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This study examined differences in alcohol use by sexual and gender identities during the COVID-19 pandemic, and assessed whether variation between groups was explained by pandemic-related stressors and minority stress. Data from 2,429 partnered adults in the National Couples' Health and Time Use Study (n = 3,593) collected from September 2020 to April 2021 were used to model drinking patterns (frequency, amount, and drinking to cope) by sexual and gender identities, COVID-19 stress and disruption, microaggressions, and supportive climate. Regression models indicated differences in drinking by gender and sexual identities, even controlling for demographic and socioeconomic factors. Gay, lesbian, and bisexual people had higher odds of drinking to cope with the pandemic than did heterosexual people, and cisgender men had higher odds than did cisgender women. Gay and lesbian people drank more regularly than did heterosexual people, as did cisgender men in relation to cisgender women. Exclusively bisexual people drank significantly more drinks than exclusively heterosexual people, and cisgender men drank significantly more drinks than did cisgender women and those who identified as trans/another gender identity. COVID-19 stress and minority stress were associated with greater alcohol consumption, but they did not account for these differentials. Moving forward, researchers will need to continuously assess these associations, as sources of discrimination and stress will persist beyond the pandemic. Although LGBTQ+ people have disproportionate sources of stress, they varied in how they used alcohol to cope. Potential sources of resilience among sexual and gender diverse individuals should be explored., Competing Interests: The authors have declared that no competing interests exist., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1 + ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants., Competing Interests: Declaration of interests E.J.B. and S.G.G. are scientific cofounders at Tellus Therapeutics—a startup company developing therapies for neonatal brain injury. There is no intellectual property associated with this manuscript., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To determine the ability of the Bayley-III cognitive and language composite scores at 18-22 months corrected age to predict WISC-IV Full Scale IQ (FSIQ) at 6-7 years in infants born extremely preterm., Study Design: Children in this study were part of the Neuroimaging and Neurodevelopmental Outcome cohort, a secondary study to the SUPPORT trial and born 24 0/7 -27 6/7  weeks gestational age. Bayley-III cognitive and language scores and WISC-IV FSIQ were compared with pairwise Pearson correlation coefficients and adjusted for medical and socioeconomic variables using linear mixed effect regression models., Results: Bayley-III cognitive (r = 0.33) and language scores (r = 0.44) were mildly correlated with WISC-IV FSIQ score. Of the children with Bayley-III cognitive scores of <70, 67% also had FSIQ of <70. There was less consistency for children with Bayley-III scores in the 85-100 range; 43% had an FSIQ of <85 and 10% an FSIQ of <70. Among those with Bayley-III language scores >100, approximately 1 in 5 had an FSIQ of <85. A cut point of 92 for the cognitive composite score resulted in sensitivity (0.60), specificity (0.64). A cut point of 88 for the language composite score produced sensitivity (0.61), specificity (0.70)., Conclusions: Findings indicate the Bayley-III cognitive and language scores correlate with later IQ, but may fail to predict delay or misclassify children who are not delayed at school age. The Bayley-III can be a useful tool to help identify children born extremely preterm who have below average cognitive scores and may be at the greatest risk for ongoing cognitive difficulties., Trial Registration: Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort: NCT00233324., Competing Interests: Declaration of Competing Interest The National Institutes of Health (M01 RR30, M01 RR32, M01 RR39, M01 RR54, M01 RR59, M01 RR64, M01 RR80, M01 RR70, M01 RR633, M01 RR750, M01 RR997, UL1 RR25008, UL1 RR25744, and UL1 TR442), the Eunice Kennedy ShriverNational Institute of Child Health and Human Development ( NICHD) (U10 HD21364, U10 HD21385, U10 HD21373, U10 HD27851, U10 HD27856, U10 HD27880, U10 HD27904, U10 HD34216, U10 HD36790, U10 HD40461, U10 HD40492, U10 HD40689, U10 HD53089, U10 HD53109, U10 HD53119, and U10 HD53124), and the National Heart, Lung, and Blood Institute (NHLBI) (via co-funding) provided grant support for the Neonatal Research Network’s Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort. The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Emotional support, particularly support from family and friends, is essential to health outcomes especially for marginalized communities. Although emotional support is recognized as a critical resource, especially during the COVID-19 pandemic, to date no research has examined access to support during the pandemic for sexual diverse populations. This study aims to apply minority stress theory by drawing on a new population-based data source of 3,642 respondents, the National Couples' Health and Time Study (NCHAT), which oversampled sexual and gender diverse populations during the pandemic. We focus on two sources of emotional support: family members and friends. Exclusively heterosexual respondents relied more on emotional support from family than respondents who identified as exclusively gay/lesbian, bisexual including pan, omni, and queer, and those reporting another sexual identity or multiple sexual identities. However, respondents who did not identify as heterosexual relied more on emotional support from friends compared to exclusively heterosexual respondents. There were no significant differences among respondents with sexual minority identities in regard to family or friend support. Other factors, such as outness to friends and family, identity centrality, aggressions, and relationship satisfaction are found to be associated support from friends and family. The findings presented here add to a growing body of work on social support while adding sexual minority-specific factors that may affect receipt of, need for, and outcomes relating to support. This work contributes to understanding of the social climate and resources available to sexual diverse populations during a major public health crisis., (Published by Elsevier Inc.)

Hypoxic ischemic encephalopathy (HIE) in neonates causes increased mortality and long-term morbidity in surviving babies. Hypothermia (HT) has improved outcomes, however, mortality remains high with ~half of surviving babies developing neurological impairment in their first years. We previously explored the use of autologous cord blood (CB) to determine if CB cells could lessen long-term damage to the brain. However, the feasibility of CB collection from sick neonates limited the utility of this approach. Allogeneic cord tissue mesenchymal stromal cells (hCT-MSC), cryopreserved and readily available, have been shown to ameliorate brain injury in animal models of HIE. We, therefore, conducted a pilot, phase I, clinical trial to test the safety and describe the preliminary efficacy of hCT-MSC in neonates with HIE. The study treated infants with moderate to severe HIE, treated with HT, with 1 or 2 doses of 2 million cells/kg/dose of hCT-MSC given intravenously. The babies were randomized to receive 1 or 2 doses with the first dose during HT and the second dose 2 months later. Babies were followed for survival and development with scoring of Bayley's at 12 postnatal months. Six neonates with moderate (4) or severe (2) HIE were enrolled. All received 1 dose of hCT-MSC during HT and 2 received a 2nd dose, 2 months later. hCT-MSC infusions were well tolerated although 5/6 babies developed low titer anti-HLA antibodies by 1 year of age. All babies survived, with average to low-average developmental assessment standard scores for ages between 12 and 17 postnatal months. Further study is warranted., (© The Author(s) 2023. Published by Oxford University Press.)

Background: Extremely preterm (EPT) birth has been related to dysregulation of stress responses and behavioral/learning problems at school age. Early adverse experiences can blunt HPA axis reactivity. We hypothesized that an attenuated cortisol awakening response would be associated with developmental and behavioral problems at school age in EPT children., Methods: This secondary analysis of a sub-cohort of the SUPPORT study included children born between 24 and 27 weeks, evaluated at 6-7 years with a neurodevelopmental battery and cortisol measures. Differences were tested between EPT and a term-born group. Relationships of cortisol awakening response to test scores were analyzed., Results: Cortisol was measured in 110 EPT and 29 term-born 6-7 year olds. Unadjusted WISC-IV and NEPSY-II scores were significantly worse among EPT children only. Conners Parent Rating Scale behavior scores were significantly worse among EPT children. After adjusting for covariates, blunted cortisol awakening responses were found to be associated with poorer scores on memory tests and greater problems with inattention for the EPT group (p < 0.05) only., Conclusions: Among children born EPT, we identified an association of blunted cortisol awakening response with memory and inattention problems. This may have implications related to stress reactivity and its relationship to learning problems in children born EPT., Gov Id: Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort: NCT00233324., Impact: In children born EPT, stress reactivity may have a relationship to learning problems. Cortisol awakening response should be a component for follow-up in EPT born children. Components of executive function, such as memory and attention, are related to stress reactivity., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Infantile Krabbe disease (IKD) can be treated with hematopoietic cell transplantation (HCT) if done during the first weeks of life before symptoms develop. To facilitate this, newborn screening (NBS) has been instituted in 8 US states. An application to add IKD to the recommended NBS panel is currently under review. In this report, the outcomes of newborns with IKD diagnosed through NBS and treated with HCT are presented. The unique challenges associated with NBS for this disease are discussed, including opportunities for earlier diagnosis and streamlining treatment referrals. This is a retrospective review of six infants with IKD detected by NBS who were referred for HCT. The timing from diagnosis to HCT was examined, and both HCT and neurodevelopmental outcomes are described. Neurologic testing before HCT revealed evidence of active IKD in all infants. All underwent HCT between 24 and 40 days of age, were successfully engrafted, and are alive 30 to 58 months later (median, 47.5 months). All are gaining developmental milestones albeit at a slower pace than unaffected age-matched peers. Gross motor function is most notably affected. NBS for these patients enabled early access to HCT, the only currently available treatment of infants with IKD. All children are alive and have derived developmental and neurologic benefits from timely HCT. Long-term follow up is ongoing. Optimization of HCT and further development of emerging therapies, all of which must be delivered early in life, are expected to further improve outcomes of infants with IKD., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: Prematurity and low birth weight (LBW) are risk factors for increased morbidity and mortality in infants with congenital heart defects (CHDs). We sought to describe survival, inhospital morbidities, and 2-year neurodevelopmental follow-up in LBW infants with CHD., Study Design: We included infants with birth weight (BW) <2,500 g diagnosed with CHD (except isolated patent ductus arteriosus) admitted January 2013 to March 2016 to a single level-IV academic neonatal intensive care unit. We reported CHD prevalence by BW and gestational age; selected in-hospital morbidities and mortality by infant BW, CHD type, and surgical intervention; and developmental outcomes by Bayley's scales of infant and toddler development, third edition (BSID-III) scores at age 2 years., Results: Among 420 infants with CHD, 28 (7%) underwent cardiac surgery. Median (25th and 75th percentiles) gestational age was 30 (range: 27-33) weeks and BW was 1,258 (range: 870-1,853) g. There were 134 of 420 (32%) extremely LBW (<1,000 g) infants, 82 of 420 (20%) were small for gestational age, and 51 of 420 (12%) multiples. Most common diagnosis: atrial septal defect (260/420, 62%), followed by congenital anomaly of the pulmonary valve (75/420, 18%). Most common surgical procedure: pulmonary artery banding (5/28, 18%), followed by the tetralogy of Fallot corrective repair (4/28, 14%). Survival to discharge was 88% overall and lower among extremely LBW (<1,000 g, 81%) infants and infants undergoing surgery (79%). Comorbidities were common (35%); retinopathy of prematurity and bronchopulmonary dysplasia were most prevalent. BSID-III scores were available on 148 of 176 (84%); any scores <85 were noted in 73 of 148 (49%), with language being most commonly affected., Conclusion: Among LBW infants with congenital heart disease, hospital mortality varied by BW and cardiac diagnosis., Key Points: · In low birth weight infants with congenital heart disease, survival varied by birth weight and cardiac diagnosis.. · Overall survival was higher than previously reported.. · There were fewer morbidities than previously reported.. · Bayley's scale-III scores at 2 years of age were <85 for nearly half.., Competing Interests: None declared., (Thieme. All rights reserved.)

Objective: This retrospective cohort study tested the hypothesis that implementing a multidisciplinary patient-specific discharge protocol for prescribing and tapering opioids after total hip arthroplasty (THA) will decrease the morphine milligram equivalent (MME) dose of opioids prescribed., Methods: With institutional review board approval, we analyzed a Perioperative Surgical Home database and prescription data for all primary THA patients three months before (PRE) and three months after (POST) implementation of this new discharge opioid protocol based on patients' prior 24-hour inpatient opioid consumption. The primary outcome was total opioid dosage in MME prescribed and opioid refills for six weeks after surgery. Secondary outcomes included the number of tablets and MME prescribed at discharge, in-hospital opioid consumption, length of stay, and postoperative complications., Results: Forty-nine cases (25 PRE and 24 POST) were included. Total median (10th-90th percentiles) MME for six weeks postoperatively was 900 (57-2082) MME PRE vs 295 (69-741) MME POST (mean difference = 721, 95% confidence interval [CI] = 127-1316, P = 0.007, Mann-Whitney U test). Refill rates did not differ. The median (10th-90th percentiles) initial discharge prescription in MME was 675 (57-1035) PRE vs 180 (18-534) POST (mean difference = 387, 95% CI = 156-618, P = 0.003, Mann-Whitney U test) MME. There were no differences in other outcomes., Conclusions: Implementation of a patient-specific prescribing and tapering protocol decreases the mean six-week dosage of opioid prescribed by 63% after THA without increasing the refill rate., (2019 American Academy of Pain Medicine. This work is written by US Government employees and is in the public domain in the US.)

Aim: To determine if genetic variation associated with decreased dopamine neurotransmission predicts a decrease in motor development in a convenience cohort study of infants born extremely-low-birthweight (ELBW)., Method: Four hundred and ninety-eight infants born ELBW had genome-wide genotyping and a neurodevelopmental evaluation at 18 to 22 months of age, corrected for preterm birth. A polygenic risk score (PRS) was created to combine into one predictor variable the hypothesized influences on motor development of alleles at seven independent single nucleotide polymorphisms previously associated with relative decreases in both dopamine neurotransmission and motor learning, by summing the number of alleles present in each infant (range=0-14). The motor development outcome was the Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development, Second Edition. The linear regression models were adjusted for seven clinical and four genetic ancestry covariates. The mean PRS of infants with cerebral palsy (CP) was compared to those without CP., Results: PRS was inversely related to PDI (p=0.011). Each 1-point increase in PRS resulted in an average decrease in PDI of 1.37 points. Patients with CP did not have a greater mean PRS than those without (p=0.67), both with and without adjustment for covariates., Interpretation: Genetic variation that favors a decrease in dopamine neurotransmission predisposes to a decrease in motor development in infants born ELBW, but not to the diagnosis of CP., What This Paper Adds: Genetic variation in dopamine neurotransmission was associated with a decrease in motor development in infants born at an extremely-low-birthweight. It does not predispose to the diagnosis of cerebral palsy., (© 2019 Mac Keith Press.)

Background: Therapeutic hypothermia reduces the risk of death, or moderate to severe neurodevelopmental impairment (NDI) in term infants with hypoxic-ischemic encephalopathy (HIE). Reports of its safety and efficacy in preterm infants are scarce., Objective: Report short and long-term outcomes of preterm infants with HIE who received therapeutic hypothermia., Methods: A retrospective cohort analysis of all preterm infants <36 weeks' gestation with HIE who received whole body hypothermia in a single center from January 2007 to April 2015. The primary outcome was death or moderate to severe NDI defined by moderate or severe cerebral palsy, severe hearing or visual impairment, or cognitive score < 85 on the Bayley Scales of Infant Development III (BSID III) at 18-24 months' adjusted age., Results: 30 infants with a median gestational age and birthweight of 35 weeks' (range; 33-35) and 2575 g (1850-4840) and a median first postnatal blood pH of 6.81 (6.58-7.14). Complications included coagulopathy (50%), early clinical seizures (43.3%), arterial hypotension (40%), persistent metabolic acidosis (37%) and thrombocytopenia (20%). Four infants died before or soon after discharge (18.2%). Eighteen surviving infants (69.2%) had follow up data; 7 of them had moderate to severe NDI (38.9%). Cognitive, motor and language mean composite BSID III scores were 84 (54-110), 83 (46-118), and 78 (46-112). Death or moderate to severe NDI occurred in 11/22 (50%) infants with known outcomes., Conclusion: Large randomized trials on efficacy and safety are needed in this highly vulnerable population as the incidence of complications and the combined outcome of death and NDI is concerning., (Copyright © 2018. Published by Elsevier B.V.)

Background and Objectives: Children born extremely preterm are at risk for cognitive difficulties and disability. The relative prognostic value of neonatal brain MRI and cranial ultrasound (CUS) for school-age outcomes remains unclear. Our objectives were to relate near-term conventional brain MRI and early and late CUS to cognitive impairment and disability at 6 to 7 years among children born extremely preterm and assess prognostic value., Methods: A prospective study of adverse early and late CUS and near-term conventional MRI findings to predict outcomes at 6 to 7 years including a full-scale IQ (FSIQ) <70 and disability (FSIQ <70, moderate-to-severe cerebral palsy, or severe vision or hearing impairment) in a subgroup of Surfactant Positive Airway Pressure and Pulse Oximetry Randomized Trial enrollees. Stepwise logistic regression evaluated associations of neuroimaging with outcomes, adjusting for perinatal-neonatal factors., Results: A total of 386 children had follow-up. In unadjusted analyses, severity of white matter abnormality and cerebellar lesions on MRI and adverse CUS findings were associated with outcomes. In full regression models, both adverse late CUS findings (odds ratio [OR] 27.9; 95% confidence interval [CI] 6.0-129) and significant cerebellar lesions on MRI (OR 2.71; 95% CI 1.1-6.7) remained associated with disability, but only adverse late CUS findings (OR 20.1; 95% CI 3.6-111) were associated with FSIQ <70. Predictive accuracy of stepwise models was not substantially improved with the addition of neuroimaging., Conclusions: Severe but rare adverse late CUS findings were most strongly associated with cognitive impairment and disability at school age, and significant cerebellar lesions on MRI were associated with disability. Near-term conventional MRI did not substantively enhance prediction of severe early school-age outcomes., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Cerebral palsy (CP) is a condition affecting young children that causes lifelong disabilities. Umbilical cord blood cells improve motor function in experimental systems via paracrine signaling. After demonstrating safety, we conducted a phase II trial of autologous cord blood (ACB) infusion in children with CP to test whether ACB could improve function (ClinicalTrials.gov, NCT01147653; IND 14360). In this double-blind, placebo-controlled, crossover study of a single intravenous infusion of 1-5 × 10 7 total nucleated cells per kilogram of ACB, children ages 1 to 6 years with CP were randomly assigned to receive ACB or placebo at baseline, followed by the alternate infusion 1 year later. Motor function and magnetic resonance imaging brain connectivity studies were performed at baseline, 1, and 2 years post-treatment. The primary endpoint was change in motor function 1 year after baseline infusion. Additional analyses were performed at 2 years. Sixty-three children (median age 2.1 years) were randomized to treatment (n = 32) or placebo (n = 31) at baseline. Although there was no difference in mean change in Gross Motor Function Measure-66 (GMFM-66) scores at 1 year between placebo and treated groups, a dosing effect was identified. In an analysis 1 year post-ACB treatment, those who received doses ≥2 × 10 7 /kg demonstrated significantly greater increases in GMFM-66 scores above those predicted by age and severity, as well as in Peabody Developmental Motor Scales-2 Gross Motor Quotient scores and normalized brain connectivity. Results of this study suggest that appropriately dosed ACB infusion improves brain connectivity and gross motor function in young children with CP. Stem Cells Translational Medicine 2017;6:2071-2078., (© 2017 The Authors Stem Cells Translational Medicine published by Wiley Periodicals, Inc. on behalf of AlphaMed Press.)

GLE1 encodes a protein important for mRNA export and appears to play roles in translation initiation and termination as well. Pathogenic variants in GLE1 mutations have been associated with lethal contracture syndrome and lethal arthrogryposis with anterior horn cell disease; phenotypes reported in individuals include fetal akinesia and a severe form of motor neuron disease, typically presenting with prenatal symptoms and perinatal lethality. In this article, we identified biallelic missense mutations in GLE1 by trio whole-exome sequencing in an individual affected with congenital motor weakness and contractures as well as feeding and respiratory difficulties. Muscle biopsy was consistent with anterior horn cell disease and supported the pathogenicity of the sequence variants. Importantly, this individual survived past the perinatal period with respiratory support and currently demonstrates age-appropriate cognition and slow but steady motor developmental progress. We propose that pathogenic variants in GLE1 can be associated with a nonperinatal lethal motor phenotype, and affected individuals can demonstrate motor skill progression, unlike prototypical anterior horn cell diseases such as spinal muscular atrophy., (© 2017 Tan et al.; Published by Cold Spring Harbor Laboratory Press.)

Background: Behavior and socioemotional development are crucial aspects of child development ., Methods: A total of 2505 children born at <27 weeks' gestation was evaluated at 18 to 22 months' corrected age between January 1, 2008 and December 12, 2012 (86% follow-up). The Brief Infant and Toddler Social and Emotional Assessment was used to evaluate behavioral and socioemotional problems. Cognition and language were evaluated by using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Logistic regression analysis was used to evaluate for perinatal and demographic factors associated with behavioral problems (≥75th percentile) and delayed socioemotional competence (≤15th percentile). Structural equation modeling with bootstrapping was used to identify possible associated risk factors and Bayley-III scores as mediators., Results: Thirty-five percent (873) of children had behavioral problems, and 26% (637) displayed deficits in socioemotional competence. Male sex, public insurance, mothers with less than a high school education, and lower maternal age were associated with behavioral problems. Deficits in competence were associated with lower birth weight, public insurance, mothers with less than a high school education, and abnormal neuromotor exam. Bayley-III language and cognitive scores were significant mediators of the relationships between risk factors and both behavioral and competence scores ( P < .05)., Conclusions: Extremely premature children are at risk for behavioral problems and deficits in socioemotional competence. Sociodemographic factors were associated with both socioemotional competence and behavioral problems. Deficits in socioemotional competence were also associated with neuromotor abnormalities and cognitive and language function., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2017 by the American Academy of Pediatrics.)

Background: Infants born near the limit of viability are at high risk for death or adverse neurodevelopmental outcomes. It is unclear whether these outcomes have improved over the past 15 years., Aim: To determine if death and neurodevelopmental impairment have declined over the past 15 years in infants born at 22 to 24 weeks' gestation., Study Design: Retrospective cohort study., Subjects: We identified infants born at 22 to 24 weeks' gestation in our center in two epochs: 1998-2004 (Epoch 1) and 2005-2011 (Epoch 2)., Outcome Measures: The primary outcome, death or neurodevelopmental impairment, was evaluated at 17-25 months' corrected gestational age with neurologic exams and Bayley Scales of Infant Development. Perinatal characteristics, major morbidities, and outcomes were compared between epochs., Results: Birth weight and gestational age were similar between 170 infants in Epoch 1 and 187 infants in Epoch 2. Mortality was significantly lower in Epoch 2, 55% vs. 42% (p=0.02). Among surviving infants, late-onset sepsis (p<0.01), bronchopulmonary dysplasia (p<0.01), and surgical necrotizing enterocolitis (p=0.04) were less common in Epoch 2. Neurodevelopmental impairment among surviving infants declined from 68% in Epoch 1 to 47% in Epoch 2, p=0.02. Odds of death or NDI were significantly lower in Epoch 2 vs. Epoch 1, OR=0.31 (95% confidence interval; 0.16, 0.58)., Conclusion: Risk of death or neurodevelopmental impairment decreased over time in infants born at 22 to 24 weeks' gestation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: To assess retinal nerve fiber layer (RNFL) thickness at term-equivalent age in very preterm (<32 weeks gestational age) vs term-born infant cohorts, and compare very preterm infant RNFL thickness with brain anatomy and neurodevelopment., Design: Cohort study., Methods: RNFL was semi-automatically segmented (1 eye per infant) in 57 very preterm and 50 term infants with adequate images from bedside portable, handheld spectral-domain optical coherence tomography imaging at 37-42 weeks postmenstrual age. Mean RNFL thickness was calculated for the papillomacular bundle (-15 degrees to +15 degrees) and temporal quadrant (-45 degrees to +45 degrees) relative to the fovea-optic nerve axis. Brain magnetic resonance imaging (MRI) scans clinically obtained in 26 very preterm infants were scored for global structural abnormalities by an expert masked to data except for age. Cognitive, language, and motor skills were assessed in 33 of the very preterm infants at 18-24 months corrected age., Results: RNFL was thinner for very preterm vs term infants at the papillomacular bundle ([mean ± standard deviation] 61 ± 17 vs 72 ± 13 μm, P < .001) and temporal quadrant (72 ± 21 vs 82 ± 16 μm, P = .005). In very preterm infants, thinner papillomacular bundle RNFL correlated with higher global brain MRI lesion burden index (R(2) = 0.35, P = .001) and lower cognitive (R(2) = 0.18, P = .01) and motor (R(2) = 0.17, P = .02) scores. Relationships were similar for temporal quadrant., Conclusions: Thinner RNFL in very preterm infants relative to term-born infants may relate to brain structure and neurodevelopment., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: The authors relate posterior segment microanatomy from perinatal spectral domain optical coherence tomography to visual acuity, brain abnormalities, and neurodevelopment., Methods: Thirteen infants (11 preterm and 2 term birth), imaged in the nursery with portable spectral domain optical coherence tomography, had visual acuity and sensorimotor testing at age 9 months to 15 months (grating acuity) or 4 years to 5 years (optotype), and medical records reviewed for brain magnetic resonance imaging reports and Bayley scales testing at age 18 months to 24 months., Results: Eight children with age-appropriate macular microanatomy without edema on perinatal spectral domain optical coherence tomography had optimal (≥ 20/40) or within normal limits (grating acuity) visual acuity. Five children with perinatal macular edema had suboptimal visual acuity (in 9/10 eyes) and sensorimotor deficits, magnetic resonance imaging abnormalities, or poor neurodevelopment. Macular edema persisted in 1 infant through 9-month corrected age., Conclusion: Maturation of the visual system and evolution of retinal anomalies can be monitored with posterior segment spectral domain optical coherence tomography. Retinal microanatomy observed in infancy might relate to subsequent vision and other central nervous system events, but additional studies are needed to determine the range of normal microanatomy in infants and how this relates to vision and neurodevelopment.

Purpose: To evaluate the association between cystoid macular edema (CME) observed in very preterm infants and developmental outcomes at 18 to 24 months corrected age., Design: Cohort study., Participants: Infants born at or less than 1500 g or at or less than 30 weeks postmenstrual age who underwent screening for retinopathy of prematurity (ROP) in an intensive care nursery., Methods: Bedside handheld spectral-domain optical coherence tomography (SD OCT; Envisu, Bioptigen, Inc, Research Triangle Park, NC) imaging was obtained from preterm infants who were being screened for ROP and graded for presence of CME, central foveal thickness (CFT), inner nuclear layer thickness, and foveal-to-parafoveal thickness ratio. At 18 to 24 months corrected age, the children were assessed with the Bayley Scales of Infant and Toddler Development, Third Edition., Main Outcome Measures: Scores on the Bayley cognitive, language, and motor subscales., Results: Among 77 children with SD OCT imaging, 53 were evaluated with the Bayley Scales. Compared with children who did not have CME as infants (n=22), the mean score for children who had CME (n=31) was 7.3 points (95% confidence interval [CI], -15.5 to 0.9; P=0.08) lower on the cognitive subscale, 14.1 points (95% CI, -22.7 to -5.5; P=0.002) lower for the language subscale, and 11.5 points (95% CI, -21.6 to -1.3; P=0.03) lower for the motor subscale. Differences were maintained after adjusting for gestational age and birth weight. Severity of CME, as assessed by foveal-to-parafoveal thickness ratio, within the CME group correlated with poorer cognitive (R2=0.16, P=0.03) and motor (R2=0.15, P=0.03) development., Conclusions: Cystoid macular edema observed on SD OCT in very preterm infants screened for ROP is associated with poorer language and motor skills at 18 to 24 months corrected age. Evaluation of the retina with SD-OCT may serve as an indicator of neurodevelopmental health for very preterm infants in the intensive care nursery., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate effects of prematurity on early optic nerve (ON) development and the usefulness of ON parameters as indicators of central nervous system (CNS) development and pathology., Design: Prospective, cross-sectional, longitudinal study., Participants: Forty-four preterm infants undergoing retinopathy of prematurity (ROP) screening and 52 term infants., Methods: We analyzed ON from portable handheld spectral-domain optical coherence tomography (SD-OCT) images (Bioptigen, Inc, Research Triangle Park, NC) of 44 preterm and 52 term infants. The highest-quality ON scan from either eye was selected for quantitative analysis. Longitudinal analysis was performed at 31-36 weeks and 37-42 weeks postmenstrual age (PMA). Preterm ON parameters also were assessed for correlation with indicators of cognitive, language, and motor development and CNS pathology., Main Outcome Measures: Vertical cup diameter (vCD), vertical disc diameter (vDD), vertical cup-to-disc ratio (vCDR), cup depth, and indicators of neurocognitive development and CNS pathology., Results: At 37-42 weeks PMA, preterm infants had larger vCD and vCDR than term infants (908 vs. 700 μm [P<0.001] and 0.68 vs. 0.53 μm [P<0.001], respectively), whereas cup depth and vDD were not significantly different. Longitudinal changes (n = 26 preterm eyes; mean interval, 4.7 weeks) in vDD and in vCDR were an increase of 74 μm (P = 0.008) and decrease of 0.05 (P = 0.015), respectively. In preterm infants (n = 44), periventricular leukomalacia was associated with larger vCD (1084 vs. 828 μm; P = 0.005) and vCDR (0.85 vs. 0.63; P<0.001), posthemorrhagic hydrocephalus was associated with shallower cup (331 vs. 456 μm; P = 0.030), and clinical magnetic resonance imaging was associated with larger vCDR (0.73 vs. 0.64; P = 0.023). In 23 preterm infants with Bayley Scales of Infant Development scores, larger vCDR was associated with lower cognitive scores (P = 0.049)., Conclusions: This is the first analysis of ON parameters in premature infants using SD-OCT. It demonstrated that by age of term birth, vCD and vCDR are larger in preterm infants who were screened for ROP than in term infants. In this prospective pilot study, ON parameters in these preterm infants associate weakly with CNS pathology and future cognitive development. Future prospective studies with larger numbers are necessary before further conclusions can be made., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To assess feasibility and safety of providing autologous umbilical cord blood (UCB) cells to neonates with hypoxic-ischemic encephalopathy (HIE)., Study Design: We enrolled infants in the intensive care nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells (up to 4 doses adjusted for volume and red blood cell content, 1-5 × 10(7) cells/dose). We recorded UCB collection and cell infusion characteristics, and pre- and post-infusion vital signs. As exploratory analyses, we compared cell recipients' hospital outcomes (mortality, oral feeds at discharge) and 1-year survival with Bayley Scales of Infant and Toddler Development, 3rd edition scores ≥85 in 3 domains (cognitive, language, and motor development) with cooled infants who did not have available cells., Results: Twenty-three infants were cooled and received cells. Median collection and infusion volumes were 36 and 4.3 mL. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours. Cell recipients and concurrent cooled infants had similar hospital outcomes. Thirteen of 18 (74%) cell recipients and 19 of 46 (41%) concurrent cooled infants with known 1-year outcomes survived with scores >85., Conclusions: Collection, preparation, and infusion of fresh autologous UCB cells for use in infants with HIE is feasible. A randomized double-blind study is needed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Determine predictors of neurocognitive outcome in early school age congenital diaphragmatic hernia (CDH) survivors., Study Design: Prospective study of infants with CDH at Duke University Medical Center. Neurocognitive delay (NCD) at school age (4 to 7years) was defined as a score<80 in any of the following areas: Verbal Scale IQ, Performance Scale IQ, Expressive Language, or Receptive Language. Logistic regression, Fisher's exact, and the Wilcoxon rank sum test were used to examine the relationship between NCD at early school age and 6 demographic and 18 medical variables., Results: Of 43 infants with CDH, twenty seven (63%) survived to hospital discharge, and 16 (59%) returned for school age testing at a median age of 4.9years. Seven (44%) of the children evaluated had NCD. Patch repair (p=0.01), extracorporeal membrane oxygenation (ECMO; p=0.02), days on ECMO (p=0.01), days of mechanical ventilation (p=0.049), and post-operative use of inhaled nitric oxide (p=0.02) were found to be associated with NCD at early school age., Conclusions: CDH survivors are at risk for neurocognitive delay persisting into school age. Perinatal factors such as patch repair and ECMO treatment may aid in identifying CDH survivors at high risk for continued learning difficulties throughout childhood., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: To determine if antenatal treatment of maternal periodontitis affects early childhood neurodevelopment., Study Design: We evaluated neurodevelopment of 331 24-month-old children born to women who participated in a randomized trial of antenatal (167) or postpartum (164) treatment of periodontitis. Children within groups defined by maternal treatment were designated as high risk for abnormal neurodevelopment (n = 96; birth at ≤34(6)/7 weeks' gestation or small for gestational age following birth at term) or low risk (n = 235; appropriate birth weight and ≥37 weeks' gestation). We measured neurodevelopment using the Bayley Scale of Infant and Toddler Development III (BSID III) and neurological examination. Treatment effect was analyzed using a chi-square or Fisher exact test. Between-group mean scores were compared using Student t test., Results: There were no differences in the incidence of neuromotor or sensory (visual or hearing) impairment or scores on the BSID III between groups. Low-risk children in the antenatal treatment group had higher language scores than those in the postpartum treatment group (92.9 versus 89.2; p = 0.05)., Conclusion: Antenatal treatment of maternal periodontitis does not appear to affect neurodevelopment at 24 months of age. The slight improvement in language development in low-risk children may be an artifact or not clinically relevant., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: We previously reported early results of a randomized trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy showing a significant reduction in the rate of death or moderate or severe disability at 18 to 22 months of age. Long-term outcomes are now available., Methods: In the original trial, we assigned infants with moderate or severe encephalopathy to usual care (the control group) or whole-body cooling to an esophageal temperature of 33.5°C for 72 hours, followed by slow rewarming (the hypothermia group). We evaluated cognitive, attention and executive, and visuospatial function; neurologic outcomes; and physical and psychosocial health among participants at 6 to 7 years of age. The primary outcome of the present analyses was death or an IQ score below 70., Results: Of the 208 trial participants, primary outcome data were available for 190. Of the 97 children in the hypothermia group and the 93 children in the control group, death or an IQ score below 70 occurred in 46 (47%) and 58 (62%), respectively (P=0.06); death occurred in 27 (28%) and 41 (44%) (P=0.04); and death or severe disability occurred in 38 (41%) and 53 (60%) (P=0.03). Other outcome data were available for the 122 surviving children, 70 in the hypothermia group and 52 in the control group. Moderate or severe disability occurred in 24 of 69 children (35%) and 19 of 50 children (38%), respectively (P=0.87). Attention-executive dysfunction occurred in 4% and 13%, respectively, of children receiving hypothermia and those receiving usual care (P=0.19), and visuospatial dysfunction occurred in 4% and 3% (P=0.80)., Conclusions: The rate of the combined end point of death or an IQ score of less than 70 at 6 to 7 years of age was lower among children undergoing whole-body hypothermia than among those undergoing usual care, but the differences were not significant. However, hypothermia resulted in lower death rates and did not increase rates of severe disability among survivors. (Funded by the National Institutes of Health and the Eunice Kennedy Shriver NICHD Neonatal Research Network; ClinicalTrials.gov number, NCT00005772.).

Objective: To determine (1) the neurocognitive development of children with sickle cell disease (SCD) from 6 months through 36 months of age, (2) the independent and combined contributions of biomedical risk and parenting risk to child neurocognitive functioning, and (3) the independent and combined contributions of biomedical risk, parent cognitive processes, and family functioning to parent adjustment., Method: The study sample included 89 African American children and their parents served through the Duke University-University of North Carolina Comprehensive Sickle Cell Center. Measures of cognitive and psychomotor development were obtained at 6, 12, 24, and 36 months of age, and parents completed self-report measures of the cognitive processes of daily stress and attributional style, psychological adjustment, and family functioning., Results: There was no significant decrease in psychomotor functioning (PDI) over time but cognitive functioning (MDI) declined, with a significant decrease occurring between the 12- and 24-month assessment points. At 24 months, poorer cognitive functioning was associated with parenting risk, in terms of a learned-helplessness attributional style, and biomedical risk, in terms of HbSS phenotype. Levels of psychological distress within the clinical range were reported by 24% of the parents, and poorer parent adjustment was associated with high levels of daily stress, less knowledge about child development, lower expectations of efficacy, and HbSC phenotype., Conclusions: The findings indicate that young children with SCD are at risk for neurocognitive impairment and provide support for the initiation of early intervention studies to promote neurocognitive development.

Illness-specific patterns of adjustment and cognitive adaptational process were identified in children (7-12 years of age) with cystic fibrosis (CF, n = 40) or sickle cell disease (SCD, n = 40). Anxiety diagnoses were most frequent for both illness subgroups but children with CF had a higher rate of oppositional disorder (27.5%) than did children with SCD (2.5%). Significant portions of the variance in adjustment were accounted for by stress appraisal (19%), expectations of efficacy (9%) and health locus of control (9%) for children with CF and by stress appraisal (21%) and self-worth (12%) for children with SCD. The interaction of general and specific illness tasks and adaptational process with developmental tasks in delineating intervention opportunities is discussed.

The continuing contribution of early biological and psychosocial risk factors to developmental outcome of 55 very low birth weight infants (< or = 1500 g) was assessed at 4 years of age. Biological risk, assessed by the Neurobiologic Risk Score, accounted for significant portions of the variance in the perceptual-performance (17%) and motor (35%) dimensions of the McCarthy Scales of Children's Abilities. Psychosocial risk, reflected in maternal appraisals of daily stress during the newborn period, did not account for a significant portion of variance in any of the McCarthy Scales. Maternal education level, however, another measure of psychosocial risk, accounted for significant portions of variance (from 6% to 34%) on each of the McCarthy Scales. Movement from low neurobiologic risk status to poor outcome status at 4 years of age was associated with a number of psychosocial variables, including maternal education and early levels of maternal daily stress. The findings are discussed in terms of early markers for very low birth weight infants who require careful follow-up and of potential intervention targets to promote developmental outcome.

Objective: To explore the relationship between developmental outcome and behavior of very-low-birth-weight (VLBW) infants (< or = 1500 g) at high and low biologic risk., Design: Descriptive, ex post facto., Setting: Clinic for follow-up of infants at high risk., Participants: A convenience sample of 102 VLBW infants, free of major congenital anomalies, who completed 6-, 15-, and 24-month developmental testing and who were part of a larger study of 274 VLBW infants., Main Outcome Measure: Bayley Scales of Infant Development., Results: Infants at high biologic risk, versus infants at low biologic risk, were less attentive and active through age 15 months and were less adept in gross and fine motor skills through age 24 months (p < or = 0.05-0.001). Infants with continuous delay were less attentive than infants with no delay or late delay through age 24 months, less active through age 15 months (p < or = 0.001-0.001), and less skilled in motor behaviors through age 24 months (p < or = 0.05-0.001)., Conclusion: Infants at high biologic risk and infants with developmental delays are less attentive, less active, and less skilled in motor tasks during the first 15-24 months of life, suggesting an association between biologic risk and behavior and developmental delay and behavior.

In light of the findings that mother-completed checklists do not adequately reflect children's perceptions of their own adjustment, two child-completed questionnaires were assessed as screening measures for behavioral or emotional problems with 50 children seen for well-child examinations. Case criterion was child-reported DSM-III symptoms through a clinical interview. Support was provided for the Revised Children's Manifest Anxiety Scale but not the Children's Depression Inventory as a child-reported screening measure. Moreover, the findings indicated that both mother-completed and child-completed measures are needed to screen adequately for behavioral or emotional problems of children seen in a primary care pediatric clinic.

The relative contribution of biological and psychosocial risk factors to developmental outcome of 102 very low birth weight infants (< 1500 g) was delineated through 24 months corrected age. Biological risk, assessed by the Neurobiologic Risk Score (NBRS), accounted for significant amounts of variance in Bayley Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) at the 6-, 15-, and 24-month assessment points. Psychosocial risk, reflected in maternal appraisals of daily stress, accounted for a significant increment in cognitive outcome (MDI), over and above that accounted for by the NBRS, at each assessment point. Cognitive functioning at each assessment point differed as a function of biological risk and psychosocial risk status. The findings are discussed in terms of maternal stress as a marker of, and salient intervention target for, caregiving environments that can maximize or minimize the effects of biological vulnerability.

Rates of poor psychological adjustment of children with sickle cell disease remained relatively constant over initial and follow-up assessment points. However, there was relatively little stability in the classification of the adjustment of individuals, low congruence in specific behavior problem patterns and diagnoses in accordance with the Diagnostic and Statistical Manual of Mental Disorders (3rd ed.; American Psychiatric Association, 1980), and less stability in child adjustment by child report than by mother report. With initial levels of adjustment controlled, children's strategies for coping with pain accounted for a significant increment in child-reported symptoms (19%) and mother-reported internalizing behavior problems (8%) at follow-up beyond the contribution of illness and demographic parameters and follow-up interval. The findings suggest that children's coping strategies are a salient intervention target for enhancing adjustment.

Found that group rates of mother-reported and child-reported adjustment problems remained relatively constant over initial and 12-month follow-up assessment points. However, there was less stability in the classification of the adjustment of individuals, in specific behavior problem patterns and diagnoses, and in child-reported adjustment than in mother-reported adjustment. With initial level of child adjustment controlled, children's perceptions of self-worth accounted for a significant increment in child-reported symptoms and mother-reported adjustment at follow-up. Maternal distress also accounted for a significant increment in child-reported symptoms. These findings add support for the role of maternal adjustment and child self-worth in the adjustment of children with cystic fibrosis.

Found moderate stability in the classification of maternal adjustment in two longitudinal studies of mothers of children and adolescents with cystic fibrosis and sickle cell disease. In terms of the transactional stress and coping model, stable poor maternal adjustment was associated with higher levels of appraisal of daily stress and palliative coping and low levels of family supportiveness. With initial levels of maternal adjustment, demographic parameters, and follow-up interval controlled, concurrent levels of daily stress accounted for significant portions of variance in maternal adjustment at follow-up for both illness groups. In addition, illness severity, child psychological adjustment, and family conflict added significant increments to maternal adjustment at follow-up in the cystic fibrosis group. Findings are discussed in terms of a basis for subsequent intervention studies to enhance the adjustment of mothers of children with chronic illness.

This study compares the Neurobiologic Risk Score (NBRS) with developmental outcome in 199 infants < or = 1500 g birth weight to determine levels of risk and to investigate the relative contributions of the NBRS and nonmedical factors to developmental outcome. The NBRS correlated significantly (p < .0001) with the Bayley Mental (MDI) and Psychomotor (PDI) Indexes, and neurologic examination score (NS) at 6, 15, and 24 months. Three risk groups were identified: low, NBRS < or = 4; intermediate, NBRS 5 to 7; and high, NBRS > or = 8 with an incidence of major handicaps at 24 months of 7%, 32%, and 50%, respectively. Of eight factors considered, the NBRS accounted for the greatest variance: MDI, 14 to 27%; PDI, 25 to 29%; NS, 34 to 42%. Additional increments of variance were contributed by gender (MDI, PDI, NS), maternal intelligence and race (MDI), and maternal education (PDI). The NBRS is a useful tool for identifying risk for developmental abnormalities due to neonatal medical events.

Found 60% of children 7-12 years old with cystic fibrosis to have a parent-reported behavior problem and 62% met the criteria for a DSM-III diagnosis based on a structured clinical interview with the child. Mixed internal and external behavior problem patterns and diagnoses of anxiety and oppositional disorder were most frequent. Support was provided for the hypothesized psycho-social/mediational roles of child perception of self-worth and maternal anxiety in child adjustment. Together, the variables of the transactional stress and coping model accounted for 39 and 43% of the variance in mother-reported internalizing and externalizing behavior problems and for 68% of the variance in child-reported problems.

Assessed the role of illness parameters, demographic parameters, and hypothesized psychosocial/mediational processes in the psychological adjustment of 68 mothers of children and adolescents (7-17 years of age) with cystic fibrosis. Together the illness and demographic parameters accounted for only 13-15% of the variance in maternal adjustment. However, the hypothesized mediational processes accounted for 35-40% increment in the variance in maternal adjustment. More specifically, maternal adjustment was associated with lower levels of perceived daily stress, less use of palliative coping methods, and family functioning characterized by high levels of supportiveness.

This study found intellectual and academic functioning of 76 children and adolescents with cystic fibrosis to be normally distributed. Intellectual functioning was related inversely to age, and both intellectual and academic functioning were related directly to socioeconomic status. Medical status did not add a significant increment in the amount of variance in intellectual and academic functioning accounted for by age and socioeconomic status.

Ten studies designed to evaluate the psychological and behavioral effects of the antiasthma agent theophylline in children have been carried out to date. In this review, we evaluate the strengths and weaknesses of those investigations and discuss whether theophylline is responsible for learning disabilities or behavioral disorders such as hyperactivity. We also discuss the similarities between studies of theophylline and those of other xanthines, such as caffeine, to suggest that some persons appear to have a heightened response to these substances and would benefit from closer monitoring, not only of serum drug levels but also of their consumption of food and beverages that contain caffeine. In addition, we describe strategies for examining whether a functional relationship exists between theophylline use and behavioral and psychological changes in children.