Objectives To determine the impact of empiric ampicillin and gentamicin use in the first week of life on microbial colonization and diversity in preterm infants. Study design The 16s ribosomal DNA ...community profiling was used to compare the microbiota of 74 infants born ≤32 weeks gestational age by degree of antibiotic use in the first week of life. The degree of antibiotic use was classified as 0 days, 1-4 days, and 5-7 days of antibiotic administration. All of the antibiotic use was empiric, defined as treatment based solely on clinical suspicion of infection without a positive culture result. Results Infants who received 5-7 days of empiric antimicrobial agents in the first week had increased relative abundance of Enterobacter ( P = .016) and lower bacterial diversity in the second and third weeks of life. Infants receiving early antibiotics also experienced more cases of necrotizing enterocolitis, sepsis, or death than those not exposed to antibiotics. Conclusions Early empiric antibiotics have sustained effects on the intestinal microbiota of preterm infants. Intestinal dysbiosis in this population has been found to be associated with elevated risk of necrotizing enterocolitis, sepsis, or death.
Processing pediatric neuroimaging data is a challenge due to pervasive morphological changes that occur in the human brain during normal development. This is of special relevance when reference data ...is used as part of the processing approach, as in spatial normalization and tissue segmentation. Current approaches construct reference data (templates) by averaging brain images from a control group of subjects, or by creating custom templates from the group under study. In this technical note, we describe a new, and generalized method of constructing such appropriate reference data by statistically analyzing a large sample (
n
=
404) of healthy children, as acquired during the NIH MRI study of normal brain development.
After eliminating non-contributing demographic variables, we modeled the effects of age (first, second, and third-order terms) and gender, for each voxel in gray matter and white matter. By appropriate weighting with the parameter estimates from these analyses, complete tissue maps can be generated automatically from this database to match a pediatric population selected for study. The algorithm is implemented in the form of a toolbox for the SPM5 image data processing suite, which we term Template-O-Matic. We compare the performance of this approach with the current method of template generation and discuss the implications of our approach.
The impact of prenatal opioid exposure on brain development remains poorly understood.
We conducted a prospective study of term-born infants with and without prenatal opioid exposure. Structural ...brain MRI was performed between 40 and 48 weeks postmenstrual age. T2-weighted images were processed using the Developing Human Connectome Project structural pipeline. We compared 63 relative regional brain volumes between groups.
Twenty-nine infants with prenatal opioid exposure and 42 unexposed controls were included. The groups had similar demographics, except exposed infants had lower birth weights, more maternal smoking and maternal Hepatitis C, fewer mothers with a college degree, and were more likely non-Hispanic White. After controlling for sex, postmenstrual age at scan, birth weight, and maternal education, exposed infants had significantly smaller relative volumes of the deep gray matter, bilateral thalamic ventrolateral nuclei, bilateral insular white matter, bilateral subthalamic nuclei, brainstem, and cerebrospinal fluid. Exposed infants had larger relative volumes of the right cingulate gyrus white matter and left occipital lobe white matter.
Infants with prenatal opioid exposure had smaller brain volumes in multiple regions compared to controls, with two regions larger in the opioid-exposed group. Further research should focus on the relative contributions of maternal opioids and other exposures.
Prenatal opioid exposure is associated with developmental and behavioral consequences, but the direct effects of opioids on the developing human brain are poorly understood. Prior small studies using MRI have shown smaller regional brain volumes in opioid-exposed infants and children. After controlling for covariates, infants with prenatal opioid exposure scanned at 40-48 weeks postmenstrual age had smaller brain volumes in multiple regions compared to controls, with two regions larger in the opioid-exposed group. This adds to the literature showing potential impact of prenatal opioid exposure on the developing brain.
To explore the relationship between maternal shared reading quality (verbal interactivity and engagement) and brain function during story listening in at-risk, preschool-age children, in the context ...of behavioral evidence and American Academy of Pediatrics, recommendations.
In this cross-sectional study, 22 healthy, 4-year-old girls from low socioeconomic status households completed functional magnetic resonance imaging using an established story listening task, followed by videotaped observation of uncoached mother-daughter reading of the same, age-appropriate picture book. Shared reading quality was independently scored applying dialogic reading and other evidence-based criteria reflecting interactivity and engagement, and applied as a predictor of neural activation during the functional magnetic resonance imaging task, controlling for income and maternal education.
Shared reading quality scores were generally low and negatively correlated with maternal distraction by smartphones (P < .05). Scores were positively correlated with activation in left-sided brain areas supporting expressive and complex language, social-emotional integration, and working memory (P < .05, false discovery rate corrected).
Maternal shared reading quality is positively correlated with brain activation supporting complex language, executive function, and social-emotional processing in at-risk, preschool-age children. These findings represent novel neural biomarkers of how this modifiable aspect of home reading environment may influence foundational emergent literacy skills, reinforce behavioral evidence and American Academy of Pediatrics, recommendations, and underscore the potential of dialogic reading interventions to promote healthy brain development, especially in at-risk households.
Early life exposure to air pollution poses a significant risk to brain development from direct exposure to toxicants or via indirect mechanisms involving the circulatory, pulmonary or ...gastrointestinal systems. In children, exposure to traffic related air pollution has been associated with adverse effects on cognitive, behavioral and psychomotor development. We aimed to determine whether childhood exposure to traffic related air pollution is associated with regional differences in brain volume and cortical thickness among children enrolled in a longitudinal cohort study of traffic related air pollution and child health. We used magnetic resonance imaging to obtain anatomical brain images from a nested subset of 12 year old participants characterized with either high or low levels of traffic related air pollution exposure during their first year of life. We employed voxel-based morphometry to examine group differences in regional brain volume, and with separate analyses, changes in cortical thickness. Smaller regional gray matter volumes were determined in the left pre- and post-central gyri, the cerebellum, and inferior parietal lobe of participants in the high traffic related air pollution exposure group relative to participants with low exposure. Reduced cortical thickness was observed in participants with high exposure relative to those with low exposure, primarily in sensorimotor regions of the brain including the pre- and post-central gyri and the paracentral lobule, but also within the frontal and limbic regions. These results suggest that significant childhood exposure to traffic related air pollution is associated with structural alterations in brain.
Literacy skill development in deaf or hard of hearing (DHH) children is essential for success in school and beyond. Our objective was to evaluate the association between age of early intervention ...(EI) enrollment for DHH children and emergent literacy in preschool.
This was a population-based study that leveraged state public health and education data on all children identified with hearing loss. The sample included children born between 2008 and 2014 enrolled in EI for hearing loss who received preschool supports (years 2011-2014) through the Ohio Department of Education. The Get it! Got it! Go!, measuring emergent literacy domains of picture naming, rhyming, and alliteration, was administered during preschool in fall and spring. Exposure was enrollment into EI before age 6 months (early) versus at/after 6 months (later). Propensity score matching and mixed model analyses were used to examine associations between EI enrollment and outcomes over time. Model least square means with 95% confidence intervals (CIs) were reported.
One hundred two successful matches were made for 256 preschoolers. Children enrolled in EI early had significantly higher mean scores (mean 95% CI) over time for emerging literacy domains of picture naming (2.42 0.47-4.37), rhyming (1.2 0.35-2.06), and alliteration (0.61 0.15-1.07) compared with later enrolled children. Children enrolled early had significantly higher emergent literacy scores at entry, although literacy development was similar between groups.
Children enrolled in EI before age 6 months had consistently higher scores in emergent literacy components over time compared with children enrolled at/after age 6 months.
The independent risk for neurodevelopmental impairments attributed to chorioamnionitis in premature infants remains controversial. Delayed brain maturation or injury identified on magnetic resonance ...imaging at term-equivalent age can be used as a surrogate measure of neurodevelopmental impairments that is less confounded by postdelivery neonatal intensive care unit environmental factors to investigate this relationship more clearly.
This study aimed to determine whether preterm infants born with moderate to severe acute histologic chorioamnionitis would have a higher magnetic resonance imaging–determined global brain abnormality score, independent of early premature birth, when compared with preterm infants with no or mild chorioamnionitis.
This was a prospective, multicenter cohort study involving infants born very prematurely ≤32 weeks’ gestational age with acute moderate to severe histologic chorioamnionitis, graded using standard histologic criteria. Brain abnormalities were diagnosed and scored using a well-characterized, standardized scoring system captured using a high-resolution 3 Tesla magnetic resonance imaging research magnet. In secondary analyses, total brain volume and 4 magnetic resonance imaging metrics of cortical maturation (cortical surface area, sulcal depth, gyral index, and inner cortical curvature) were calculated using an automated algorithm and correlated with chorioamnionitis. The association of funisitis (any grade) with brain abnormalities was also explored. We investigated if premature birth mediated the relationship between histologic chorioamnionitis and brain abnormality score using mediation analysis.
Of 353 very preterm infants, 297 infants had mild or no chorioamnionitis (controls), and 56 were diagnosed with moderate to severe acute histologic chorioamnionitis. The primary outcome brain abnormality score was significantly higher in histologic chorioamnionitis-exposed infants than in the controls (median, 4 vs 7; P<.001). Infants with acute histologic chorioamnionitis had significantly lower brain tissue volume (P=.03) and sulcal depth (P=.04), whereas other morphometric indices did not differ statistically. In the multiple regression analysis, we observed persistent significant relationships between moderate to severe acute histologic chorioamnionitis and brain abnormality scores (β=2.84; 1.51–4.16; P<.001), total brain volume (P=.03), and sulcal depth (P=.02). Funisitis was also significantly associated with brain abnormality score after adjustment for clinical confounders (P=.005). Mediation analyses demonstrated that 50% of brain abnormalities was an indirect consequence of premature birth, and the remaining 50% was a direct effect of moderate to severe acute histologic chorioamnionitis when compared with preterm infants with no or mild chorioamnionitis exposure. Examining gestational age as a mediator, funisitis did not exert a significant direct effect on brain abnormalities after the significant indirect effects of preterm birth were accounted for.
Acute histologic chorioamnionitis increases the risk for brain injury and delayed maturation, both directly and indirectly, by inducing premature birth.
Asthma is a heterogeneous respiratory disease characterized by airway inflammation and obstruction. Despite recent advances, the genetic regulation of asthma pathogenesis is still largely unknown. ...Gene expression profiling techniques are well suited to study complex diseases including asthma. In this study, differentially expressed genes (DEGs) followed by weighted gene co-expression network analysis (WGCNA) and machine learning techniques using dataset generated from airway epithelial cells (AECs) and nasal epithelial cells (NECs) were used to identify candidate genes and pathways and to develop asthma classification and predictive models. The models were validated using bronchial epithelial cells (BECs), airway smooth muscle (ASM) and whole blood (WB) datasets. DEG and WGCNA followed by least absolute shrinkage and selection operator (LASSO) method identified 30 and 34 gene signatures and these gene signatures with support vector machine (SVM) discriminated asthmatic subjects from controls in AECs (Area under the curve: AUC = 1) and NECs (AUC = 1), respectively. We further validated AECs derived gene-signature in BECs (AUC = 0.72), ASM (AUC = 0.74) and WB (AUC = 0.66). Similarly, NECs derived gene-signature were validated in BECs (AUC = 0.75), ASM (AUC = 0.82) and WB (AUC = 0.69). Both AECs and NECs based gene-signatures showed a strong diagnostic performance with high sensitivity and specificity. Functional annotation of gene-signatures from AECs and NECs were enriched in pathways associated with IL-13, PI3K/AKT and apoptosis signaling. Several asthma related genes were prioritized including SERPINB2 and CTSC genes, which showed functional relevance in multiple tissue/cell types and related to asthma pathogenesis. Taken together, epithelium gene signature-based model could serve as robust surrogate model for hard-to-get tissues including BECs to improve the molecular etiology of asthma.
Very preterm infants (born at less than 32 weeks gestational age) are at high risk for serious motor impairments, including cerebral palsy (CP). The brain network changes that antecede the early ...development of CP in infants are not well characterized, and a better understanding may suggest new strategies for risk-stratification at term, which could lead to earlier access to therapies. Graph theoretical methods applied to diffusion MRI-derived brain connectomes may help quantify the organization and information transfer capacity of the preterm brain with greater nuance than overt structural or regional microstructural changes. Our aim was to shed light on the pathophysiology of early CP development, before the occurrence of early intervention therapies and other environmental confounders, to help identify the best early biomarkers of CP risk in VPT infants. In a cohort of 395 very preterm infants, we extracted cortical morphometrics and brain volumes from structural MRI and also applied graph theoretical methods to diffusion MRI connectomes, both acquired at term-equivalent age. Metrics from graph network analysis, especially global efficiency, strength values of the major sensorimotor tracts, and local efficiency of the motor nodes and novel non-motor regions were strongly inversely related to early CP diagnosis. These measures remained significantly associated with CP after correction for common risk factors of motor development, suggesting that metrics of brain network efficiency at term may be sensitive biomarkers for early CP detection. We demonstrate for the first time that in VPT infants, early CP diagnosis is anteceded by decreased brain network segregation in numerous nodes, including motor regions commonly-associated with CP and also novel regions that may partially explain the high rate of cognitive impairments concomitant with CP diagnosis. These advanced MRI biomarkers may help identify the highest risk infants by term-equivalent age, facilitating earlier interventions that are informed by early pathophysiological changes.
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