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OBJECTIVES: To examine elevated neonatal inflammatory and neurotrophic proteins from children born extremely preterm in relation to later childhood brain Magnetic Resonance Imaging volumes and cognition. STUDY DESIGN: We measured circulating inflammation-related proteins and neurotrophic proteins on postnatal days 1, 7, and 14 in 166 children at 10 years of age (73 males; 93 females). Top quartile levels on ≥2 days for ≥3 inflammation-related proteins and for ≥4 neurotrophic proteins defined exposure. We examined associations among protein levels, brain Magnetic Resonance Imaging volumes, and cognition with multiple linear and logistic regressions. RESULTS: Analyses were adjusted for gestational age at birth and sex. Children with ≥3 elevated inflammation-related proteins had smaller grey matter, brain stem/cerebellar, and total brain volumes than those without elevated inflammation-related proteins, adjusted for neurotrophic proteins. When adjusted for inflammation-related proteins, children with ≥4 neurotrophic proteins, compared with children with no neurotrophic proteins, had larger grey matter and total brain volumes. Higher grey matter, white matter, and cerebellum and brainstem volumes were significantly correlated with higher IQ. Grey and white matter volumes were correlated with each other (r = −0.18; P = .021), and cerebellum and brainstem was highly correlated with grey matter (r = 0.55; P < .001) and white matter (r = 0.29; P < .001). Adjusting for other brain compartments, cerebellum and brainstem was associated with IQ (P = .016), but the association with white matter was marginally significant (P = .051). Grey matter was not associated with IQ. After adjusting for brain volumes, elevated inflammation-related proteins remained significantly associated with a lower IQ, and elevated neurotrophic proteins remained associated with a higher IQ. CONCLUSIONS: Newborn inflammatory and neurotrophin protein levels are associated with later brain volumes and cognition, but their effects on cognition are not entirely explained by altered brain volumes.

Background The incidence of attention deficit hyperactivity disorder is higher among children born very preterm than among children who are mature at birth. Methods We studied 583 ten-year-old children who were born before 28 weeks of gestation whose IQ was above 84 and had a parent-completed Child Symptom Inventory-4, which allowed classification of the child as having or not having symptoms of attention deficit hyperactivity disorder. For 422 children, we also had a teacher report, and for 583 children, we also had a parent report of whether or not a physician made an attention deficit hyperactivity disorder diagnosis. Results The risk profile of screening positive for attention deficit hyperactivity disorder based on a parent's report differed from the risk profile based on the teacher's report, whereas the risk profile according to a physician and according to any two observers closely resembled the parent-reported profile. Among the statistically significant risk factors were young maternal age (parent, physician, and two observers), maternal obesity (parent, physician, and two observers), maternal smoking (parent, physician, and two observers), magnesium given at delivery for seizure prophylaxis (parent and two observers), recovery of Mycoplasma sp. from the placenta (teacher and two observers), low gestational age (parent and two observers), low birth weight (teacher and physician), singleton (parent, physician, and two observers), male (parent, teacher, physician, and two observers), mechanical ventilation on postnatal day seven (physician), receipt of a sedative (parent and two observers), retinopathy of prematurity (parent), necrotizing enterocolitis (physician), antibiotic receipt (physician and two observers), and ventriculomegaly on brain scan (parent and two observers). Conclusions The multiplicity of risk factors identified can be subsumed as components of four broad themes: low socioeconomic state, immaturity or vulnerability, inflammation, and epigenetic phenomena.

The association of hand preference (left, mixed, and right) with cognitive, academic, motor, and behavioral function was evaluated in 864 extremely preterm children at 10 years of age. Left-handed and right-handed children performed similarly but mixed-handed children had greater odds of functional deficits across domains than right-handed children.

To evaluate the difference in 10-year neurocognitive outcomes between extremely low gestational age newborns without bacteremia and those with suspected or confirmed late-onset bacteremia.Neurocognitive function was evaluated at 10 years of age in 889 children born at28 weeks of gestation and followed from birth. Definite (culture-positive) late-onset bacteremia during postnatal weeks 2-4 was identified in 223 children, and 129 children had suspected bacteremia.Infants with the lowest gestational age and birth weight z-score had the highest prevalence of definite and suspected late-onset bacteremia. Compared with peers with no or suspected bacteremia, infants with definite bacteremia performed worse on tests of general cognitive ability, language, academic achievement, and executive function, even after adjustment for potential confounders. Adjustment for low IQ attenuated the associations between bacteremia and all dysfunctions at age 10 years. Children with suspected bacteremia did not differ appreciably from those with no evidence of bacteremia. The motor domain was unaffected.Extremely low gestational age newborns who had definite late bacteremia during postnatal weeks 2-4 are at heightened risk of neurocognitive limitations at age 10 years.

OBJECTIVE: To assess the association between maternal prepregnancy body mass index and adequacy of pregnancy weight gain in relation to neurocognitive function in school-aged children born extremely preterm.STUDY DESIGN: Study participants were 535 ten-year-old children enrolled previously in the prospective multicenter Extremely Low Gestational Age Newborns cohort study who were products of singleton pregnancies. Soon after delivery, mothers provided information about prepregnancy weight. Prepregnancy body mass index and adequacy of weight gain were characterized based on this information. Children underwent a neurocognitive evaluation at 10 years of age.RESULTS: Maternal prepregnancy obesity was associated with increased odds of a lower score for Differential Ability Scales-II Verbal IQ, for Developmental Neuropsychological Assessment-II measures of processing speed and visual fine motor control, and for Wechsler Individual Achievement Test-III Spelling. Children born to mothers who gained an excessive amount of weight were at increased odds of a low score on the Oral and Written Language Scales Oral Expression assessment. Conversely, children whose mother did not gain an adequate amount of weight were at increased odds of a lower score on the Oral and Written Language Scales Oral Expression and Wechsler Individual Achievement Test-III Word Reading assessments.CONCLUSION: In this cohort of infants born extremely preterm, maternal obesity was associated with poorer performance on some assessments of neurocognitive function. Our findings are consistent with the observational and experimental literature and suggest that opportunities may exist to mitigate risk through education and behavioral intervention before pregnancy.

No prospective cohort study of high-risk children has used rigorous exposure assessment and optimal diagnostic procedures to examine the perinatal antecedents of autism spectrum disorder separately among those with and without cognitive impairment.We sought to identify perinatal factors associated with increased risk for autism spectrum disorder with and without intellectual disability (intelligence quotient70) in children born extremely preterm.This prospective multicenter (14 institutions in 5 states) birth cohort study included children born at 23-27 weeks' gestation in 2002 through 2004 who were evaluated for autism spectrum disorder and intellectual disability at age 10 years. Pregnancy information was obtained from medical records and by structured maternal interview. Cervical-vaginal "infection" refers to maternal report of bacterial infection (n = 4), bacterial vaginosis (n = 30), yeast infection (n = 62), mixed infection (n = 4), or other/unspecified infection (n = 43; eg, chlamydia, trichomonas, or herpes). We do not know the extent to which infection per se was confirmed by microbial colonization. We use the terms "fetal growth restriction" and "small for gestational age" interchangeably in light of the ongoing challenge to discern pathologically from constitutionally small newborns. Severe fetal growth restriction was defined as a birthweight Z-score for gestational age at delivery-2 (ie, ≥2 SD below the median birthweight in a referent sample that excluded pregnancies delivered for preeclampsia or fetal indications). Participants were classified into 4 groups based on whether or not they met rigorous diagnostic criteria for autism spectrum disorder and intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, autism spectrum disorder-/intellectual disability+, and autism spectrum disorder-/intellectual disability-). Temporally ordered multinomial logistic regression models were used to examine the information conveyed by perinatal factors about increased risk for autism spectrum disorder and/or intellectual disability (autism spectrum disorder+/intellectual disability-, autism spectrum disorder+/intellectual disability+, and autism spectrum disorder-/intellectual disability+).In all, 889 of 966 (92%) children recruited were assessed at age 10 years, of whom 857 (96%) were assessed for autism spectrum disorder; of these, 840 (98%) children were assessed for intellectual disability. Autism spectrum disorder+/intellectual disability- was diagnosed in 3.2% (27/840), autism spectrum disorder+/intellectual disability+ in 3.8% (32/840), and autism spectrum disorder-/intellectual disability+ in 8.5% (71/840). Maternal report of presumed cervical-vaginal infection during pregnancy was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.7; 95% confidence interval, 1.2-6.4). The lowest gestational age category (23-24 weeks) was associated with increased risk of autism spectrum disorder+/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.3-6.6) and autism spectrum disorder+/intellectual disability- (odds ratio, 4.4; 95% confidence interval, 1.7-11). Severe fetal growth restriction was strongly associated with increased risk for autism spectrum disorder+/intellectual disability- (odds ratio, 9.9; 95% confidence interval, 3.3-30), whereas peripartum maternal fever was uniquely associated with increased risk of autism spectrum disorder-/intellectual disability+ (odds ratio, 2.9; 95% confidence interval, 1.2-6.7).Our study confirms that low gestational age is associated with increased risk for autism spectrum disorder irrespective of intellectual ability, whereas severe fetal growth restriction is strongly associated with autism spectrum disorder without intellectual disability. Maternal report of cervical-vaginal infection is associated with increased risk of autism spectrum disorder with intellectual disability, and peripartum maternal fever is associated with increased risk for intellectual disability without autism spectrum disorder.

Resting-state fMRI (rs-fMRI) holds promise as a clinical tool to characterize and monitor the phenotype of different neurological and psychiatric disorders. The most common analysis approach requires the definition of one or more regions-of-interest (ROIs). However this need for a priori ROI information makes rs-fMRI inadequate to survey functional connectivity differences associated with a range of neurological disorders where the ROI information may not be available. A second problem encountered in fMRI measures of connectivity is the need for an arbitrary correlation threshold to determine whether or not two areas are connected. This is problematic because in many cases the differences in tissue connectivity between disease groups and/or control subjects are threshold dependent. In this work we propose a novel voxel-based contrast mechanism for rs-fMRI, the Intrinsic Connectivity Distribution (ICD), that neither requires a priori information to define a ROI, nor an arbitrary threshold to define a connection. We show the sensitivity of previous methods to the choice of connection thresholds and evaluate ICD using a survey study comparing young adults born prematurely to healthy term control subjects. Functional connectivity differences were found in hypothesized language processing areas in the left temporal-parietal areas. In addition, significant clinically-relevant differences were found between preterm and term control subjects, highlighting the importance of whole brain surveys independent of a priori information.

Management of congenital diaphragmatic hernia (CDH) remains challenging. Despite advances in technologic and therapeutic strategies such as high-frequency mechanical ventilation, inhaled nitric oxide (iNO), and delayed surgical repair, the condition continues to carry a substantial mortality risk. In recent years, with increasing prenatal identification of fetuses affected by CDH, more effort has been directed toward strategies allowing in utero intervention, with the goal of improving survival. Unfortunately, a universally successful fetal treatment for CDH remains elusive. Over the past several decades, collective knowledge has markedly increased regarding the range of short- and long-term morbidities experienced by CDH survivors, and medical care has evolved as understanding of the disease has progressed. Affected patients demand and deserve a multidisciplinary approach, both in the inpatient arena and follow-up setting, with experts in neonatology, surgery, pulmonology, cardiology, and neurodevelopment working together to optimize outcomes. This article reviews the basic pathophysiology behind CDH, describes recent updates in the field, and outlines the long-term outcomes for these fascinating and complex patients.

Objectives To test the hypothesis that higher blood levels of neurotrophic proteins (proteins that support neuronal survival and function) in the first 2 weeks of life are associated with a lower risk of cognitive impairment at 10 years. Study design We evaluated 812 10-year-old children with neonatal blood specimens enrolled in the multicenter prospective Extremely Low Gestational Age Newborn Study, assessing 22 blood proteins collected on 3 days over the first 2 weeks of life. Using latent profile analysis, we derived a cognitive function level based on standardized cognitive and executive function tests. We defined high exposure as the top quartile neurotrophic protein blood level on ≥2 days either for ≥4 proteins or for a specific cluster of neurotrophic proteins (defined by latent class analysis). Multinomial logistic regression analyzed associations between high exposures and cognitive impairment. Results Controlling for the effects of inflammatory proteins, persistently elevated blood levels of ≥4 neurotrophic proteins were associated with reduced risk of moderate (OR, 0.35; 95% CI, 0.18-0.67) and severe cognitive impairment (OR, 0.22; 95% CI, 0.09-0.53). Children with a cluster of elevated proteins including angiopoietin 1, brain-derived neurotrophic factor, and regulated upon activation, normal T-cell expressed, and secreted had a reduced risk of adverse cognitive outcomes (OR range, 0.31-0.6). The risk for moderate to severe cognitive impairment was least with 0-1 inflammatory and >4 neurotrophic proteins. Conclusions Persisting elevations of circulating neurotrophic proteins during the first 2 weeks of life are associated with lowered risk of impaired cognition at 10 years of age, controlling for increases in inflammatory proteins.

Aggressive management of diabetes using American Diabetes Association (ADA) best practice guidelines in hospitalized patients reduces morbidity and mortality. Inpatient electronic medical records systems improve care in chronic diseases by identifying care needs and improving the data available for decision making and disease management. The purpose of this quality improvement project was to evaluate the impact of ADA best practice guidelines of glycemic management once they have been entered into the electronic medical record (EMR) of hospitalized diabetics. Kotter’s organizational change process guided the project. The project question investigated whether nurses’ use of ADA Best Practice Guidelines incorporated into the EMR improves glycemic management in hospitalized patients. A quality improvement project pretestposttest design evaluated the intervention to assess whether the program goals were met. A convenience sample of 8 nurses practicing in a subacute health care facility participated in the program with data obtained from a convenience sampling of diabetic patients admitted to the facility (n=50). A1C, diabetes types, and hypo/hyperglycemic treatment event data were compared 30 days pre- and post-intervention. Outcome data calculated using descriptive statistics revealed improved documentation for A1C results (4% to 96%), the different types of diabetes (from 100% documented as Type 1 to 28 % documented as Type2) and increased corrective measures for abnormal glycemic events (increased 16% to 44%). EMR alerts and reminders provided timely information to health care practitioners, resulting in better management for the diabetic patient, thus affecting social change of diabetes care.

Background: Preclinical data demonstrate that gamma-aminobutyric acid (GABA) interneurons initiate connectivity in the developing brain. Objectives: The goal of this study was to compare GABA concentration and its relationship to functional connectivity in the brains of term and preterm infants at term-equivalent age. Methods: Infants received both magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) scans at term-equivalent age. Whole brain functional connectivity MRI data using intrinsic connectivity distribution maps were compared to identify areas with differences in resting-state functional connectivity between the preterm and term control groups. MRS measured concentrations of GABA, glutamate, N-acetyl-aspartate (NAA) and choline; NAA/choline was then calculated for comparison between the 2 groups. Results: Preterm infants had lower right frontal GABA and glutamate concentrations than term controls and showed a significantly different relationship between connectivity and GABA concentration in the right frontal lobe. Preterm infants had a positive correlation between GABA concentration and connectivity, while term controls demonstrated a negative correlation between these two developmentally regulated parameters. Conclusion: These results suggest that regional GABA concentrations are associated with normal and altered neonatal resting-state connectivity.

Objectives To compare the prevalence of cognitive, neurologic, and behavioral outcomes at 10 years of age in 428 girls and 446 boys who were born extremely preterm. Study design A total of 889 of 966 eligible children previously enrolled in the multicenter Extremely Low Gestational Age Newborns Study from 2002-2004 were evaluated at 10 years of age. Children underwent a neuropsychological battery and testing for autism spectrum disorder (ASD), and parents reported on their child's behavior, development, and seizures. Results Of the children, 28% of boys and 21% of girls exhibited moderate to severe impairment on summary measures of cognitive abilities. Boys had a higher prevalence of impairment than girls in nearly all measures of cognition, were more than twice as likely to have microcephaly (15% in boys, 8% in girls), and require more often assistive devices to ambulate (6% in boys, 4% in girls). In contrast, boys and girls had comparable risk for a history of seizure (identified in 10% of the cohort) or epilepsy (identified in 7% of the cohort). The boy-to-girl ratio of ASD (9% in boys, 5% in girls) was lower than expected compared with the overall US autism population. Conclusions In this contemporary cohort of children born extremely premature and evaluated at school age, boys had higher prevalence of cognitive, neurologic, and behavioral deficits than girls. The ratio of boys to girls among those with ASD deserves further study as does the perinatal environmental-genetic interactions that might contribute to male preponderance of deficits in this high-risk sample.

Preterm (PT) subjects are at risk for developmental delay, and task-based studies suggest that developmental disorders may be due to alterations in neural connectivity. Since emerging data imply the importance of right cerebellar function for language acquisition in typical development, we hypothesized that PT subjects would have alternate areas of cerebellar connectivity, and that these areas would be responsible for differences in cognitive outcomes between PT subjects and term controls at age 20 years. Nineteen PT and 19 term control young adults were prospectively studied using resting-state functional MRI (fMRI) to create voxel-based contrast maps reflecting the functional connectivity of each tissue element in the grey matter through analysis of the intrinsic connectivity contrast degree (ICC-d). Left cerebellar ICC-d differences between subjects identified a region of interest that was used for subsequent seed-based connectivity analyses. Subjects underwent standardized language testing, and correlations with cognitive outcomes were assessed. There were no differences in gender, hand preference, maternal education, age at study, or Peabody Picture Vocabulary Test (PPVT) scores. Functional connectivity (FcMRI) demonstrated increased tissue connectivity in the biventer, simple and quadrangular lobules of the L cerebellum (p0.05) in PTs compared to term controls; seed-based analyses from these regions demonstrated alterations in connectivity from L cerebellum to both R and L inferior frontal gyri (IFG) in PTs compared to term controls. For PTs but not term controls, there were significant positive correlations between these connections and PPVT scores (R IFG: r=0.555, p=0.01; L IFG: r=0.454, p=0.05), as well as Verbal Comprehension Index (VCI) scores (R IFG: r=0.472, p=0.04). These data suggest the presence of a left cerebellar language circuit in PT subjects at young adulthood. These findings may represent either a delay in maturation or the engagement of alternative neural pathways for language in the developing PT brain.

The driving abilities of adults appear to diminish in conjunction with age-related physical and cognitive changes. In this exploratory study, rehabilitation strategies used with 21 older adults were examined to determine the most effective method of retraining driving skills. Subjects, who met the study's eligibility criteria (aged 55 years or older, held a valid driver's license, drove a minimum of 1000 miles/year, and no participation in an adult re-education program) received driver simulation training, classroom viewing of driver simulation films, or no treatment. Outcome measures included on-road and clinical evaluations, as well as self-report information. A significant difference was found between treatment type and subjects' accuracy scores for on-road evaluation, thus suggesting that driving simulation may result in a significant improvement in older adults' driving performance as compared to other intervention strategies. The study has particular relevance to occupational therapy practitioners, with their growing involvement in driving programs throughout the United States.