Faculty Bibliography

BACKGROUND:Teratogenicity of heavy prenatal alcohol exposure is established, but uncertainty remains regarding the impact of moderate alcohol exposure on cognitive deficits in infants. Separating in utero effects from environmental confounding is a challenge for observational studies; consideration of alcohol use by partners as well as mothers may help clarify this. This study examined associations between prenatal alcohol use by both mothers and their partners and infant cognitive developmental outcomes at 12-months. METHODS:Pregnant women (n = 1331) and their partners (n = 699) were recruited from antenatal clinics of three metropolitan public hospitals in Australia, and completed detailed interviews about alcohol consumptions throughout pregnancy. Infants were assessed with the Bayley Scales of Infant Development - Third edition (Bayley) at 12-months of age. RESULTS:Alcohol use during pregnancy was reported by 65.7% of mothers and 84.1% of partners. Using multiple methods to adjust for confounding factors, no evidence for impaired cognitive ability associated with alcohol use by mothers or their partners was observed. Children born to women who drank low-levels of alcohol had slightly higher Bayley cognitive scores than those born to abstaining women. There was some evidence for an interaction between sociodemographic factors and prenatal alcohol exposure on infant cognitive outcomes. CONCLUSION:This finding corroborates existing evidence to suggest there are no detrimental effects to infant cognitive development at 12-months of age following low-level prenatal alcohol exposure. Future prospective studies involving families of a broad range of backgrounds would be informative to clarify interaction between alcohol exposure and environmental factors on developmental outcomes.

Context:Vitamin D inadequacy is common in the adult population of the United States. Although the genetic determinants underlying vitamin D inadequacy have been studied in people of European ancestry, less is known about populations with Hispanic or African ancestry. Objective:The Trans-Ethnic Evaluation of Vitamin D (TRANSCEN-D) genomewide association study (GWAS) consortium was assembled to replicate genetic associations with 25-hydroxyvitamin D [25(OH)D] concentrations from the Study of Underlying Genetic Determinants of Vitamin D and Highly Related Traits (SUNLIGHT) meta-analyses of European ancestry and to identify genetic variants related to vitamin D concentrations in African and Hispanic ancestries. Design:Ancestry-specific (Hispanic and African) and transethnic (Hispanic, African, and European) meta-analyses were performed with Meta-Analysis Helper software (METAL). Patients or Other Participants:In total, 8541 African American and 3485 Hispanic American (from North America) participants from 12 cohorts and 16,124 European participants from SUNLIGHT were included in the study. Main Outcome Measures:Blood concentrations of 25(OH)D were measured for all participants. Results:Ancestry-specific analyses in African and Hispanic Americans replicated single nucleotide polymorphisms (SNPs) in GC (2 and 4 SNPs, respectively). An SNP (rs79666294) near the KIF4B gene was identified in the African American cohort. Transethnic evaluation replicated GC and DHCR7 region SNPs. Additionally, the transethnic analyses revealed SNPs rs719700 and rs1410656 near the ANO6/ARID2 and HTR2A genes, respectively. Conclusions:Ancestry-specific and transethnic GWASs of 25(OH)D confirmed findings in GC and DHCR7 for African and Hispanic American samples and revealed findings near KIF4B, ANO6/ARID2, and HTR2A. The biological mechanisms that link these regions with 25(OH)D metabolism warrant further investigation.

Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a viable therapeutic, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons (BFCNs) in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aβ) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

Massive galaxy clusters have been found that date to times as early as three billion years after the Big Bang, containing stars that formed at even earlier epochs^1-3. The high-redshift progenitors of these galaxy clusters-termed 'protoclusters'-can be identified in cosmological simulations that have the highest overdensities (greater-than-average densities) of dark matter^4-6. Protoclusters are expected to contain extremely massive galaxies that can be observed as luminous starbursts ⁷ . However, recent detections of possible protoclusters hosting such starbursts^8-11 do not support the kind of rapid cluster-core formation expected from simulations ¹² : the structures observed contain only a handful of starbursting galaxies spread throughout a broad region, with poor evidence for eventual collapse into a protocluster. Here we report observations of carbon monoxide and ionized carbon emission from the source SPT2349-56. We find that this source consists of at least 14 gas-rich galaxies, all lying at redshifts of 4.31. We demonstrate that each of these galaxies is forming stars between 50 and 1,000 times more quickly than our own Milky Way, and that all are located within a projected region that is only around 130 kiloparsecs in diameter. This galaxy surface density is more than ten times the average blank-field value (integrated over all redshifts), and more than 1,000 times the average field volume density. The velocity dispersion (approximately 410 kilometres per second) of these galaxies and the enormous gas and star-formation densities suggest that this system represents the core of a cluster of galaxies that was already at an advanced stage of formation when the Universe was only 1.4 billion years old. A comparison with other known protoclusters at high redshifts shows that SPT2349-56 could be building one of the most massive structures in the Universe today.

Limited access to evidence-based behavioral parent training (BPT) for addressing attention deficit/hyperactivity disorder (ADHD) has been a growing concern internationally. Models to improve access to BPT are needed, particularly those that can be readily implemented in community settings and that leverage the potential workforce to increase capacity to deliver BPT. The purpose of this study was to evaluate a BPT model which included oft-used content, methods, processes of BPT (common-elements), non-professionally delivered (task-shifted/shared) BPT intervention, and an efficient ancillary support system (training, fidelity, and supervision methods) for families of youth with parental concerns about ADHD. In a randomized controlled trial of 161 families of children (79% male; mean age 7.04 [1.55]), the Caring in Chaos (CiC) BPT model, delivered by community volunteers across 12 community-based sites in Denmark, was compared to a wait-list control condition on key child and parent outcomes at immediate post-treatment and 4-month follow-up assessment points. Results suggested that the CiC model led to significantly greater improvement in parenting behavior, parenting sense of competence, child functional impairment, parental stress and parental depressive symptoms compared to the wait list condition at immediate post-treatment, with maintenance of gains in most of these areas at follow-up assessment. No effect of intervention was found on ADHD symptoms. The results of this study suggest that developing efficient BPT intervention models, such as the CiC model, can result in readily implemented interventions by a variety of individuals in community settings. Such models are necessary to bend the curve on addressing unmet needs of families of youth with concerns about ADHD.

Barker et al.'s. () review addresses one of the most fundamental questions in the fields of child psychology and psychiatry - How can adverse experiences shape development to a sufficient degree and in profound and enduring ways to create long term risk for later mental disorder and disability? In particular they discuss the plausibility of differential methylation as an epigenetic mechanism by which such exposures can become neuro-biologically embedded. Our commentary rises six question relating to key issues that need to be addressed as we search for definitive evidence from human studies that such mechanisms actually do make an important causal contribution to abnormal trajectories of development to disorder.

Executive function deficits are common in children and adolescents with epilepsy. Though the Wisconsin Card Sorting Task (WCST) is often considered the "gold standard" for executive function assessment, its sensitivity-particularly in the case of the 64-card version (WCST-64)-is insufficiently established in pediatric samples, including children and adolescents with epilepsy. The present investigation assesses the sensitivity of the WCST-64 in children and adolescents with epilepsy in comparison to another measure: the Tower of London - Drexel Version (TOL-DX). A total of 88 consecutively referred children and adolescents with epilepsy were administered both the WCST-64 and TOL-DX as part of a comprehensive neuropsychological evaluation. The sensitivity of WCST-64 and TOL-DX variables were established and relations with epilepsy severity measures and other executive function measures were assessed. Of the WCST-64 variables, Perseverative Responses is the most sensitive, but detected executive function impairment in only 19% of this clinically referred sample; in contrast, the TOL-DX Rule Violations detected executive function impairment in half of the sample. Further, TOL-DX performances are more strongly related to epilepsy severity variables and other executive function measures in comparison to the WCST-64. Despite its popularity amongst clinicians, the WCST-64 is not as sensitive to executive dysfunction in comparison to other measures of comparable administration time, such as the TOL-DX.

OBJECTIVE:There is limited research on metabolic abnormalities in psychotropic-naïve patients with serious mental illness (SMI). Our study examined metabolic conditions in a large, ethnically diverse sample of psychotropic-naïve and non-naïve adults with SMI at an urban public hospital. METHODS:In this cross-sectional study of 923 subjects, the prevalences of hyperglycemia meeting criteria for type 2 diabetes mellitus (T2DM) based on fasting plasma glucose and obesity defined by BMI and abdominal girth were compared across duration of psychotropic medication exposure. Multiple logistic regression models used hyperglycemia and obesity as dependent variables and age, sex, race/ethnicity, and years on psychotropics as independent variables. RESULTS:Psychotropic-naïve patients, including both schizophrenia and non-psychotic subgroups, showed an elevated prevalence of hyperglycemia meeting criteria for T2DM and a decreased prevalence of obesity compared to the general population. Obesity rates significantly increased for those on psychotropic medications more than 5 years, particularly for patients without psychosis (BMI: aOR = 5.23 CI = 1.44-19.07; abdominal girth: aOR = 6.40 CI = 1.98-20.69). Women had a significantly higher obesity rate than men (BMI: aOR = 1.63 CI = 1.17-2.28; abdominal girth: aOR = 3.86 CI = 2.75-5.44). Asians had twice the prevalence of hyperglycemia as whites (aOR = 2.29 CI = 1.43-3.67), despite having significantly less obesity (BMI: aOR = .39 CI = .20-.76; abdominal girth: aOR = .34 CI = .20-.60). Hispanics had a higher rate of obesity by BMI than whites (aOR = 1.91 CI = 1.22-2.99). CONCLUSIONS:This study showed disparities between obesity and T2DM in psychotropic-naïve patients with SMI, suggesting separate risk pathways for these two metabolic conditions.