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Sleep problems are common in individuals with ADHD; however, the exact underlying mechanism is unknown. I Data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research (N = 27,076), the Taiwan Biobank (N = 2373) and the Hamamatsu Birth Cohort for Mothers and Children (N = 726) were used for analysis. Linkage disequilibrium score-based genetic correlation showed a genetic correlation between melatonin secretion and ADHD diagnosis (rg[SD] = -0.134 [0.012], P

ABSTRACTBashofu is a traditional Okinawan textile made from thin banana fibers. The raw materials derived from banana leaf sheaths are composed of plant fibers and unwanted constituents such as the plant cuticle layer. The unwanted constituents are hand-scraped by the traditional way that follows boiling the raw materials in a mild alkali solution. However, even after this mild degumming, the plant cuticle layer of current materials can still be too hard to be hand-scraped from the fibers. For smooth fiber separation, the unwanted constituents should be specifically degraded before hand-scraping. Fatty acid polyesters are the main components of plant cuticle layer and are not present in fibers. We attempted to specifically degrade the materials by Stenotrophomonas sp. with the ability to degrade Tween-20, as a result, the treated materials became softer and thinner with uniform thickness. Such changes in the morphology of the material allowed the plant cuticle layer to be easily separated from the banana fibers during hand-scraping, and the cross section of the extracted fibers was not affected by this bacterial treatment. This treatment would be used as a minimal improvement of the traditional Bashofu making in the future and would reduce the hard work for elderly artisans.

Abstract Catalytic RNAs, or ribozymes, catalyze diverse chemical reactions that could have sustained primordial life in the hypothetical RNA world. Many natural ribozymes and laboratory evolved ribozymes exhibit efficient catalysis mediated by elaborate catalytic cores within complex tertiary structures. However, such complex RNA structures and sequences are unlikely to have emerged by chance during the earliest phase of chemical evolution. Here, we explored simple and small ribozyme motifs capable of ligating two RNA fragments in a template-directed fashion (ligase ribozymes). One-round selection of small ligase ribozymes followed by deep sequencing revealed a ligase ribozyme motif comprising a three-nucleotide loop opposite to the ligation junction. The observed ligation was magnesium(II) dependent and appears to form a 2′–5′ phosphodiester linkage. The fact that such a small RNA motif can function as a catalyst supports a scenario in which RNA or other primordial nucleic acids played a central role in chemical evolution of life.

Objective: Genetic and environmental factors contribute to the development of Attention Deficit/Hyperactivity Disorder (ADHD). Perinatal inflammation is one of the promising environmental risk factors for ADHD, but the relationship between the genetic risk for ADHD and perinatal inflammation requires further examination. Methods: A possible gene-environmental interaction between perinatal inflammation and ADHD polygenic risk score (ADHD-PRS) on ADHD symptoms was investigated in children aged 8–9 from the Hamamatsu Birth Cohort for Mothers and Children (N = 531). Perinatal inflammation was evaluated by the level of concentration of three cytokines assayed in umbilical cord blood. The genetic risk for ADHD was assessed by calculating ADHD-PRS for each individual using a previously collected genome-wide association study of ADHD. Results: Perinatal inflammation (β [SE], 0.263 [0.017]; P

Abstract It is unclear whether neurodevelopmental progress from infancy to early childhood remains stable. Moreover, little is known about the risk factors, if any, affecting neurodevelopmental descending transition patterns and the relationship between these patterns and later childhood adaptive behaviours. We used data of 875 children from the Hamamatsu Birth Cohort Study in Japan. Children’s neurodevelopment at 18 and 32 months and adaptive behaviours at 40 months were evaluated. Perinatal factors and infant overweight status at 18 months were investigated to identify descending-transition-associated risk factors. In the latent transition analysis, ultimately, three classes were identified for each time-point, resulting in nine transition patterns; among them, 10.4% of children showed descending class shifts (normal to delayed class). Such decelerated growth was predicted by maternal pre-pregnancy overweight status (odds ratio [OR] 2.49; 95% confidence interval [CI] 1.23, 5.02), low maternal educational history (OR 1.20; 95% CI 1.04, 1.36), and infant overweight status at 18 months (OR 5.89; 95% CI 1.26, 27.45). Children with descending transition showed poor functioning in adaptive behaviours at the age of 40 months. To prevent subsequent poor adaptive functioning, it may be necessary to consider that a certain percentage of children show decelerated growth.

Abstract Background Mastering language involves the development of expressive and receptive skills among children. While it has been speculated that early temperament plays a role in the acquisition of language, the actual mechanism has not yet been explored. We investigated whether temperament at 18 months predicted expressive or receptive language skills at 40 months. Methods A representative sample of 901 children and their mothers who were enrolled and followed-up longitudinally in the Hamamatsu Birth Cohort for Mothers and Children study was included in the analysis. Child temperament was measured at 18 months using the Japanese version of the Early Childhood Behavior Questionnaire. Expressive and receptive language skills were measured at 40 months using the Mullen Scales of Early Learning. Results The multiple regression analysis, adjusting for potential confounders, suggested that higher motor activation (fidgeting) at 18 months was associated with lower expressive and receptive language skills at 40 months. Higher perceptual sensitivity was associated with higher expressive and receptive language skills at 40 months. Conclusions Specific temperament at 18 months of age predicted the development of the child’s expressive and receptive language skills at 40 months.

IntroductionPrenatal maternal stress (PNMS), including exposure to natural disasters, has been shown to serve as a risk factor for future child psychopathology and suboptimal brain development, particularly among brain regions shown to be sensitive to stress and trauma exposure. However, statistical approaches deployed in most studies are usually constrained by a limited number of variables for the sake of statistical power. Explainable machine learning, on the other hand, enables the study of high data dimension and offers novel insights into the prominent subset of behavioral phenotypes and brain regions most susceptible to PNMS. In the present study, we aimed to identify the most important child neurobehavioral and brain features associated with in utero exposure to Superstorm Sandy (SS).MethodsBy leveraging an explainable machine learning technique, the Shapley additive explanations method, we tested the marginal feature effect on SS exposures and examined the individual variable effects on disaster exposure.ResultsResults show that certain brain regions are especially sensitive to in utero exposure to SS. Specifically, in utero SS exposure was associated with larger gray matter volume (GMV) in the right caudate, right hippocampus, and left amygdala and smaller GMV in the right parahippocampal gyrus. Additionally, higher aggression scores at age 5 distinctly correlated with SS exposure.DiscussionThese findings suggest in utero SS exposure may be associated with greater aggression and suboptimal developmental alterations among various limbic and basal ganglia brain regions.

Abstract Prenatal exposure to perfluoroalkyl substances (PFAS) has been reported to affect body weight from birth to childhood, but the results remain inconclusive. We investigated whether umbilical cord blood concentrations of perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) are associated with children’s risk trajectory for obesity. 600 children were randomly selected from the Hamamatsu Birth Cohort for Mothers and Children (HBC study) and their umbilical cord serum PFAS concentrations were quantified. Participants underwent BMI measurements at ages 1, 4, 10, 18, 24, 32, 40, 50, and 66 months. Growth curve modeling with random intercept was performed with standardized BMI as outcome variable. PFOS was negatively associated with standardized BMI (β = − 0.34; p = 0.01), with a marginally significant interaction with the child’s age (β = 0.0038; p = 0.08). PFOA was negatively associated with standardized BMI (β = − 0.26, 95% CI − 0.51, 0; p = 0.05), with a significant interaction with the child’s age (β = 0.005; p = 0.01). Stratified analysis by sex revealed that these effects were significant only among girls. Prenatal exposure to PFAS initially was associated with lower standardized BMI during infancy, but this effect dissipated over time and reversed in direction during later childhood. The effects of prenatal PFAS on higher standardized BMI is stronger in girls.

Abstract Background Both genetic and pre- and perinatal factors, including birth weight, have been implicated in the onset of attention deficit hyperactivity disorder (ADHD) traits among children. This study aimed to elucidate to what extent the genetic risk of ADHD moderates the association between birth weight and ADHD traits among Japanese children. Methods We conducted a longitudinal birth cohort study (Hamamatsu Birth Cohort for Mother and Children Study) to investigate the association of genetic risk for ADHD and low birth weight with ADHD traits among Japanese children. Out of 1258 children, we included 796 who completed follow-ups at 8 to 9 years of age. Birth weight was categorized as

Abstract We investigated the anatomical differences in the choroidal structure between pregnant women in the first trimester of pregnancy and age-matched healthy nonpregnant women using enhanced depth imaging optical coherence tomography (EDI-OCT) and choroidal binarization analysis. The main parameters measured in the two study groups, namely, pregnant women in the first trimester and healthy nonpregnant women, were choroidal thickness and the choroidal luminal area. Binarization of the EDI-OCT images from each patient was performed, and the choroidal vascularity index (CVI) was calculated. The correlations between the baseline characteristics of the subjects and the CVI were investigated using linear mixed model analysis. As a result, there was no statistically significant difference in the mean age, best-corrected visual acuity, axial length, central retinal thickness, subfoveal choroidal thickness, systolic blood pressure (BP), or diastolic BP between the two study groups. Conversely, a significant difference was observed in the CVI (P = 0.012) between the two groups. The multivariate analysis identified a significant correlation between the CVI and the systolic BP (P = 0.0044, linear mixed test). Taken together, a larger choroidal luminal area was associated with a higher systolic BP, especially in the first trimester of pregnancy. Our findings may provide further insight into the choroidal changes that occur during pregnancy.

Maternal stress during pregnancy exerts long-term effects on the mental well-being of the offspring. However, the long-term effect of prenatal exposure on the offspring’s mental status is only partially understood. The placenta plays a vital role in connecting the maternal side to the fetus, thereby serving as an important interface between maternal exposure and fetal development. Here, we profiled the placental transcriptome of women who were pregnant during a hurricane (Superstorm Sandy), which struck New York City in 2012. The offspring were followed longitudinally and their temperament was assessed during the first 6–12 months of age. The data identified a significant correlation between a Superstorm Sandy stress factor score and infant temperament. Further, analysis of the placental transcriptomes identified an enrichment of functional pathways related to inflammation, extracellular matrix integrity and sensory perception in the specimen from those infants with “Slow-to-Warm-up” temperament during the first year of life. Together, these findings provide initial evidence that maternal exposure to climate-related disasters results in altered placental transcriptome, which may be related to long-term emotional and behavioral consequences in children.

Little is known about the trajectory patterns and sex differences in adaptive behaviors in the general population. We examined the trajectory classes of adaptive behaviors using a representative sample and examined whether the class structure and trajectory patterns differed between females and males. We further explored sex differences in neurodevelopmental traits in each latent class. Participants (n = 994) were children in the Hamamatsu Birth Cohort for Mothers and Children (HBC Study)—a prospective birth cohort study. Adaptive behaviors in each domain of communication, daily living skills, and socialization were evaluated at five time points when participants were 2.7, 3.5, 4.5, 6, and 9 years old using the Vineland Adaptive Behavior Scales–Second Edition. Parallel process multigroup latent class growth analysis extracted sex-specific trajectory classes. Neurodevelopmental traits of children at age 9, autistic traits, attention deficit hyperactivity disorder (ADHD) traits, and cognitive ability were examined for females and males in each identified class. A 4-class model demonstrated the best fit. Moreover, a 4-class model that allowed for differences in class probabilities and means of growth parameters between females and males provided a better fit than a model assuming no sex differences. In the communication domain, females scored higher than their male counterparts in all four classes. In the daily living skills and socialization domains, the two higher adaptive classes (Class 1: females, 18.6%; males, 17.8%; Class 2: females, 48.8%; males, 49.8%) had similar trajectories for males and females, whereas in the two lower adaptive behavior classes (Class 3: females, 27.5%; males, 29.4%; Class 4: females, 5.1%; males, 3.0%), females had higher adaptive scores than their male counterparts. In Class 4, females were more likely to have autistic and ADHD traits exceeding the cutoffs, while males were more likely to have below-average IQ. Different trajectories in females and males suggest that adaptive skills may require adjustment based on the sex of the child, when standardizing scores, in order to achieve better early detection of skill impairment.

IntroductionAccumulating evidence has shown that maternal metabolic conditions, such as pre-pregnancy overweight, diabetes mellitus, and hypertensive disorders of pregnancy (HDP) are potential risk factors of autism spectrum disorder (ASD). However, it remains unclear how these maternal conditions lead to neurodevelopmental outcomes in the offspring, including autistic symptoms. Leptin, an adipokine that has pro-inflammatory effects and affects fetal neurodevelopment, is a candidate mediator of the association between maternal metabolic factors and an increased risk of ASD. However, whether prenatal exposure to leptin mediates the association between maternal metabolic conditions and autistic symptoms in children has not been investigated yet.MethodsThis study investigated the associations between mothers' metabolic conditions (pre-pregnancy overweight, diabetes mellitus during or before pregnancy, and HDP), leptin concentrations in umbilical cord serum, and autistic symptoms among 762 children from an ongoing cohort study, using generalized structural equation modeling. We used the Social Responsive Scale, Second Edition (SRS-2) at 8–9 years old to calculate total T-scores. Additionally, we used the T-scores for two subdomains: Social Communication and Interaction (SCI) and Restricted Interests and Repetitive Behavior (RRB).ResultsUmbilical cord leptin levels were associated with pre-pregnancy overweight [coefficient = 1.297, 95% confidence interval (CI) 1.081–1.556, p = 0.005] and diabetes mellitus (coefficient = 1.574, 95% CI 1.206–2.055, p = 0.001). Furthermore, leptin levels were significantly associated with SRS-2 total T-scores (coefficient = 1.002, 95% CI 1.000–1.004, p = 0.023), SCI scores (coefficient = 1.002, 95% CI 1.000–1.004, p = 0.020), and RRB scores (coefficient = 1.001, 95% CI 1.000–1.003, p = 0.044) in children. Associations between maternal metabolic factors and autistic symptoms were not significant.DiscussionThe present study uncovered an association between cord leptin levels and autistic symptoms in children, while maternal metabolic conditions did not have an evident direct influence on the outcome. These results imply that prenatal pro-inflammatory environments affected by maternal metabolic conditions may contribute to the development of autistic symptoms in children. The findings warrant further investigation into the role of leptin in the development of autistic symptoms.

This study was conducted to examine retinal sensitivity (RS) in eyes with pachychoroid diseases and to analyze its association with the presence or absence of quiescent choroidal neovascularization (CNV), that can be protective against retinal dysfunction or atrophy in other macular diseases such as age-related macular degeneration. A total of 12 eyes of 12 patients aged ≥45 years having the characteristic findings of central serous chorioretinopathy but not presenting any exudative changes were included in this study. Choroidal vascular hyper permeability (CVH) was identified by indocyanine green angiography, and the presence or absence of CNV was evaluated by optical coherence tomography angiography. RS at 68 points was examined by microperimetry. The average RS corresponding to within and outside CVH was compared. The association between the difference in RS and the presence or absence of CNV was also analyzed. CNV was detected in six eyes (50%). In eyes without CNV, the RS within CVH was similar compared with that outside CVH. However, in eyes with CNV, the RS within CVH was significantly decreased compared with that outside CVH. Multiple regression analysis revealed the presence of CNV as an independent factor associated with RS. In eyes with pachychoroid diseases, RS decreased within the CVH area under the coexistence of nonexudative CNV.

Introduction: Obesity is highly heritable, and recent evidence demonstrates that obesity is associated with cognitive deficits, specifically working memory. However, the relationship between genetic risks for obesity and working memory is not clear. In addition, whether the effect of these genetic risks on working memory in children is mediated by increased body mass index (BMI) has not been elucidated.Methods: In order to test whether the polygenic risk score (PRS) for obesity in adulthood (adulthood-BMI-PRS) is associated with working memory at 8 years of age, and whether the effect is mediated by childhood BMI, in children from the general population, participants in the Hamamatsu Birth Cohort for Mothers and Children (HBC) study in Hamamatsu, Japan, underwent testing for association of adulthood-BMI-PRS with working memory. HBC data collection began in December 2007 and is ongoing. Adulthood-BMI-PRS values were generated using summary data from the recent genome-wide association study (GWAS) undertaken in Japan, and the significance of thresholds was calculated for each outcome. Outcomes measured included the working memory index (WMI) of Weschler Intelligence Scale-4 (WISC-IV) scores and the BMI at 8 years of age. Gene-set enrichment analysis was conducted to clarify the molecular basis common to adulthood-BMI and childhood-WMI. Mediation analysis was performed to assess whether childhood-BMI of children mediated the association between adulthood-BMI-PRS and working memory.Results: A total of 734 participants (377 males, 357 females) were analyzed. Adulthood-BMI-PRS was associated with lower childhood-WMI (β[SE], −1.807 [0.668]; p = 0.010, corrected) of WISC-IV. Gene-set enrichment analyses found that regulation of neurotrophin Trk receptor signaling (β[SE], −2.020 [6.39]; p = 0.002, corrected), negative regulation of GTPase activity (β[SE], 2.001 [0.630]; p = 0.002, corrected), and regulation of gene expression epigenetic (β[SE], −2.119 [0.664]; p = 0.002, corrected) were enriched in BMI in adulthood and WMI in childhood. Mediation analysis showed that there is no mediation effect of childhood-BMI between the adulthood-BMI-PRS and working memory deficits in children.Conclusion: Adulthood-BMI-PRS was associated with working memory among children in the general population. These genetic risks were not mediated by the childhood-BMI itself and were directly associated with working memory deficits.

The placenta plays a central role in the epigenetic programming of neurodevelopment by prenatal stress (PS), but this pathway is not fully understood. It difficult to study in humans because the conditions for intense, traumatic PS are almost impossible to create ethically. This study was able to capitalize on a 2012 disaster that hit New York, Superstorm Sandy, to examine the impact of traumatic stress on placental gene expression while also examining normative PS, and compare the two. Of the 303 expectant mothers participating in the Stress in Pregnancy Study, 95 women were pregnant when Superstorm Sandy struck. During their pregnancy, participants completed self-report measures of PS and distress that were combined, using latent profile analysis, into one global indicator of normative PS. Placental tissue was collected at delivery and frozen for storage. RNA expression was assessed for 40 placental genes known to associate with the stress response system and neurodevelopment in offspring. Results showed that normative PS increased expression of just MECP2, HSD11B2, and ZNF507, whereas Superstorm Sandy PS decreased expression of CDKL5, CFL1, DYRK1A, HSD11B2, MAOA, MAOB, NCOR1, and ZNF507. Interaction analyses indicated that Superstorm Sandy PS was associated with decreased gene expression for the low and high PS group for CFL1, DYRK1A, HSD11B2, MAOA, and NCOR1 and increased expression for the moderate PS group for FOXP1, NR3C1, and NR3C2. This study supports the idea that a moderate amount of normative PS may buffer the impact of traumatic PS, in this case caused by Superstorm Sandy, on placental gene expression, which suggests that the placenta itself mirrors the organism's ability to develop an epigenetic resilience to, and inoculation from, stress.

Background While it has been implied that an infant’s exposure to maternal postpartum depression (PPD) may be associated with delayed development of expressive language, it remains unclear whether such a delay persists into childhood and whether the onset of PPD onset—early (within 4 weeks after childbirth) vs. late (between 5 and 12 weeks postpartum)—is relevant in this context. Objective To examine whether children of mothers with early- or late-onset PPD have reduced expressive language scores during infancy and early childhood (up to 40 months of age). Methods This longitudinal, observational study was conducted as a part of the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), a population-representative sample in Japan. A total of 969 neonates and their mothers were included in the analysis. Exposures Early- and late-onset PPD was measured using the Edinburgh Postnatal Depression Scale. Main Outcomes and Measures Expressive language development was measured using the Mullen Scales of Early Learning. Six points over time were monitored (10, 14, 18, 24, 32, and 40 months postpartum). The relationship between the exposure variable and any change in expressive language score was evaluated using multiple linear regression analysis and growth curve analysis, both adjusted for covariates. Results Results from the adjusted regression analysis showed that children of mothers with late-onset PPD had significantly lower expressive language scores at 18 months of age and beyond, with a score reduction of approximately 0.6 standard deviations from the reference value at 40 months of age (95% CI [−0.888 to −0.265], p

In this study, we show augmented autophagy in the retinal pigment epithelial cell line ARPE-19 when cultured in the presence of the lipofuscin pigment A2E. A2E alone does not induce RPE cell death, but cell death was induced in the presence of A2E with the autophagy inhibitor 3-methyladenine (3MA), with a concomitant increase in the generation of mitochondrial reactive oxygen species. On the other hand, the ATP production capacity of mitochondria was decreased in the presence of A2E, and pharmacological inhibition of autophagy had no additional effects. The altered mRNA expression level of mitochondrial function markers was confirmed by real-time polymerase chain reaction, which showed that the antioxidant enzymes SOD1 and SOD2 were not reduced in the presence of A2E alone, but significantly suppressed with the addition of 3MA. Furthermore, transmission electron micrography revealed autophagic vacuole formation in the presence of A2E, and inhibition of autophagy resulted in the accumulation of abnormal mitochondria with loss of cristae. Spheroid culture of human RPE cells demonstrated debris accumulation in the presence of A2E, and this accumulation was accelerated in the presence of 3MA. These results indicate that autophagy in RPE cells is a vital cytoprotective process that prevents the accumulation of damaged cellular molecules.

BACKGROUND:Gene-environment interactions mediate through the placenta and shape the fetal brain development. Between the environmental determinants of the fetal brain, maternal psychosocial stress in pregnancy has been shown to negatively influence the infant temperament development. This in turn may have adverse consequences on the infant neurodevelopment extending throughout the entire life-span. However little is known about the underlying biological mechanisms of the effects of maternal psychosocial stress in pregnancy on infant temperament. Environmental stressors such as maternal psychosocial stress in pregnancy activate the stress response cascade that in turn drives the increase in the cellular energy demand of vital organs with high metabolic rates such as, in pregnancy, the placenta. Key players of the stress response cascade are the mitochondria. RESULTS:Here, we tested the expression of all 13 protein-coding genes encoded by the mitochondria in 108 placenta samples from the Stress in Pregnancy birth cohort, a study that aims at determining the influence of in utero exposure to maternal psychosocial stress in pregnancy on infant temperament. We showed that the expression of the protein-coding mitochondrial-encoded gene MT-ND2 was positively associated with indices of maternal psychosocial stress in pregnancy including Prenatal Perceived Stress (β = 0.259; p-regression = 0.004; r2-regression = 0.120), State Anxiety (β = 0.218; p-regression = 0.003; r2-regression = 0.153), Trait Anxiety (β = 0.262; p-regression = 0.003; r2-regression = 0.129) and Pregnancy Anxiety Total (β = 0.208; p-regression = 0.010; r2-regression = 0.103). In the meantime MT-ND2 was negatively associated with the infant temperament indices of Activity Level (β = -0.257; p-regression = 0.008; r2-regression = 0.165) and Smile and Laughter (β = -0.286; p-regression = 0.036; r2-regression = 0.082). Additionally, MT-ND6 was associated with the maternal psychosocial stress in pregnancy index of Prenatal Perceived Stress (β = -0.231; p-regression = 0.004; r2-regression = 0.120), while MT-CO2 was associated with the maternal psychosocial stress in pregnancy indices of State Anxiety (β = 0.206; p-regression = 0.003; r2-regression = 0.153) and Trait Anxiety (β = 0.205; p-regression = 0.003; r2-regression = 0.129). CONCLUSIONS:Our data support the role of mitochondria in responding to maternal psychosocial stress in pregnancy, as assessed in placenta, while also suggesting an important role for the mitochondria in the infant temperament development.

This study was aimed to assess the diversity of the meconium microbiome and determine if the bacterial community is affected by maternal diabetes status.The first intestinal discharge (meconium) was collected from 23 newborns stratified by maternal diabetes status: 4 mothers had pre-gestational type 2 diabetes mellitus (DM) including one mother with dizygotic twins, 5 developed gestational diabetes mellitus (GDM) and 13 had no diabetes. The meconium microbiome was profiled using multi-barcode 16S rRNA sequencing followed by taxonomic assignment and diversity analysis.All meconium samples were not sterile and contained diversified microbiota. Compared with adult feces, the meconium showed a lower species diversity, higher sample-to-sample variation, and enrichment of Proteobacteria and reduction of Bacteroidetes. Among the meconium samples, the taxonomy analyses suggested that the overall bacterial content significantly differed by maternal diabetes status, with the microbiome of the DM group showing higher alpha-diversity than that of no-diabetes or GDM groups. No global difference was found between babies delivered vaginally versus via Cesarean-section. Regression analysis showed that the most robust predictor for the meconium microbiota composition was the maternal diabetes status that preceded pregnancy. Specifically, Bacteroidetes (phyla) and Parabacteriodes (genus) were enriched in the meconium in the DM group compared to the no-diabetes group.Our study provides evidence that meconium contains diversified microbiota and is not affected by the mode of delivery. It also suggests that the meconium microbiome of infants born to mothers with DM is enriched for the same bacterial taxa as those reported in the fecal microbiome of adult DM patients.

BACKGROUND:Many young people experiment with cannabis, yet only a subgroup progress to dependence suggesting individual differences that could relate to factors such as genetics and behavioral traits. Dopamine receptor D2 (DRD2) and proenkephalin (PENK) genes have been implicated in animal studies with cannabis exposure. Whether polymorphisms of these genes are associated with cannabis dependence and related behavioral traits is unknown. METHODOLOGY/PRINCIPAL FINDINGS:Healthy young adults (18-27 years) with cannabis dependence and without a dependence diagnosis were studied (N = 50/group) in relation to a priori-determined single nucleotide polymorphisms (SNPs) of the DRD2 and PENK genes. Negative affect, Impulsive Risk Taking and Neuroticism-Anxiety temperamental traits, positive and negative reward-learning performance and stop-signal reaction times were examined. The findings replicated the known association between the rs6277 DRD2 SNP and decisions associated with negative reinforcement outcomes. Moreover, PENK variants (rs2576573 and rs2609997) significantly related to Neuroticism and cannabis dependence. Cigarette smoking is common in cannabis users, but it was not associated to PENK SNPs as also validated in another cohort (N = 247 smokers, N = 312 non-smokers). Neuroticism mediated (15.3%-19.5%) the genetic risk to cannabis dependence and interacted with risk SNPs, resulting in a 9-fold increase risk for cannabis dependence. Molecular characterization of the postmortem human brain in a different population revealed an association between PENK SNPs and PENK mRNA expression in the central amygdala nucleus emphasizing the functional relevance of the SNPs in a brain region strongly linked to negative affect. CONCLUSIONS/SIGNIFICANCE:Overall, the findings suggest an important role for Neuroticism as an endophenotype linking PENK polymorphisms to cannabis-dependence vulnerability synergistically amplifying the apparent genetic risk.

Introduction: Prenatal maternal stress (PNMS), including exposure to natural disasters, has been shown to serve as a risk factor for future child psychopathology and suboptimal brain development, particularly among brain regions shown to be sensitive to stress and trauma exposure. However, statistical approaches deployed in most studies are usually constrained by a limited number of variables for the sake of statistical power. Explainable machine learning, on the other hand, enables the study of high data dimension and offers novel insights into the prominent subset of behavioral phenotypes and brain regions most susceptible to PNMS. In the present study, we aimed to identify the most important child neurobehavioral and brain features associated with in utero exposure to Superstorm Sandy (SS). Methods: By leveraging an explainable machine learning technique, the Shapley additive explanations method, we tested the marginal feature effect on SS exposures and examined the individual variable effects on disaster exposure. Results: Results show that certain brain regions are especially sensitive to in utero exposure to SS. Specifically, in utero SS exposure was associated with larger gray matter volume (GMV) in the right caudate, right hippocampus, and left amygdala and smaller GMV in the right parahippocampal gyrus. Additionally, higher aggression scores at age 5 distinctly correlated with SS exposure. Discussion: These findings suggest in utero SS exposure may be associated with greater aggression and suboptimal developmental alterations among various limbic and basal ganglia brain regions. [ABSTRACT FROM AUTHOR]

Introduction: Prenatal maternal stress (PNMS), including exposure to natural disasters, has been shown to serve as a risk factor for future child psychopathology and suboptimal brain development, particularly among brain regions shown to be sensitive to stress and trauma exposure. However, statistical approaches deployed in most studies are usually constrained by a limited number of variables for the sake of statistical power. Explainable machine learning, on the other hand, enables the study of high data dimension and offers novel insights into the prominent subset of behavioral phenotypes and brain regions most susceptible to PNMS. In the present study, we aimed to identify the most important child neurobehavioral and brain features associated with in utero exposure to Superstorm Sandy (SS). Methods: By leveraging an explainable machine learning technique, the Shapley additive explanations method, we tested the marginal feature effect on SS exposures and examined the individual variable effects on disaster exposure. Results: Results show that certain brain regions are especially sensitive to in utero exposure to SS. Specifically, in utero SS exposure was associated with larger gray matter volume (GMV) in the right caudate, right hippocampus, and left amygdala and smaller GMV in the right parahippocampal gyrus. Additionally, higher aggression scores at age 5 distinctly correlated with SS exposure. Discussion: These findings suggest in utero SS exposure may be associated with greater aggression and suboptimal developmental alterations among various limbic and basal ganglia brain regions. [ABSTRACT FROM AUTHOR]

While cannabis is among the most used recreational drugs during pregnancy, the impact of maternal cannabis use (mCB) on fetal and child development remains unclear. Here, we assessed the effects of mCB on psychosocial and physiological measures in young children along with the potential relevance of the in utero environment reflected in the placental transcriptome. Children (~3 to 6 y) were assessed for hair hormone levels, neurobehavioral traits on the Behavioral Assessment System for Children (BASC-2) survey, and heart rate variability (HRV) at rest and during auditory startle. For a subset of children with behavioral assessments, placental specimens collected at birth were processed for RNA sequencing. Hair hormone analysis revealed increased cortisol levels in mCB children. In addition, mCB was associated with greater anxiety, aggression, and hyperactivity. Children with mCB also showed a reduction in the high-frequency component of HRV at baseline, reflecting reduced vagal tone. In the placenta, there was reduced expression of many genes involved in immune system function including type I interferon, neutrophil, and cytokinesignaling pathways. Finally, several of these mCB-linked immune genes organized into coexpression networks that correlated with child anxiety and hyperactivity. Overall, our findings reveal a relationship between mCB and immune response gene networks in the placenta as a potential mediator of risk for anxiety-related problems in early childhood. [ABSTRACT FROM AUTHOR]

Background. While it has been implied that an infant's exposure to maternal post-partum depression (PPD) may be associated with delayed development of expressive language, it remains unclear whether such a delay persists into childhood and whether the onset of PPD onset-early (within 4 weeks after childbirth) vs. late (between 5 and 12 weeks postpartum)-is relevant in this context. Objective. To examine whether children of mothers with early- or late-onset PPD have reduced expressive language scores during infancy and early childhood (up to 40 months of age). Methods. This longitudinal, observational study was conducted as a part of the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), a population-representative sample in Japan. A total of 969 neonates and their mothers were included in the analysis. Exposures. Early- and late-onset PPD was measured using the Edinburgh Postnatal Depression Scale. Main Outcomes and Measures. Expressive language development was measured using the Mullen Scales of Early Learning. Six points over time were monitored (10, 14, 18, 24, 32, and 40 months postpartum). The relationship between the exposure variable and any change in expressive language score was evaluated using multiple linear regression analysis and growth curve analysis, both adjusted for covariates. Results. Results from the adjusted regression analysis showed that children of mothers with late-onset PPD had significantly lower expressive language scores at 18 months of age and beyond, with a score reduction of approximately 0.6 standard deviations from the reference value at 40 months of age (95% CI [-0.888 to -0.265], p<:001). This association was confirmed on growth curve analysis, which revealed a significant, monotonic decline of expressive language development between 10 and 40 months of age among children of mothers with late-onset PPD, but not among children of mothers with early-onset PPD. Conclusion. Exposure to late-onset PPD may lead to a persistent decline in the rate of expressive language development in offspring during infancy and early childhood, highlighting the significance of monitoring for late-onset PPD to facilitate early detection and intervention. [ABSTRACT FROM AUTHOR]

Purpose To determine changes in multiple cytokine concentrations in the anterior chamber during the induction phase of ranibizumab treatment in patients with neovascular age-related macular degeneration (AMD). Methods This prospective study included 48 treatmentnaïve neovascular AMD eyes of 48 patients who received three consecutive monthly injections of ranibizumab at the Japan Community Health Care Organization Tokyo Shinjuku Medical Center between November 2010 and August 2012. We collected -0.2 mL aqueous humour before the first and third (2 months later) injections. Controls were 80 eyes with cataracts without retinal disease. The cytokines C-X-C motif chemokine ligand 1 (CXCL1), interferon-γ-induced protein 10 (IP-10), C-X-C motif chemokine ligand 12 (CXCL12), C-X-C motif chemokine ligand 13 (CXCL13), monocyte chemoattractant protein 1 (MCP-1), CCL11, C-C motif chemokine ligand 11 (CCL11), interleukin-6 (IL-6), interleukin-10 (IL-10) and matrix metalloproteinase 9 (MMP-9) were analysed using multiplex cytokine assays. results Mean ages of the patients with AMD and controls were 73 and 75 years, respectively, and 31 (65%) and 37 (46%) subjects were men, respectively. Polypoidal choroidal vasculopathy was found in 27 eyes (56%). Mean concentrations of cytokines in aqueous humour in patients with neovascular AMD before the first and third ranibizumab injections were as follows (in pg/mL): CXCL1, 8.4 and 3.3; IP-10, 110 and 55; CXCL12, 480 and 240; CXCL13, 9.2 and 2.6; MCP-1, 620 and 220; CCL11, 7.1 and 2.8; IL-6, 5.9 and 1.6; IL-10, 0.15 and 0.015 (all p<0.0001), and MMP-9, 0.92 and 1.5 (p=0.0216), respectively. Concentrations of all cytokines decreased significantly after two consecutive ranibizumab injections, except for MMP-9, which increased significantly. Conclusions After two monthly consecutive antivascular endothelial growth factor injections, inflammatory cytokine levels in the aqueous humour of the eyes with AMD were strongly suppressed, while MMP-9 levels increased. [ABSTRACT FROM AUTHOR]

The placenta is the principal organ regulating respiratory, nutritional, endocrine and metabolic functions on behalf of the developing fetus. Changes in gene expression patterns of placenta-specific genes may influence fetal growth. We profiled the expression of 17 genes related to placenta functioning in term placentas (n = 677) to identify genes differentially expressed across birth weight categories [small (SGA), appropriate (AGA) and large (LGA) for gestational age]. ABCG2, CEBPB, CRH, GCM1, GPC3, INSL4, PGF and PLAC1 were inversely associated with LGA status, with odds ratios (ORs) and 95% confidence intervals (CI) ranging from GCM1 (OR = 0.44, 95% CI: 0.29, 0.70) to CRH (OR = 0.73, 95% CI: 0.61, 0.88). NR3C1 was positively associated with LGA status (OR = 2.33, 95% CI: 1.43, 3.78). PLAC1 (OR = 0.66, 95% CI: 0.47, 0.92) and ABCG2 (OR = 0.63, 95% CI: 0.44, 0.91) were additionally inversely associated with SGA status, and PGF was positively associated with SGA status (OR = 1.59, 95% CI = 1.08, 2.35). General trends were confirmed in an independent cohort (n = 306). Given that aberrant fetal growth may have long-lasting effects, our results suggest the potential utility of placental gene expression profiles as potential early markers of disease onset later in life. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the morphological changes in retinal microstructures following modified photodynamic therapy (PDT) for chronic central serous chorioretinopathy. Subjects and methods: Retrospective study of 21 consecutive eyes (age, 59±8.0 years [mean ± SD]) of 21 patients with chronic central serous chorioretinopathy. Inner foveal thickness (the distance between the internal limiting membrane and external limiting membrane), photoreceptor outer segment (PROS) length at the point without serous retinal detachment and choroidal thickness were assessed with enhanced depth imaging optical coherence tomography before treatment and at 1, 3 and 6 months after modified PDT. Results: Six eyes had half-dose and 15 eyes had half-fluence PDT. PROS length within the irradiated area was significantly decreased by 3.9% at 1 month compared with that before modified PDT (43.5±5.72 and 40.5±7.53, P=0.020 [paired t-test]) and returned to baseline length at 3 and 6 months (43.0±5.42 and 43.5±4.33 μm [mean ± SD]; P=0.53 and 1.00 [paired t-test]). PROS length of the nonirradiated area at 1, 3 and 6 months after modified PDT did not significantly differ from that before PDT (41.8±6.35, 41.4±5.33, 41.9±4.67 and 42.3±4.26 μm [mean ± SD]; P=0.66, 0.90 and 0.60, respectively [paired t-test]). There was no significant change in inner foveal thickness during the observation period. At all time points, choroidal thickness was significantly thinner than it was before PDT (P<0.001, paired t-test). Conclusion: Modified PDT may cause mild temporary microstructural changes. [ABSTRACT FROM AUTHOR]

Purpose: To assess the relationship between combined serum lutein and zeaxanthin (L+Z) concentration and macular pigment optical density (MPOD), and to investigate the effect of L+Z+docosahexaenoic acid (DHA) dietary supplementation on the spatial distribution of MPOD. Methods: Twenty healthy fellow eyes with unilateral wet age-related macular degeneration or chronic central serous chorioretinopathy were included. All participants received a dietary supplement for 6 months that contained 20 mg L, 1 mg Z, and 200 mg DHA. The best-corrected visual acuity and contrast sensitivity (CS) were measured at baseline and at 1, 3, and 6 months. Serum L+Z concentrations were measured at baseline and at 3 months. MPOD was calculated at each time point using fundus autofluorescent images. Results: Serum L+Z concentration was correlated with MPOD at 1°-2° eccentricity at baseline (r=0.63, P=0.003) and 3 months (r=0.53, P=0.015). Serum L+Z concentration increased by a factor of 2.3±1.0 (P<0.0001). At 6 months, MPOD was significantly higher compared to the baseline level at 0°-0.25° (P=0.034) and 0.25°-0.5° (P=0.032) eccentricity. CS improved after 3 or 6 months of L+Z+DHA supplementation (P<0.05). Conclusion: Juxtafoveal MPOD was associated with serum L+Z concentration. Foveal MPOD was increased by L+Z+DHA dietary supplementation. [ABSTRACT FROM AUTHOR]

Objective: To examine the independent and synergistic effects of gestational diabetes mellitus (GDM) and low socioeconomic status (SES) on neurodevelopment and attention-deficit/hyperactivity disorder (ADHD) outcomes. Design: Cohort study. Setting: Flushing, New York. Participants: A total of 212 preschool children as a part of the ongoing cohort study. Main Exposures: Gestational diabetes mellitus and low SES. Main Outcome Measures: Primary outcomes are ADHD diagnosis based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria at age 6 years and several well-validated measures of neurobehavioral outcomes, cognitive functioning, ADHD symptoms, and temperament at age 4 years. Secondary outcomes are parent and teacher reports of behavioral and emotional problems at age 6 years. Neurobehavioral measures in relation to GDM and low SES were examined using generalized estimating equations and multivariate logistic regression analyses. Results: Both maternal GDM and low SES were associated with an approximately 2-fold increased risk for ADHD at age 6 years. However, the risk by GDM was greater among lower SES families than among higher SES families. Children exposed to both GDM and low SES demonstrated compromised neurobehavioral functioning, including lower IQ, poorer language, and impoverished behavioral and emotional functioning. A test of additive interaction found that the risk for ADHD increased over 14-fold (P=.006) when children were exposed to both GDM and low SES. Neither children exposed to maternal GDM alone nor those exposed to low SES alone had a notable increased risk for ADHD. Conclusions: Maternal GDM and low SES, especially in combination, heighten the risk for childhood ADHD. Long-term prevention efforts should be directed at mothers with GDM to avoid suboptimal neurobehavioral development and mitigate the risk for ADHD among their offspring. [ABSTRACT FROM AUTHOR]

Objective: To characterize the conjoined effects of low birth weight (LBW) and childhood abuse on impaired adaptation and illness in adolescence and adulthood. Design: Longitudinal study of a birth cohort. Setting: Baltimore, Md. Participants: Children (N=1748) were followed from birth to adulthood (mean age, 26 years) as part of the Johns Hopkins Collaborative Perinatal Study. Main Exposures: Childhood abuse and LBW. Main Outcome Measures: Indicators of adaptation were delinquency, school suspension, repeating grades, academic honors, quality of life, and socioeconomic status. Indicators of psychiatric and medical problems were depression, social dysfunction, somatization, asthma, and hypertension. Results: Participants with both LBW and subsequent childhood abuse, relative to those with neither risk, were at a substantially elevated risk for psychological problems: 10-fold for depression; nearly 9-fold for social dysfunction, and more than 4-fold for somatization. However, they were not at an elevated risk for medical problems in adulthood. Those exposed to childhood abuse were more likely to report delinquency, school suspension, repeating grades during adolescence, and impaired well-being in adulthood, regardless of LBW status. For those with LBW alone, the prevalence of those problems was comparable with that of individuals without either risk factor. Conclusions: Children with LBW and childhood abuse are at much greater risk for poor adaptation and psychiatric problems than those with LBW alone and those with neither risk. Preventive interventions should target families with LBW children who are at greater risk for childhood abuse. [ABSTRACT FROM AUTHOR]

The inapplicability of the DLVO theory to multilayered anionic bilayers is found in terms of the co-ion-valence dependence of the lamellar repeat distance. Most of the added salt is expelled from the interlamellar space to the bulk due to the Gibbs-Donnan effect on multiple bilayers with the bulk. The electrostatic double-layer interaction is well expressed by the formula recently proposed by Trefalt. The osmotic pressure due to the expelled ions, rather than the van der Waals interaction, is the main origin of the attractive force between the bilayers. [ABSTRACT FROM AUTHOR]