cohort studies. Setting: Cohorts participating in the Environmental influences on Child Health Outcomes (ECHO) consortium with births from 1999 to 2020. Participants: A total of 10 800 pregnant women in twenty-three cohorts with food frequency data on fish consumption; 12 646 from thirty-five cohorts with information on supplement use. Results: Overall, 24·6 % reported consuming fish never or less than once per month, 40·1 % less than once a week, 22·1 % 1–2 times per week and 13·2 % more than twice per week. The relative risk (RR) of ever (v. never) consuming fish was higher in participants who were older (1·14, 95 % CI 1·10, 1·18 for 35–40 v. <29 years), were other than non-Hispanic White (1·13, 95 % CI 1·08, 1·18 for non-Hispanic Black; 1·05, 95 % CI 1·01, 1·10 for non-Hispanic Asian; 1·06, 95 % CI 1·02, 1·10 for Hispanic) or used tobacco (1·04, 95 % CI 1·01, 1·08). The RR was lower in those with overweight v. healthy weight (0·97, 95 % CI 0·95, 1·0). Only 16·2 % reported n -3 supplement use, which was more common among individuals with a higher age and education, a lower BMI, and fish consumption (RR 1·5, 95 % CI 1·23, 1·82 for twice-weekly v. never). Conclusions: One-quarter of participants in this large nationwide dataset rarely or never consumed fish during pregnancy, and n -3 supplement use was uncommon, even among those who did not consume fish. [ABSTRACT FROM AUTHOR]

The Environmental Influences on Child Health Outcomes (ECHO)-Wide Cohort Study (EWC), a collaborative research design comprising 69 cohorts in 31 consortia, was funded by the National Institutes of Health (NIH) in 2016 to improve children's health in the United States. The EWC harmonizes extant data and collects new data using a standardized protocol, the ECHO-Wide Cohort Data Collection Protocol (EWCP). EWCP visits occur at least once per life stage, but the frequency and timing of the visits vary across cohorts. As of March 4, 2022, the EWC cohorts contributed data from 60,553 children and consented 29,622 children for new EWCP data and biospecimen collection. The median (interquartile range) age of EWCP-enrolled children was 7.5 years (3.7–11.1). Surveys, interviews, standardized examinations, laboratory analyses, and medical record abstraction are used to obtain information in 5 main outcome areas: pre-, peri-, and postnatal outcomes; neurodevelopment; obesity; airways; and positive health. Exposures include factors at the level of place (e.g. air pollution, neighborhood socioeconomic status), family (e.g. parental mental health), and individuals (e.g. diet, genomics). [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Early Life Iron Deficiency Impairs Spatial Cognition in Neonatal Piglets," by J. L. Rytych, M.R. Elmore, M. D. Burton et al. in a 2012 issue of the journal.

Background: Options to treat pulmonary hypertension (PH) in neonates with bronchopulmonary dysplasia (BPD) are few and largely ineffective. Improving the bioavailability of nitric oxide (NO) might be an efficacious treatment for BPD-PH. When administered orally, the NO-l-arginine precursor, l-citrulline, increases NO production in children and adults, however, pharmacokinetic (PK) studies of oral l-citrulline have not been performed in infants and children. Objectives: This study characterized the PK of enterally administered l-citrulline in neonates at risk of developing BPD-PH to devise a model-informed dosing strategy. Methods and results: Ten premature neonates (≤ 28 weeks gestation) were administered a single dose of 150 mg/kg (powder form solubilized in sterile water) oral l-citrulline at 32 ± 1 weeks postmenstrual age. Due to the need to limit blood draws, time windows were used to maximize the sampling over the dosing interval by assigning neonates to one of two groups (ii) samples collected pre-dose and at 1- and 2.5-h post-dose, and (ii) pre-dose and 0.25- and 3-h post-dose. The l-arginine concentrations (µmol/L) and the l-citrulline (µmol/L) plasma concentration-time data were evaluated using non-compartmental analysis (Phoenix WinNonlin version 8.1). Optimal dosage strategies were derived using a simulation-based methodology. Simulated doses of 51.5 mg or 37.5 mg/kg given four times a day produced steady-state concentrations close to a target of 50 µmol/L. The volume of distribution (V/F) and clearance (CL/F) were 302.89 ml and 774.96 ml/h, respectively, with the drug exhibiting a half-life of 16 minutes. The AUC from the time of dosing to the time of last concentration was 1473.3 h*μmol/L, with Cmax and Tmax of 799 μmol/L and 1.55 h, respectively. Conclusion: This is the first PK study in neonates presenting data that can be used to inform dosing strategies in future randomized controlled trials evaluating enteral l-citrulline as a potential treatment to reduce PH associated with BPD in premature neonates. Registration: Clinical trials.gov Identifier: NCT03542812. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Experts hypothesized increased weight gain in children associated with the coronavirus disease 2019 (COVID-19) pandemic. Our objective was to evaluate whether the rate of change of child body mass index (BMI) increased during the COVID-19 pandemic compared with prepandemic years. METHODS: The study population of 1996 children ages 2 to 19 years with at least 1 BMI measure before and during the COVID-19 pandemic was drawn from 38 pediatric cohorts across the United States participating in the Environmental Influences on Child Health Outcomes-wide cohort study. We modeled change in BMI using linear mixed models, adjusting for age, sex, race, ethnicity, maternal education, income, baseline BMI category, and type of BMI measure. Data collection and analysis were approved by the local institutional review board of each institution or by the central Environmental Influences on Child Health Outcomes institutional review board. RESULTS: BMI increased during the COVID-19 pandemic compared with previous years (0.24 higher annual gain in BMI during the pandemic compared with previous years, 95% confidence interval 0.02 to 0.45). Children with BMI in the obese range compared with the healthy weight range were at higher risk for excess BMI gain during the pandemic, whereas children in higher-income households were at decreased risk of BMI gain. CONCLUSIONS: One effect of the COVID-19pandemic is an increase in annual BMI gain during the COVID-19 pandemic compared with the 3 previous years among children in our national cohort. This increased risk among US children may worsen a critical threat to public health and health equity. [ABSTRACT FROM AUTHOR]

Effective therapies are urgently needed for infants with forms of pulmonary hypertension that develop or persist beyond the first week of life. The L-arginine nitric oxide ( NO) precursor, L-citrulline, improves NO signalling and ameliorates pulmonary hypertension in newborn animals. In vitro studies demonstrate that manipulating L-citrulline transport alters NO production. Conclusion Strategies that increase the supply and transport of L-citrulline merit pursuit as novel approaches to managing infants with chronic, progressive pulmonary hypertension. [ABSTRACT FROM AUTHOR]

The corona virus disease (COVID-19) pandemic disrupted daily life worldwide, and its impact on child well-being remains a major concern. Neighborhood characteristics affect child well-being, but how these associations were affected by the pandemic is not well understood. We analyzed data from 1039 children enrolled in the Environmental influences on Child Health Outcomes Program whose well-being was assessed using the Patient-Reported Outcomes Measurement Information System Global Health questionnaire and linked these data to American Community Survey (ACS) data to evaluate the impacts of neighborhood characteristics on child well-being before and during the pandemic. We estimated the associations between more than 400 ACS variables and child well-being t-scores stratified by race/ethnicity (non-Hispanic white vs. all other races and ethnicities) and the timing of outcome data assessment (pre-vs. during the pandemic). Network graphs were used to visualize the associations between ACS variables and child well-being t-scores. The number of ACS variables associated with well-being t-scores decreased during the pandemic period. Comparing non-Hispanic white with other racial/ethnic groups during the pandemic, different ACS variables were associated with child well-being. Multiple ACS variables representing census tract-level housing conditions and neighborhood racial composition were associated with lower well-being t-scores among non-Hispanic white children during the pandemic, while higher percentage of Hispanic residents and higher percentage of adults working as essential workers in census tracts were associated with lower well-being t-scores among non-white children during the same study period. Our study provides insights into the associations between neighborhood characteristics and child well-being, and how the COVID-19 pandemic affected this relationship. • Explored neighborhood characteristics and child well-being in a nation-wide sample. • Pandemic attenuated neighborhood characteristics and child well-being associations. • 142 ACS variables associated with pre-pandemic well-being, dropped to 20 during pandemic. • Racial disparities in neighborhood-child well-being associations. [ABSTRACT FROM AUTHOR]

Aim Neurodevelopmental delay in childhood is common in infants born preterm, but is difficult to predict before infants leave the neonatal intensive care unit ( NICU). We hypothesized that event-related potential ( ERP) methodology characterizing the cortical differentiation of speech sounds in hospitalized infants would predict cognitive and language outcomes during early childhood. Methods We conducted a prospective study of 57 infants in NICU (34 male, gestational age at birth 24-40wks), quantifying the amplitude of ERP responses to speech sounds before discharge (median gestational age 37.1wks), followed by standardized neurodevelopmental assessments at 12 months and 24 months. Analyses were performed using ordinary least squares linear regression. Results Overall validity of constructs using all ERP variables, as well as sex, maternal education, gestational age, and age at ERP, was good and allowed significant prediction of cognitive and communication outcomes at 12 months and 24 months ( R2=22-42%; p<0.05). Quantitative models incorporating specific ERPs, gestational age, and age at ERP explained a large proportion of the variance in cognition and receptive language on the Bayley Scales of Infant Development at 24 months ( R2>50%; p<0.05). Interpretation This study establishes ERP methodology as a valuable research tool to quantitatively assess cortical function in the NICU and to predict meaningful outcomes in early childhood. [ABSTRACT FROM AUTHOR]

Background: Characterizing the prevalence and persistence of symptoms associated with COVID-19 infection following hospitalization and their impact is essential to planning post-acute community-based clinical services. This study seeks to identify persistent COVID-19 symptoms in patients 35 days post-hospitalization and their impact on quality of life, health, physical, mental, and psychosocial function. Methods and findings: This prospective cohort study used the PROMIS® Instruments to identify symptoms and quality of life parameters in consecutively enrolled patients between March 22 and April 16, 2020, in New Jersey. The 183 patients (median age 57 years; 61.5% male, 54.1% white) reported persistent symptoms at 35 days, including fatigue (55.0%), dyspnea (45.3%), muscular pain (51%), associated with a lower odds rating general health (41.5%, OR 0.093 [95% CI: 0.026, 0.329], p = 0.0002), quality of life (39.8%; OR 0.116 [95% CI: 0.038, 0.364], p = 0.0002), physical health (38.7%, OR 0.055 [95% CI: 0.016, 0.193], p <0.0001), mental health (43.7%, OR 0.093 [95% CI: 0.021, 0.418], p = 0.0019) and social active role (38.7%, OR 0.095 [95% CI: 0.031, 0.291], p<0.0001), as very good/excellent, particularly adults aged 65 to 75 years (OR 8·666 [95% CI: 2·216, 33·884], p = 0·0019). Conclusions: COVID-19 symptoms commonly persist to 35 days, impacting quality of life, health, physical and mental function. Early post-acute evaluation of symptoms and their impact on function is necessary to plan community-based services. [ABSTRACT FROM AUTHOR]

Lung macrophages mature after birth, placing newborn infants, particularly those born preterm, within a unique window of susceptibility to disease. We hypothesized that in preterm infants, lung macrophage immaturity contributes to the development of bronchopulmonary dysplasia (BPD), the most common serious complication of prematurity. By measuring changes in lung macrophage gene expression in preterm patients at risk of BPD, we show here that patients eventually developing BPD had higher inflammatory mediator expression even on the first day of life. Surprisingly, the ex vivo response to LPS was similar across all samples. Our analysis did however uncover macrophage signature genes whose expression increased in the first week of life specifically in patients resilient to disease. We propose that these changes describe the dynamics of human lung macrophage differentiation. Our study therefore provides new mechanistic insight into both neonatal lung disease and human developmental immunology. Debashis Sahoo et al. study the gene expression profiles in the lung macrophages of preterm patients. They identify an expression signature that contributes to increased susceptibility or resistance to inflammatory lung disease. Their work provides insights to human developmental immunology. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a serious yet common morbidity of preterm birth. Although prior work suggests a possible role for phthalate exposure in the development of BPD, no study has rigorously evaluated this. Our objective was to determine whether hospital-based phthalate exposure is associated with the development of BPD and to identify developmental windows sensitive to exposure. Study Design: This is a prospective multicenter cohort study of 360 preterm infants born at 23–33 weeks gestation participating in the Developmental Impact of NICU Exposures (DINE) cohort. 939 urine specimens collected during the NICU stay were analyzed for biomarkers of phthalate exposure by liquid chromatography with tandem mass spectrometry. The modified Shennan definition was used to diagnose bronchopulmonary dysplasia. Reverse distributed-lag modeling identified developmental windows sensitive to specific phthalate exposure, controlling for relevant covariates including sex and respiratory support. Thirty-five percent of participants were diagnosed with BPD. Exposure to specific phthalate mixtures at susceptible points in preterm infant development are associated with later diagnosis of BPD in models adjusted for use of respiratory support. The weighted influence of specific phthalate metabolites in the mixtures varied by sex. Metabolites of di(2-ethylhexyl) phthalate, a phthalate previously linked to neonatal respiratory support equipment, drove this association, particularly among female infants, at 26- to 30-weeks post-menstrual age. This is the largest and only multi-site study of NICU-based phthalate exposure and clinical impact yet reported. In well-constructed models accounting for infant sex and respiratory support, we found a significant positive association between ultimate diagnosis of BPD and prior exposure to phthalate mixtures with DEHP predominance at 26- to 30-weeks PMA or 34–36-weeks PMA. This information is critically important as it identifies a previously unrecognized and modifiable contributing factor to BPD. [ABSTRACT FROM AUTHOR]

Endothelial glycolysis plays a critical role in the regulation of angiogenesis. We investigated the role of Sirtuin 3 (SIRT3) on endothelial cell (EC) glycolytic metabolism, angiogenesis, and diastolic function. Our aim was to test the hypothesis that loss of SIRT3 in ECs impairs endothelial glycolytic metabolism and angiogenesis and contributes to myocardial capillary rarefaction and the development of diastolic dysfunction. Using SIRT3 deficient ECs, SIRT3 was found to regulate a metabolic switch between mitochondrial respiration and glycolysis. SIRT3 knockout (KO)-ECs exhibited higher mitochondrial respiration and reactive oxygen species (ROS) formation. SIRT3 knockout (KO)-ECs exhibited a reduction in the expression of glycolytic enzyme, PFKFB3, and a fall in glycolysis and angiogenesis. Blockade of PFKFB3 reduced glycolysis and downregulated expression of VEGF and Angiopoietin-1 (Ang-1) in ECs. Deletion of SIRT3 in ECs also impaired hypoxia-induced expression of HIF-2α, VEGF, and Ang-1, as well as reduced angiogenesis. In vivo, endothelial-specific SIRT3 KO (ECKO) mice exhibited a myocardial capillary rarefaction together with a reduced coronary flow reserve (CFR) and diastolic dysfunction. Histologic study further demonstrated that knockout of SIRT3 in ECs significantly increased perivascular fibrosis in the coronary artery. These results implicate a role of SIRT3 in modulating endothelial function and cardiac function. Ablation of SIRT3 leads to impairment of EC glycolytic metabolism and angiogenic signaling, which may contribute to coronary microvascular rarefaction and diastolic dysfunction in SIRT3 ECKO mice. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases. [ABSTRACT FROM AUTHOR]

Aberrant interactions between Hsp90 and its client proteins could contribute to pulmonary hypertension. We tested the hypotheses that (1) the interaction between Hsp90 and its known client protein, eNOS, is impaired in pulmonary resistance arteries (PRA) from piglets with pulmonary hypertension caused by exposure to 3 or 10 days hypoxia and that (2) Hsp90 interacts with the prostanoid pathway proteins, prostacyclin synthase (PGIS) and/or thromboxane synthase (TXAS). We also determined whether Hsp90 antagonism with geldanamycin, alters agonist-induced synthesis of prostacyclin and thromboxane, or alters PRA responses to these prostaglandin metabolites. Compared with normoxic piglets, less eNOS coimmunoprecipitated with Hsp90 in PRA from hypoxic piglets. Despite reduced Hsp90-eNOS interactions, dilation to acetylcholine was enhanced in geldanamycin-treated PRA from hypoxic, but not normoxic, piglets. In PRAs from all groups of piglets, PGIS and TXAS coimmunoprecipitated with Hsp90. Geldanamycin reduced acetylcholine-induced synthesis of prostacyclin and thromboxane and altered responses to the thromboxane mimetic, U46619, in PRA from all groups. Although geldanamycin enhanced responses to prostacyclin in PRA from both groups of hypoxic piglets, geldanamycin had no effect on prostacyclin responses in PRA from either group of normoxic piglets. Our findings indicate that Hsp90 influences both prostanoid and eNOS signalling in the pulmonary circulation of newborn piglets and that the impact of pharmacologic inhibition of Hsp90 on these signalling pathways is altered during exposure to chronic hypoxia. [ABSTRACT FROM AUTHOR]

Our main objective was to determine whether reactive oxygen species (ROS), such as superoxide (O2-) and hydrogen peroxide (H2O2), contribute to altered pulmonary vascular responses in piglets with chronic hypoxia-induced pulmonary hypertension. Piglets were raised in either room air (control) or hypoxia for 3 days. The effect of the cell-permeable superoxide dismutase mimetic (SOD; M40403) and/or PEG-catalase (PEG-CAT) on responses to acetylcholine (ACh) was measured in endothelium-intact and denuded pulmonary resistance arteries (PRAs; 90-to-300-µm diameter). To determine whether NADPH oxidase is an enzymatic sour e of ROS, PRA responses to ACh were measured in the presence a d absence of a NADPH oxidase inhibitor, apocynin (APO). A Western blot technique was used to assess expression of the NADPH oxidase subunit, p67phox. A lucigenin-derived chemiluminescence technique was used to measure ROS production stimulated by the NADP oxidase substrate, NADPH. ACh responses, which were dilation i intact control arteries but constriction in both intact and denuded hypoxic arteries, were diminished by M40403, PEG-CAT, the combination of M40403 plus PEG-CAT, as well as by APO. Although total amounts were not different, membrane-associated p67phox was g eater in PRAs from hypoxic compared with control piglets. NADPH-stimulated lucigenin luminescence was nearly doubled in PRAs from hypoxic vs. control piglets. We conclude that ROS generated by NADPH oxidase contribute to the aberrant pulmonary arterial responses in piglets exposed to 3 days of hypoxia. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate positive health outcomes among children born at < 32 weeks of gestation, and to determine whether children with three common neonatal morbidities and two neurodevelopmental impairments would have similar positive health outcomes to children and adolescents without these exposures and impairments., Study Design: In this secondary analysis of prospectively acquired data derived from three multi-center cohorts of children born very preterm (the ELGAN cohort [birth years 2001 to 2004], the NOVI cohort [birth years 2014 to 2016], and the DINE cohort [birth years 2010 to 2020]), we examined associations between the three common neonatal morbidities (bronchopulmonary dysplasia, necrotizing enterocolitis, and intraventricular hemorrhage, diagnosed before hospital discharge), two neurodevelopmental impairments (developmental delays and cerebral palsy, diagnosed at preschool age follow-up), and perceptions of physical, mental, and social well-being (in either early childhood or adolescence), using the Patient-Reported Outcomes Measurement Information System (PROMIS®) scales for positive health., Results: After adjusting for confounders, bronchopulmonary dysplasia, intraventricular hemorrhage, and cerebral palsy were associated with lower positive health scores, reported by parent-proxy during early childhood. None of the exposures or impairments were associated with lower positive health scores at adolescence, reported by the children themselves., Conclusion: Parents of children born very preterm with bronchopulmonary dysplasia, intraventricular hemorrhage, or cerebral palsy rated their children's positive health lower than did parents of children without these morbidities. However, adolescents' own reports of positive health outcomes were not associated with either neonatal pre-discharge morbidities or preschool neurodevelopmental impairments., Competing Interests: Declaration of interests ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☒ The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brian Smith and the Duke University Clinical Research Institute reports financial support was provided by National Institutes of Health. Judy Aschner, MD and Hackensack Meridian School of Medicine, Nutley, NJ and Albert Einstein College of Medicine reports financial support was provided by National Institute of Health. Barry Lester, PhD and Brown University reports financial support was provided by National Institutes of Health. T. Michael O’Shea, MD the University of North Carolina reports financial support was provided by National Institutes of Health. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Most research to understand postacute sequelae of SARS-CoV-2 infection (PASC), or long COVID, has focused on adults, with less known about this complex condition in children. Research is needed to characterize pediatric PASC to enable studies of underlying mechanisms that will guide future treatment., Objective: To identify the most common prolonged symptoms experienced by children (aged 6 to 17 years) after SARS-CoV-2 infection, how these symptoms differ by age (school-age [6-11 years] vs adolescents [12-17 years]), how they cluster into distinct phenotypes, and what symptoms in combination could be used as an empirically derived index to assist researchers to study the likely presence of PASC., Design, Setting, and Participants: Multicenter longitudinal observational cohort study with participants recruited from more than 60 US health care and community settings between March 2022 and December 2023, including school-age children and adolescents with and without SARS-CoV-2 infection history., Exposure: SARS-CoV-2 infection., Main Outcomes and Measures: PASC and 89 prolonged symptoms across 9 symptom domains., Results: A total of 898 school-age children (751 with previous SARS-CoV-2 infection [referred to as infected] and 147 without [referred to as uninfected]; mean age, 8.6 years; 49% female; 11% were Black or African American, 34% were Hispanic, Latino, or Spanish, and 60% were White) and 4469 adolescents (3109 infected and 1360 uninfected; mean age, 14.8 years; 48% female; 13% were Black or African American, 21% were Hispanic, Latino, or Spanish, and 73% were White) were included. Median time between first infection and symptom survey was 506 days for school-age children and 556 days for adolescents. In models adjusted for sex and race and ethnicity, 14 symptoms in both school-age children and adolescents were more common in those with SARS-CoV-2 infection history compared with those without infection history, with 4 additional symptoms in school-age children only and 3 in adolescents only. These symptoms affected almost every organ system. Combinations of symptoms most associated with infection history were identified to form a PASC research index for each age group; these indices correlated with poorer overall health and quality of life. The index emphasizes neurocognitive, pain, and gastrointestinal symptoms in school-age children but change or loss in smell or taste, pain, and fatigue/malaise-related symptoms in adolescents. Clustering analyses identified 4 PASC symptom phenotypes in school-age children and 3 in adolescents., Conclusions and Relevance: This study developed research indices for characterizing PASC in children and adolescents. Symptom patterns were similar but distinguishable between the 2 groups, highlighting the importance of characterizing PASC separately for these age ranges.

Objective: To evaluate associations between change in weight z score after neonatal intensive care unit (NICU) discharge and neurodevelopmental outcomes and obesity at 12-48 months of age among individuals born very preterm., Study Design: This secondary analysis used data from infants born very preterm participating in the Environmental influences on Child Health Outcomes cohort (n = 1400). Growth during infancy was calculated as change in weight z score between NICU discharge and follow-up at a mean of 27 months of age. Very low weight gain was defined as a change in weight z score <-1.67; very high weight gain was a change in weight z score >1.67. Neurodevelopmental outcomes included the Bayley Scales of Infant and Toddler Development, Child Behavior Checklist 1.5-5 years, and Modified Checklist for Autism in Toddlers. Multivariable linear regression was used to estimate associations between increase in weight z score and neurodevelopmental outcomes., Results: Very low weight gain between NICU discharge and follow-up (experienced by 6.4% of participants) was associated with lower scores on cognitive (adjusted mean difference: -4.26; 95% CI: -8.55, -0.04) and language (adjusted mean difference: -4.80; 95% CI: -9.70, -0.11) assessments. Very high weight gain (experienced by 13.6% of participants) was associated with an increased obesity risk (adjusted relative risk: 6.20; 95% CI: 3.99, 9.66) but not with neurodevelopmental outcomes., Conclusions: Very high weight gain in the first 12-48 months after NICU discharge was associated with a higher risk of obesity at follow-up; very low weight gain was associated with lower scores on cognitive and language assessments., Competing Interests: Declaration of Competing Interest Research reported in this publication was supported by the Environmental influences on Child Health Outcomes (ECHO) Program, Office of the Director, National Institutes of Health, under Award Numbers U2COD023375 (B. Smith, PI), U24OD023382 (Data Analysis Center), U24OD023319 (R. Gershon, PI) with co-funding from the Office of Behavioral and Social Science Research, UH3OD023348 (T M. O'Shea, PI; R.C. Fry, PI), 2UG1HD027904 (J. Maron, PI), UH3OD023320 (JL Aschner, PI), UH3OD023347 (BM Lester, PI), UG3OD035513 (A. Stroustrup, PI). The authors declare no conflicts of interest. The sponsor, National Institutes of Health (NIH), participated in the overall design and implementation of the ECHO Program, which was funded as a cooperative agreement between NIH and grant awardees. The sponsor approved the Steering Committee-developed ECHO protocol and its amendments including COVID-19 measures. The sponsor had no access to the central database, which was housed at the ECHO Data Analysis Center. Data management and site monitoring were performed by the ECHO Data Analysis Center and Coordinating Center. All analyses for scientific publication were performed by the study statistician, independently of the sponsor. The lead author wrote all drafts of the manuscript and made revisions based on co-authors and the ECHO Publication Committee (a subcommittee of the ECHO Operations Committee) feedback without input from the sponsor. The study sponsor did not review nor approve the manuscript for submission to the journal., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults., Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science., Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions., Clinical Trials.gov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Brett Anderson reported receiving direct support for work not related to RECOVER work/publications from Genentech and the National Institute of Allergy and Immunology. Walter Dehority reported receiving grant support from Merck and participating in research for the Moderna COVID-19 pediatric vaccine trial and the Pfizer Paxlovid trial. Alex Fiks reported receiving support from NJM insurance and personal consulting fees not related to this paper from Rutgers University and the American Academy of Pediatrics. Ashraf Harahsheh reported serving as a scientific advisory board member unrelated to this paper for OP2 DRUGS. Lawrence Kleinman reported serving as an unpaid member of the Board of Directors for the DARTNet Institute, as a principle investigator at Quality Matters, Inc., and as the Vice Chair for the Borough of Metuchen Board of Health. Dr. Kleinman also reported grant support for work not related to RECOVER work/publications from NIH, HRSA, and the Robert Wood Johnson Foundation. Dr. Kleinman also reported minority individual stock ownership in Apple Computer, Sanofi SA, Experion, GlaxoSmithKline, Magyar Bank, Regeneron Pharmaceuticals, JP Morgan Chase, and Amgen Inc. Torri Metz reported participating as a Principle Investigator in the medical advisory board for the planning of a Pfizer clinical trial of SARS-CoV-2 vaccination in pregnancy. She is also a principle investigator for a Pfizer study evaluating the pharmacokinetics of Paxlovid in pregnant people with COVID-19. Joshua Milner reported serving as a member of the Scientific Advisory Board for Blueprint Medicines, in a capacity unrelated to RECOVER work/publications. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Gross et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objective: Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Based on our single-dose pharmacokinetic study, we evaluated the ability of a multi-dose enteral L-citrulline strategy to achieve a target trough steady-state L-citrulline plasma concentration and its tolerability in premature infants., Study Design: Plasma L-citrulline concentrations were measured in six premature infants receiving 60 mg/kg L-citrulline every 6 h for 72 h before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study., Results: Target trough plasma L-citrulline concentrations were achieved in 2/6 subjects. No serious adverse events occurred., Conclusions: Multi-dose L-citrulline was well tolerated. These results will assist in the design of phase II RCTs evaluating L-citrulline dosage strategies to achieve target plasma L-citrulline concentrations in infants at risk for BPD-PH., Clinical Trials: gov ID: NCT03542812., (© 2023. The Author(s).)

Background: In the United States, disparities in gestational age at birth by maternal race, ethnicity, and geography are theorized to be related, in part, to differences in individual- and neighborhood-level socioeconomic status (SES). Yet, few studies have examined their combined effects or whether associations vary by maternal race and ethnicity and United States Census region., Methods: We assembled data from 34 cohorts in the Environmental influences on Child Health Outcomes (ECHO) program representing 10,304 participants who delivered a liveborn, singleton infant from 2000 through 2019. We investigated the combined associations of maternal education level, neighborhood deprivation index (NDI), and Index of Concentration at the Extremes for racial residential segregation (ICE Race ) on gestational weeks at birth using linear regression and on gestational age at birth categories (preterm, early term, post-late term relative to full term) using multinomial logistic regression., Results: After adjustment for NDI and ICE Race , gestational weeks at birth was significantly lower among those with a high school diploma or less (-0.31 weeks, 95% CI: -0.44, -0.18), and some college (-0.30 weeks, 95% CI: -0.42, -0.18) relative to a master's degree or higher. Those with a high school diploma or less also had an increased odds of preterm (aOR 1.59, 95% CI: 1.20, 2.10) and early term birth (aOR 1.26, 95% CI: 1.05, 1.51). In adjusted models, NDI quartile and ICE Race quartile were not associated with gestational weeks at birth. However, higher NDI quartile (most deprived) associated with an increased odds of early term and late term birth, and lower ICE Race quartile (least racially privileged) associated with a decreased odds of late or post-term birth. When stratifying by region, gestational weeks at birth was lower among those with a high school education or less and some college only among those living in the Northeast or Midwest. When stratifying by race and ethnicity, gestational weeks at birth was lower among those with a high school education or less only for the non-Hispanic White category., Conclusion: In this study, maternal education was consistently associated with shorter duration of pregnancy and increased odds of preterm birth, including in models adjusted for NDI and ICE Race ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Dunlop, Burjak, Dean, Alshawabkeh, Avalos, Aschner, Breton, Charifson, Cordero, Dabelea, D’Sa, Duarte, Elliott, Eick, Ferrara, Fichorova, Ganiban, Gern, Hedderson, Herbstman, Hipwell, Huddleston, Karagas, Karr, Kerver, Koinis-Mitchell, Lyall, Madan, Marsit, McEvoy, Meeker, Oken, O’Shea, Padula, Sathyanarayana, Schantz, Schmidt, Snowden, Stanford, Weiss, Wright, Wright, Zhang and McGrath.)

Background: The extent to which physical and social attributes of neighborhoods play a role in childhood asthma remains understudied., Objective: To examine associations of neighborhood-level opportunity and social vulnerability measures with childhood asthma incidence., Design, Setting, and Participants: This cohort study used data from children in 46 cohorts participating in the Environmental Influences on Child Health Outcomes (ECHO) Program between January 1, 1995, and August 31, 2022. Participant inclusion required at least 1 geocoded residential address from birth and parent or caregiver report of a physician's diagnosis of asthma. Participants were followed up to the date of asthma diagnosis, date of last visit or loss to follow-up, or age 20 years., Exposures: Census tract-level Child Opportunity Index (COI) and Social Vulnerability Index (SVI) at birth, infancy, or early childhood, grouped into very low (<20th percentile), low (20th to <40th percentile), moderate (40th to <60th percentile), high (60th to <80th percentile), or very high (≥80th percentile) COI or SVI., Main Outcomes and Measures: The main outcome was parent or caregiver report of a physician's diagnosis of childhood asthma (yes or no). Poisson regression models estimated asthma incidence rate ratios (IRRs) associated with COI and SVI scores at each life stage., Results: The study included 10 516 children (median age at follow-up, 9.1 years [IQR, 7.0-11.6 years]; 52.2% male), of whom 20.6% lived in neighborhoods with very high COI and very low SVI. The overall asthma incidence rate was 23.3 cases per 1000 child-years (median age at asthma diagnosis, 6.6 years [IQR, 4.1-9.9 years]). High and very high (vs very low) COI at birth, infancy, or early childhood were associated with lower subsequent asthma incidence independent of sociodemographic characteristics, parental asthma history, and parity. For example, compared with very low COI, the adjusted IRR for asthma was 0.87 (95% CI, 0.75-1.00) for high COI at birth and 0.83 (95% CI, 0.71-0.98) for very high COI at birth. These associations appeared to be attributable to the health and environmental and the social and economic domains of the COI. The SVI during early life was not significantly associated with asthma incidence. For example, compared with a very high SVI, the adjusted IRR for asthma was 0.88 (95% CI, 0.75-1.02) for low SVI at birth and 0.89 (95% CI, 0.76-1.03) for very low SVI at birth., Conclusions: In this cohort study, high and very high neighborhood opportunity during early life compared with very low neighborhood opportunity were associated with lower childhood asthma incidence. These findings suggest the need for future studies examining whether investing in health and environmental or social and economic resources in early life would promote health equity in pediatric asthma.

Objective: Ongoing pediatric cohort studies offer opportunities to investigate the impact of the COVID-19 pandemic on children's health. With well-characterized data from tens of thousands of US children, the Environmental influences on Child Health Outcomes (ECHO) Program offers such an opportunity., Methods: ECHO enrolled children and their caregivers from community- and clinic-based pediatric cohort studies. Extant data from each of the cohorts were pooled and harmonized. In 2019, cohorts began collecting data under a common protocol, and data collection is ongoing with a focus on early life environmental exposures and five child health domains: birth outcomes, neurodevelopment, obesity, respiratory, and positive health. In April of 2020, ECHO began collecting a questionnaire designed to assess COVID-19 infection and the pandemic's impact on families. We describe and summarize the characteristics of children who participated in the ECHO Program during the COVID-19 pandemic and novel opportunities for scientific advancement., Results: This sample ( n  = 13,725) was diverse by child age (31% early childhood, 41% middle childhood, and 16% adolescence up to age 21), sex (49% female), race (64% White, 15% Black, 3% Asian, 2% American Indian or Alaska Native, <1% Native Hawaiian or Pacific Islander, 10% Multiple race and 2% Other race), Hispanic ethnicity (22% Hispanic), and were similarly distributed across the four United States Census regions and Puerto Rico., Conclusion: ECHO data collected during the pandemic can be used to conduct solution-oriented research to inform the development of programs and policies to support child health during the pandemic and in the post-pandemic era., Competing Interests: All authors report funding from the National Institutes of Health., (© 2023 Bekelman, Trasande, Law, Blackwell, Jacobson, Bastain, Breton, Elliott, Ferrara, Karagas, Aschner, Bornkamp, Camargo, Comstock, Dunlop, Ganiban, Gern, Karr, Kelly, Lyall, O'Shea, Schweitzer and LeWinn.)

The National Institutes of Health's Environmental influences on Child Health Outcomes (ECHO) Program was designed to address solution-oriented research questions about the links between children's early life environment and their risks of pre-, peri-, and post-natal complications, asthma, obesity, neurodevelopmental disorders, and positive health. Children born very preterm are at increased risk for many of the outcomes on which ECHO focuses, but the contributions of environmental factors to this risk are not well characterized. Three ECHO cohorts consist almost exclusively of individuals born very preterm. Data provided to ECHO from cohorts can be used to address hypotheses about (1) differential risks of chronic health and developmental conditions between individuals born very preterm and those born at term; (2) health disparities across social determinants of health; and (3) mechanisms linking early-life exposures and later-life outcomes among individuals born very preterm. IMPACT: The National Institutes of Health's Environmental Influences on Child Health Outcomes Program is conducting solution-oriented research on the links between children's environment and health. Three ECHO cohorts comprise study participants born very preterm; these cohorts have enrolled, to date, 1751 individuals born in 14 states in the U.S. in between April 2002 and March 2020. Extensive data are available on early-life environmental exposures and child outcomes related to neurodevelopment, asthma, obesity, and positive health. Data from ECHO preterm cohorts can be used to address questions about the combined effects of preterm birth and environmental exposures on child health outcomes., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Approximately 8-42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH.

Background: Childhood maltreatment is associated with adverse health outcomes and this risk can be transmitted to the next generation. We aimed to investigate the association between exposure to maternal childhood maltreatment and common childhood physical and mental health problems, neurodevelopmental disorders, and related comorbidity patterns in offspring., Methods: We conducted a retrospective cohort study using data from the Environmental influences on Child Health Outcomes (ECHO) Program, which was launched to investigate the influence of early life exposures on child health and development in 69 cohorts across the USA. Eligible mother-child dyads were those with available data on maternal childhood maltreatment exposure and at least one child health outcome measure (autism spectrum disorder, attention-deficit hyperactivity disorder [ADHD], internalising problems, obesity, allergy, and asthma diagnoses). Maternal history of childhood maltreatment was obtained retrospectively from the Adverse Childhood Experiences or Life Stressor Checklist questionnaires. We derived the prevalence of the specified child health outcome measures in offspring across childhood and adolescence by harmonising caregiver reports and other relevant sources (such as medical records) across cohorts. Child internalising symptoms were assessed using the Child Behavior Checklist. Associations between maternal childhood maltreatment and childhood health outcomes were measured using a series of mixed-effects logistic regression models. Covariates included child sex (male or female), race, and ethnicity; maternal and paternal age; maternal education; combined annual household income; maternal diagnosis of depression, asthma, ADHD, allergy, or autism spectrum disorder; and maternal obesity. Two latent class analyses were conducted: to characterise patterns of comorbidity of child health outcomes; and to characterise patterns of co-occurrence of childhood maltreatment subtypes. We then investigated the association between latent class membership and maternal childhood maltreatment and child health outcomes, respectively., Findings: Our sample included 4337 mother-child dyads from 21 longitudinal cohorts (with data collection initiated between 1999 and 2016). Of 3954 mothers in the study, 1742 (44%) had experienced exposure to abuse or neglect during their childhood. After adjustment for confounding, mothers who experienced childhood maltreatment were more likely to have children with internalising problems in the clinical range (odds ratio [OR] 2·70 [95% CI 1·95-3·72], p<0·0001), autism spectrum disorder (1·70 [1·13-2·55], p=0·01), ADHD (2·09 [1·63-2·67], p<0·0001), and asthma (1·54 [1·34-1·77], p<0·0001). In female offspring, maternal childhood maltreatment was associated with a higher prevalence of obesity (1·69 [1·17-2·44], p=0·005). Children of mothers exposed to childhood maltreatment were more likely to exhibit a diagnostic pattern characterised by higher risk for multimorbidity. Exposure to multiple forms of maltreatment across all subtypes of maternal childhood maltreatment was associated with the highest risk increases for most offspring health outcomes, suggesting a dose-response relationship., Interpretation: Our findings suggest that maternal childhood maltreatment experiences can be a risk factor for disease susceptibility in offspring across a variety of outcomes and emphasise the need for policies focusing on breaking the intergenerational transmission of adversity., Funding: Environmental influences on Child Health Outcomes Program, Office of the Director, National Institutes of Health., Competing Interests: Declaration of interests CSD, AEH, HNS, TGO, RKM, CB, ESB, EO, CKB, MBE, RJW, SCLD, TMB, NRB, and JP report funding from the National Institutes of Health (NIH). RKM reports research support from the Health Resources and Services Administration and the New York State Department of Health and participation as Chair of the Scientific Advisory Committee for the GlaxoSmithKline Bieimumab Pregnancy Registry. SCLD reports consulting fees from Nestlé Nutrition. JP reports research support from Takeda (formerly Shire) and Aevi Genomics and consulting fees from Innovative Science. ESB reports honoria from the NIH Study Sections. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age <12 months) enrolled in one of the 53 prospective cohort studies in the ECHO Program during 2001−2021. The exposure was bronchiolitis hospitalization during infancy. The outcome was a diagnosis of asthma by a physician by age 12 years. We examined their longitudinal association and determined the potential effect modifications of major demographic factors. Results: The analytic cohort consisted of 11,762 infants, 10% of whom had bronchiolitis hospitalization. Overall, 15% subsequently developed asthma. In the Cox proportional hazards model adjusting for 10 patient-level factors, compared with the no-bronchiolitis hospitalization group, the bronchiolitis hospitalization group had a significantly higher rate of asthma (14% vs. 24%, HR = 2.77, 95%CI = 2.24−3.43, p < 0.001). There was significant heterogeneity by race and ethnicity (Pinteraction = 0.02). The magnitude of the association was greater in non-Hispanic White (HR = 3.77, 95%CI = 2.74−5.18, p < 0.001) and non-Hispanic Black (HR = 2.39, 95%CI = 1.60−3.56; p < 0.001) infants, compared with Hispanic infants (HR = 1.51, 95%CI = 0.77−2.95, p = 0.23). Conclusions: According to the nationwide cohort data, infants hospitalized with bronchiolitis are at a higher risk for asthma, with quantitative heterogeneity in different racial and ethnic groups.

Rationale: Asthma and obesity often co-occur. It has been hypothesized that asthma may contribute to childhood obesity onset., Objectives: To determine if childhood asthma is associated with incident obesity and examine the role of asthma medication in this association., Methods: We studied 8,716 children between ages 6 and 18.5 years who were nonobese at study entry participating in 18 US cohorts of the Environmental influences on Child Health Outcomes program (among 7,299 children with complete covariate data mean [SD] study entry age = 7.2 [1.6] years and follow up = 5.3 [3.1] years)., Measurements and Main Results: We defined asthma based on caregiver report of provider diagnosis. Incident obesity was defined as the first documented body mass index ≥95th percentile for age and sex following asthma status ascertainment. Over the study period, 26% of children had an asthma diagnosis and 11% developed obesity. Cox proportional hazards models with sex-specific baseline hazards were fitted to assess the association of asthma diagnosis with obesity incidence. Children with asthma had a 23% (95% confidence intervals [CI] = 4, 44) higher risk for subsequently developing obesity compared with those without asthma. A novel mediation analysis was also conducted to decompose the total asthma effect on obesity into pathways mediated and not mediated by asthma medication use. Use of asthma medication attenuated the total estimated effect of asthma on obesity by 64% (excess hazard ratios = 0.64; 95% CI = -1.05, -0.23)., Conclusions: This nationwide study supports the hypothesis that childhood asthma is associated with later risk of obesity. Asthma medication may reduce this association and merits further investigation as a potential strategy for obesity prevention among children with asthma., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Displaying heart rate characteristic (HRC) scores was associated with lower sepsis-associated mortality in very low birth weight (VLBW) infants in a multicenter randomized controlled trial (HeRO trial). The aim of this study was to test whether HRC indices rise before diagnosis of urinary tract infection (UTI) or meningitis, with and without concomitant BSI., Methods: Blood, urine, and cerebrospinal fluid (CSF) culture data after 3 days of age and within 120 days of study enrollment were analyzed from 2989 VLBW infants. The HRC index was analyzed 12 h prior to positive cultures compared to 36 h prior, using paired signed-rank tests., Results: UTI, meningitis, and BSI were diagnosed in 10%, 2%, and 24% of infants, respectively. The mean hourly HRC index was significantly higher 12 h prior to diagnosis of UTI and BSI compared to 36 h prior (UTI 2.07 versus 1.81; BSI 2.62 versus 2.25, both p < 0.0001). The baseline HRC index was higher for meningitis, compared to UTI or BSI, but without a statistically significant rise in the day prior to meningitis diagnosis., Conclusions: In a large cohort of VLBW infants enrolled in the HeRO trial, the HRC index increased in the 24-h period prior to diagnosis of UTI and BSI but not meningitis.

Newborn pigs with chronic hypoxia-induced pulmonary hypertension (PH) have evidence of endothelial nitric oxide synthase (eNOS) uncoupling. In this model, we showed that therapies that promote eNOS coupling, either tetrahydrobiopterin (BH 4 ), a NOS cofactor, or l-citrulline, a NO-l-arginine precursor, inhibit PH. We wanted to determine whether cotreatment with l-citrulline and a BH 4 compound, sapropterin dihydrochloride, improves NO signaling and chronic hypoxia-induced PH more markedly than either alone. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received sole treatment with l-citrulline or BH 4 , or were cotreated with l-citrulline and BH 4 , from day 3 through day 10 of hypoxia. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios and NO production. In untreated hypoxic piglets, pulmonary vascular resistance (PVR) was higher and NO production and eNOS dimer-to-monomer ratios were lower than in normoxic piglets. Compared with the untreated hypoxic group, PVR was lower in hypoxic piglets cotreated with l-citrulline and BH 4 and in those treated with l-citrulline alone but not for those treated solely with BH 4 . NO production and eNOS dimer-to-monomer ratios were greater for all three treated hypoxic groups compared with the untreated group. Notably, greater improvements in PVR, eNOS dimer-to-monomer ratios, and NO production were found in hypoxic piglets cotreated with l-citrulline and BH 4 than in piglets treated with either alone. Cotreatment with l-citrulline and BH 4 more effectively improves NO signaling and inhibits chronic hypoxia-induced PH than either treatment alone. Combination therapies may offer enhanced therapeutic capacity for challenging clinical conditions, such as chronic neonatal PH.

In the absence of effective interventions to prevent preterm births, improved survival of infants who are born at the biological limits of viability has relied on advances in perinatal care over the past 50 years. Except for extremely preterm infants with suboptimal perinatal care or major antenatal events that cause severe respiratory failure at birth, most extremely preterm infants now survive, but they often develop chronic lung dysfunction termed bronchopulmonary dysplasia (BPD; also known as chronic lung disease). Despite major efforts to minimize injurious but often life-saving postnatal interventions (such as oxygen, mechanical ventilation and corticosteroids), BPD remains the most frequent complication of extreme preterm birth. BPD is now recognized as the result of an aberrant reparative response to both antenatal injury and repetitive postnatal injury to the developing lungs. Consequently, lung development is markedly impaired, which leads to persistent airway and pulmonary vascular disease that can affect adult lung function. Greater insights into the pathobiology of BPD will provide a better understanding of disease mechanisms and lung repair and regeneration, which will enable the discovery of novel therapeutic targets. In parallel, clinical and translational studies that improve the classification of disease phenotypes and enable early identification of at-risk preterm infants should improve trial design and individualized care to enhance outcomes in preterm infants.

We have previously shown that Na + -coupled neutral amino acid transporter 1 (SNAT1) modulates nitric oxide (NO) production in pulmonary arterial endothelial cells (PAECs) from newborn piglets. Specifically, the ability to increase NO production in response to the l-arginine-NO precursor l-citrulline is dependent on SNAT1 expression. Elucidating factors that regulate SNAT1 expression in PAECs could provide new insights and therapeutic targets relevant to NO production. Our major goals were to determine if reactive oxygen species (ROS) modulate SNAT1 expression in PAECs from newborn piglets and to evaluate the role of NADPH oxidase 1 (NOX1) and uncoupled endothelial NO synthase, enzymatic sources of ROS, in hypoxia-induced increases in SNAT1 expression. Treatment with either H 2 O 2 or xanthine plus xanthine oxidase increased SNAT1 expression in PAECs from newborn piglets cultured under normoxic conditions. Hypoxia-induced increases in SNAT1 expression were inhibited by treatments with the ROS-removing agents catalase and superoxide dismutase, NOX1 siRNA, and the NO synthase inhibitor N G -nitro-l-arginine methyl ester. Both tetrahydropbiopterin (BH 4 ) and l-citrulline, two therapies that decrease ROS by recoupling endothelial NO synthase, reduced the hypoxia-induced increase in SNAT1 expression. BH 4 and l-citrulline treatment improved NO production in hypoxic PAECs despite a reduction in SNAT1 expression. In conclusion, SNAT1 expression is modulated by ROS in PAECs from newborn piglets. However, ROS-mediated decreases in SNAT1 expression per se do not implicate a reduction in NO production. Although SNAT1 may be critical to l-citrulline-induced increases in NO production, therapies designed to alter SNAT1 expression may not lead to a concordant change in NO production. NEW & NOTEWORTHY Na + -coupled neutral amino acid transporter 1 (SNAT1) modulates nitric oxide (NO) production in piglet pulmonary arterial endothelial cells. Factors that regulate SNAT1 expression in pulmonary arterial endothelial cells are unclear. Here, we show that ROS-reducing strategies inhibit hypoxia-induced increases in SNAT1 expression. l-Citrulline and tetrahydropbiopterin decrease SNAT1 expression but increase NO production. Although SNAT1 is modulated by ROS, changes in SNAT1 expression may not cause a concordant change in NO production.

Objective: To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT)., Study Design: We performed a retrospective analysis of length of stay metrics among 3 subpopulations (all patients, all survivors, and survivors with positive blood or urine cultures) enrolled in a multicenter, RCT of HRC monitoring., Results: Among all patients in the RCT, infants randomized to receive HRC monitoring were more likely than controls to be discharged alive and prior to day 120 (83.6% vs 80.1%, P = .014). The postmenstrual age at discharge for survivors with positive blood or urine cultures was 3.2 days lower among infants randomized to receive HRC monitoring when compared with controls (P = .026). Although there were trends in other metrics toward reduced length of stay in HRC-monitored patients, none reached statistical significance., Conclusions: HRC monitoring is associated with reduced mortality in VLBW patients and a reduction in length of stay among infected surviving VLBW infants., Trial Registration: ClinicalTrials.gov: NCT00307333., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Failure of the normal circulatory adaptation to extrauterine life results in persistent pulmonary hypertension of the newborn (PPHN). Although this condition is most often secondary to parenchymal lung disease or lung hypoplasia, it may also be idiopathic. PPHN is characterized by elevated pulmonary vascular resistance with resultant right-to-left shunting of blood and hypoxemia. Although the preliminary diagnosis of PPHN is often based on differential cyanosis and labile hypoxemia, the diagnosis is confirmed by echocardiography. Management strategies include optimal lung recruitment and use of surfactant in patients with parenchymal lung disease, maintaining optimal oxygenation and stable blood pressures, avoidance of respiratory and metabolic acidosis and alkalosis, and pulmonary vasodilator therapy. Extracorporeal membrane oxygenation is considered when medical management fails. Although mortality associated with PPHN has decreased significantly with improvements in medical care, there remains the potential risk for neurodevelopmental disability which warrants close follow-up of affected infants after discharge., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

We previously showed that newborn piglets who develop pulmonary hypertension during exposure to chronic hypoxia have diminished pulmonary vascular nitric oxide (NO) production and evidence of endothelial NO synthase (eNOS) uncoupling (Fike CD, Dikalova A, Kaplowitz MR, Cunningham G, Summar M, Aschner JL. Am J Respir Cell Mol Biol 53: 255-264, 2015). Tetrahydrobiopterin (BH 4 ) is a cofactor that promotes eNOS coupling. Current clinical strategies typically invoke initiating treatment after the diagnosis of pulmonary hypertension, rather than prophylactically. The major purpose of this study was to determine whether starting treatment with an oral BH 4 compound, sapropterin dihydrochloride (sapropterin), after the onset of pulmonary hypertension would recouple eNOS in the pulmonary vasculature and ameliorate disease progression in chronically hypoxic piglets. Normoxic (control) and hypoxic piglets were studied. Some hypoxic piglets received oral sapropterin starting on day 3 of hypoxia and continued throughout an additional 7 days of hypoxic exposure. Catheters were placed for hemodynamic measurements, and pulmonary arteries were dissected to assess eNOS dimer-to-monomer ratios (a measure of eNOS coupling), NO production, and superoxide (O 2 ·- ) generation. Although higher than in normoxic controls, pulmonary vascular resistance was lower in sapropterin-treated hypoxic piglets than in untreated hypoxic piglets. Consistent with eNOS recoupling, eNOS dimer-to-monomer ratios and NO production were greater and O 2 ·- generation was less in pulmonary arteries from sapropterin-treated than untreated hypoxic animals. When started after disease onset, oral sapropterin treatment inhibits chronic hypoxia-induced pulmonary hypertension at least in part by recoupling eNOS in the pulmonary vasculature of newborn piglets. Rescue treatment with sapropterin may be an effective strategy to inhibit further development of pulmonary hypertension in newborn infants suffering from chronic cardiopulmonary conditions associated with episodes of prolonged hypoxia., (Copyright © 2016 the American Physiological Society.)