Nabilone treatment for severe behavioral problems in adults with intellectual and developmental disabilities: Protocol for a phase I open-label clinical trial.

Severe behavioral problems (SBPs) are common contributors to morbidity and reduced quality of life for adults with intellectual and developmental disabilities (IDD) and their families. Current medications for SBPs show equivocal effectiveness and are associated with a high risk of side effects. New and safe treatments are urgently needed. While preliminary studies suggest that medical cannabinoids, particularly the synthetic cannabinoid nabilone, are plausible treatment options for SBPs in adults with IDD, data on the tolerability, safety and efficacy of nabilone in this population has never been investigated. Thus, we propose this first-ever Phase I pre-pilot open-label clinical trial to obtain preliminary data on the adherence, tolerability and safety profiles of nabilone in adults with IDD, and explore changes in SBPs pre- to post-treatment. We hypothesize that nabilone has favorable tolerability and safety profile for adults with IDD. The preliminary results will inform the next-stage pilot randomized controlled trials, followed by fully powered clinical trials eventually. This research helps fill the evidence gap in the use of cannabinoids in individuals with IDD to meet the needs of patients, families, and service providers.

An analysis of birth defects and developmental disabilities for children of participants of the Air Force Health Study.

Analyses were conducted of the occurrence of eight general categories of birth defects and developmental disabilities for children fathered by participants of the Air Force Heath Study (AFHS). Participants were male Air Force veterans of the Vietnam War. Children were categorized into conceived before and after the start of the participant's Vietnam War service. Analyses accounted for correlation between outcomes for multiple children fathered by each of the participants. For each of the eight general categories of birth defects and developmental disabilities, the probability of its occurrence increased substantially for children conceived after compared to before the start of Vietnam War service. These results support the conclusion of an adverse effect on reproductive outcomes due to Vietnam War service. Data for children conceived after the start of Vietnam War service for participants with measured dioxin values were used to estimate dose-response curves for the effect of dioxin exposure on the occurrence of each of the eight general categories of birth defects and developmental disabilities. These curves were assumed to be constant up to a threshold and then monotonic after that threshold. For seven of the eight general categories of birth defects and developmental disabilities, the estimated dose-response curves increased nonlinearly after associated thresholds. These results support the conclusion that the adverse effect to conception after the start of Vietnam War service may be attributable to high enough exposures to dioxin, a toxic contaminant of Agent Orange used for herbicide spraying in the Vietnam War.

Acute ischemic strokes in patients with developmental disabilities: A cross-sectional analysis.

OBJECTIVE: Patients with developmental disabilities (DD) are frequently excluded from acute ischemic stroke (AIS) randomized control trials. We sought to evaluate the impact of having DD on this patient cohort. METHODS: The National Inpatient Sample was analyzed to explore the impact of AIS and treatment on discharge dispositions in patients with DD. Clinical characteristics, treatments, and outcomes were compared to fully-abled patients with AIS. RESULTS: 1,605,723 patients with AIS were identified from 2010-2019, of whom 4094 (0.30%) had a DD. AIS patients with DD were younger (60.31 vs 70.93 years, p < 0.01), less likely to be Caucasian (66.37%vs 68.09%, p = 0.01), and had higher AIS severity (0.63 vs 0.58, p < 0.01). Tissue plasminogen activator (tPA) was administered in 99,739 (6.2%) fully-abled patients and 196 (4.79%) of patients with DD (p < 0.01). Endovascular thrombectomy (EVT) was performed in 21,066 (1.31%) of fully-abled patients and 35 (0.85%) of patients with DD (p < 0.01). The presence of developmental disabilities were predictive of lower rates of tPA (OR:0.71,CI:0.56-0.87,p < 0.01) and EVT (OR:0.24,CI:0.16-0.36,p < 0.01). In a propensity score-matched cohort of all AIS patients who underwent EVT, there was no difference in functional outcome (p = 0.41), in-hospital mortality (0.10), and LOS (p = 0.79). CONCLUSION: AIS patients with DD were less likely to receive tPA and EVT compared to fully-abled patients. Individuals with DD had higher mortality and worse discharge disposition. There was no significant difference in post-EVT outcomes between fully-abled patients and patients with developmental disabilities. In the absence of prospective clinical trials, population based cross-sectional analyses such as the present study provide valuable clinical insight.

The metabolic adverse effects of antipsychotic use in individuals with intellectual and/or developmental disability: A systematic review and meta-analysis.

OBJECTIVE: Individuals with intellectual and/or developmental disability (IDD) are often prescribed antipsychotics (APs). However, despite their known propensity to cause metabolic adverse effects, including weight gain, diabetes, and increased risk of cardiovascular events, there is currently a limited body of literature describing the metabolic consequences of AP use in this population. METHODS: We searched MEDLINE, EMBASE, PsychINFO, CENTRAL, and CINAHL databases to identify all randomized trials that reported on the metabolic effects of APs in individuals with IDD. Random effects meta-analyses were used to examine weight gain as both a continuous and dichotomous outcome. RESULTS: Eighteen randomized trials met our inclusion criteria with a total of 1376 patients across a variety of IDDs. AP use was associated with significantly greater weight gain compared with placebo (Continuous: mean difference = 1.10 kg, [0.79, 1.40], p < 0.00001, I2  = 54%; Dichotomous: odds ratio = 3.94, [2.15, 7.23], p < 0.00001, I2  = 0). Sub-group analysis revealed no significant effect of AP type. Data regarding the effects of APs on other metabolic outcomes were limited. CONCLUSION: This review (PROSPERO # CRD42021255558) demonstrates that AP use is associated with significant weight gain among patients with IDD. Concerningly, most reported studies were in children and adolescents, which sets up an already vulnerable population for adverse medical sequalae at an early age. There was also a lack of long-term studies in adults with IDD. Further studies are required to better understand how AP use affects metabolic parameters in this group of individuals.

Prenatal Nicotine or Cannabis Exposure and Offspring Neurobehavioral Outcomes.

OBJECTIVE: To study the association between nicotine or cannabis metabolite presence in maternal urine and child neurodevelopmental outcomes. METHODS: We conducted a secondary analysis of two parallel multicenter randomized controlled trials of treatment for hypothyroxinemia or subclinical hypothyroidism among pregnant individuals enrolled at 8-20 weeks of gestation. All maternal-child dyads with a maternal urine sample at enrollment and child neurodevelopmental testing were included (N=1,197). Exposure was urine samples positive for nicotine (cotinine) or cannabis 11-nor-9-carboxy-delta-9-tetrahydrocannabinol [THC-COOH]) or both metabolites. Primary outcome was child IQ at 60 months. Secondary outcomes included cognitive, motor and language, attention, behavioral and social competency, and differential skills assessments at 12, 24, 36, and 48 months. Quantile regression analysis was performed with confounder adjustment. RESULTS: Of 1,197 pregnant individuals, 99 (8.3%) had positive cotinine samples and 47 (3.9%) had positive THC-COOH samples; 33 (2.8%) were positive for both. Groups differed in self-reported race and ethnicity, education, marital status, insurance, and thyroid status. Median IQ was similar between cotinine-exposed and -unexposed children (90 vs 95, adjusted difference in medians -2.47, 95% CI -6.22 to 1.29) and THC-COOH-exposed and -unexposed children (89 vs 95, adjusted difference in medians -1.35, 95% CI -7.76 to 5.05). In secondary outcome analysis, children with THC-COOH exposure compared with those unexposed had higher attention scores at 48 months of age (57 vs 49, adjusted difference in medians 6.0, 95% CI 1.11-10.89). CONCLUSIONS: Neither prenatal nicotine nor cannabis exposure was associated with a difference in IQ. Cannabis exposure was associated with worse attention scores in early childhood. Longitudinal studies assessing associations between child neurodevelopmental outcomes and prenatal nicotine and cannabis exposure with a focus on timing and quantity of exposure are needed. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00388297.

Attenuation of growth hormone production at the fetal stage is critical for dioxin-induced developmental disorder in rat offspring.

Although dioxins and related chemicals have been suspected to disrupt child development, their toxic mechanism remains poorly understood. Our previous studies in rat fetuses revealed that maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a highly-toxic dioxin, suppresses fetal synthesis of pituitary growth hormone (GH) that is essential for development. This study examined the hypothesis that attenuating GH expression in fetuses triggers developmental disorders. Treating pregnant rats with 1 µg/kg TCDD reduced the circulating level of GH and its downstream factor, insulin-like growth factor-1 (IGF-1), in the offspring only during the fetal and early neonatal stages. Although maternal TCDD exposure resulted in low body weight and length at babyhood and defects in the learning and memory ability at adulthood, GH supplementation in TCDD-exposed fetuses restored or tended to restore the defects including IGF-1 downregulation. Moreover, maternal TCDD exposure decreased the number of GH-positive cells during the fetal/neonatal stage. A microarray analysis showed that TCDD reduced the expression of death-associated protein-like 1 (DAPL1), a cell cycle-dependent proliferation regulator, in the fetal pituitary gland. In addition, TCDD treatment attenuated proliferating cells and cyclin mRNA expression in the fetal pituitary gland. Aryl hydrocarbon receptor (AHR)-knockout fetuses were insensitive to TCDD treatment, indicating that the TCDD-induced reduction in DAPL1 and GH mRNAs expression was due to AHR activation. Finally, DAPL1 knockdown suppressed GH and cyclin D2 expression in fetal pituitary cells. These results provide a novel evidence that dioxin suppresses GH-producing cell proliferation and GH synthesis due to partly targeting DAPL1, thereby impairing offspring development.

Caffeine exposure in utero is associated with structural brain alterations and deleterious neurocognitive outcomes in 9-10 year old children.

Caffeine, a very widely used and potent neuromodulator, easily crosses the placental barrier, but relatively little is known about the long-term impact of gestational caffeine exposure (GCE) on neurodevelopment. Here, we leverage magnetic resonance imaging (MRI) data, collected from a very large sample of 9157 children, aged 9-10 years, as part of the Adolescent Brain and Cognitive Developmentsm (ABCD ®) study, to investigate brain structural outcomes at 27 major fiber tracts as a function of GCE. Significant relationships between GCE and fractional anisotropy (FA) measures in the inferior fronto-occipito fasciculus and corticospinal tract of the left hemisphere (IFOF-LH; CST-LH) were detected via mixed effects binomial regression. We further investigated the interaction between these fiber tracts, GCE, cognitive measures (working memory, task efficiency), and psychopathology measures (externalization, internalization, somatization, and neurodevelopment). GCE was associated with poorer outcomes on all measures of psychopathology but had negligible effect on cognitive measures. Higher FA values in both fiber tracts were associated with decreased neurodevelopmental problems and improved performance on both cognitive tasks. We also identified a decreased association between FA in the CST-LH and task efficiency in the GCE group. These findings suggest that GCE can lead to future neurodevelopmental complications and that this occurs, in part, through alteration of the microstructure of critical fiber tracts such as the IFOF-LH and CST-LH. These data suggest that current guidelines regarding limiting caffeine intake during pregnancy may require some recalibration.

Reproductive and developmental toxicity screening study of an acetone extract of rosemary.

In 2017, JECFA requested reproductive and developmental toxicity studies to finalize an acceptable daily intake for solvent rosemary extracts. Thus, an OECD 421 reproductive/developmental toxicity study was conducted using an acetone rosemary extract that complied with JECFA and EFSA food additive specifications. Rosemary extract was provided to rats at dietary concentrations of 0 (control), 2100, 3600, or 5000 mg/kg, for 14 days before mating, during mating, and thereafter (throughout gestation and up to Lactation Day 13 for females) until necropsy. General toxicity (clinical signs, body weight, food consumption) and reproductive/developmental outcomes (fertility and mating performance, estrous cycles, anogenital distance, thyroid hormones, reproductive organ weights, thyroid histopathology) were assessed. There were no signs of general toxicity and no effects on reproduction; thus, the highest concentration tested (equivalent to mean daily intakes of 316 or 401 mg/kg bw/day [149 or 189 mg/kg bw/day carnosol and carnosic acid] for males and females, respectively) was established as the no-observed-adverse-effect level for general and reproductive toxicity. Dose-related reductions in T4 were observed for Day 13 pups (not seen on Day 4) but were not accompanied by thyroid weight changes or histopathological findings; further investigations are required to determine the biological relevance of these T4 reductions.

In utero exposure to protease inhibitor-based antiretroviral regimens delays growth and developmental milestones in mice.

Antiretroviral therapy (ART) in pregnancy has dramatically reduced HIV vertical transmission rates. Consequently, there is a growing number of children that are HIV exposed uninfected (CHEUs). Studies suggest that CHEUs exposed in utero to ART may experience developmental delays compared to their peers. We investigated the effects of in utero ART exposure on perinatal neurodevelopment in mice, through assessment of developmental milestones. Developmental milestone tests (parallel to reflex testing in human infants) are reflective of brain maturity and useful in predicting later behavioral outcomes. We hypothesized that ART in pregnancy alters the in utero environment and thereby alters developmental milestone outcomes in pups. Throughout pregnancy, dams were treated with boosted-atazanavir combined with either abacavir/lamivudine (ATV/r/ABC/3TC), or tenofovir/emtricitabine (ATV/r/TDF/FTC), or water as control. Pups were assessed daily for general somatic growth and on a battery of tests for primitive reflexes including surface-righting, negative-geotaxis, cliff-aversion, rooting, ear-twitch, auditory-reflex, forelimb-grasp, air-righting, behaviors in the neonatal open field, and olfactory test. In utero exposure to either ART regimen delayed somatic growth in offspring and evoked significant delays in the development of negative geotaxis, cliff-aversion, and ear-twitch reflexes. Exposure to ATV/r/ABC/3TC was also associated with olfactory deficits in male and forelimb grasp deficits in female pups. To explore whether delays persisted into adulthood we assessed performance in the open field test. We observed no significant differences between treatment arm for males. In females, ATV/r/TDF/FTC exposure was associated with lower total distance travelled and less ambulatory time in the centre, while ATV/r/ABC/3TC exposure was associated with higher resting times compared to controls. In utero PI-based ART exposure delays the appearance of primitive reflexes that involve vestibular and sensory-motor pathways in a mouse model. Our findings suggest that ART could be disrupting the normal progress/maturation of the underlying neurocircuits and encourage further investigation for underlying mechanisms.

Early childhood general anesthesia exposure associated with later developmental delay: A national population-based cohort study.

Exposure to general anesthesia has been reported to induce neurotoxicity, impair learning, memory, attention, motor functions, as well as affect behavior in adult rodents and nonhuman primates. Though many have speculated similar effects in humans, previous literature has shown conflicting findings. To investigate the differences in risk of developmental delay among young children exposed to general anesthesia compared to matched unexposed individuals, a population-based cohort study was conducted with a longitudinal dataset spanning 2000 to 2013 from the Taiwan National Health Insurance Research Database (NHIRD). Procedure codes were used to identify children who received anesthesia. For each exposed child, two unexposed children matched by gender and age were enrolled into the comparison cohort. Neurocognitive outcome was measured by the presence of ICD-9-CM codes related to developmental delay (DD). Cox regression models were used to obtain hazard ratios of developing DD after varying levels of anesthesia exposure. After excluding 4,802 individuals who met the exclusion criteria, a total of 11,457 children who received general anesthesia before two years of age was compared to 22,914 children (matched by gender and age) unexposed to anesthesia. Increased risk of DD was observed in the exposure group with a hazard ratio (HR) of 1.320 (95% CI 1.143-1.522, P < 0.001). Subgroup analysis demonstrated further elevated risks of DD with multiple anesthesia exposures (1 anesthesia event: HR 1.145, 95% CI 1.010-1.246, P = 0.04; 2 anesthesia events: HR 1.476, 95% CI 1.155-1.887, P = 0.005; ≥3 anesthesia events: HR 2.222, 95% CI 1.810-2.621, P < 0.001) and longer total anesthesia durations (Total anesthesia <2 hours: HR 1.124, 95% CI 1.003-1.499, P = 0.047; Total anesthesia 2-4 hours: HR 1.450, 95% CI 1.157-1.800, P = 0.004; Total anesthesia > 4 hours: HR 1.598, 95% CI 1.343-1.982, P < 0.001) compared with children unexposed to anesthesia. These results suggest that children exposed to general anesthesia before two years of age have an increased risk of DD. This risk is further elevated with increased frequency of anesthesia, and longer total anesthesia duration. The findings of this study should prompt clinical practitioners to proceed with caution when assessing young patients and planning managements involving procedures requiring general anesthesia.

In utero exposure to analgesic opioids and language development in 5-year old children.

PURPOSE: An increasing consumption of opioids has been reported. The primary aim of the present study was follow-up of neurocognitive development in children exposed to analgesic opioids during pregnancy, using three different validated instruments to assess language and communication development at 5 years. METHODS: The Norwegian Mother and Child Cohort Study (MoBa) prospectively included pregnant women 1999 to 2008. Participants reported medication use at pregnancy week 17/18 and 30, and 6 months after birth. Children's language competence and communication skills at 5 years were reported by mothers on three different validated scales; The Ages and Stages Questionnaire (ASQ), The Speech and Language Assessment Scale (SLAS) and The Twenty Statements about Language-Related Difficulties list (Language20Q). RESULTS: A total of 27 428 women with 33 407 singleton pregnancies were included. Use of analgesic opioids was reported in 584 pregnancies (1.7%). No associations between opioid use and lower language competence or communication skills were found. For ASQ, the OR of being in the lowest category vs the group with maximum mean score was 0.82 (95%CI 0.57, 1.17), for SLAS the OR of scoring worse than typical for age vs better than typical for age was 0.84 (0.61, 1.17) in children exposed to opioids in utero. For Language20Q using the best performance category as reference, the OR of scoring in the lower performance category was 0.57 (0.35, 0.91) with exposure to opioids. CONCLUSION: Use of analgesic opioids in pregnant women does not seem to negatively affect language development or communication skills in children at 5 years.

Association of Neurodevelopmental Outcomes With Environmental Exposure to Cyclohexanone During Neonatal Congenital Cardiac Operations: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Cyclohexanone is an industrial solvent used as a coupling agent in medical plastics. Perioperative exposure to cyclohexanone could play a role in lower scores on measures of neurodevelopmental outcomes after neonatal cardiac operations. Objective: To examine the presence and association of serum cyclohexanone level with neonatal cardiac operations and neurodevelopmental outcomes. Design, Setting, and Participants: This ad hoc secondary analysis used data from the Corticosteroid Therapy in Neonates Undergoing Cardiopulmonary Bypass randomized clinical trial. The cohort included neonates younger than 31 days and with at least 37 weeks postgestational age at surgical treatment who were enrolled at a single center between June 1, 2012, and October 31, 2016, and who had completed a neurodevelopmental assessment at age 12 months. Data were analyzed from July 8 to August 20, 2019. Exposures: Serum cyclohexanone and its metabolites were measured preoperatively (prior to skin incision), postoperatively (immediately after the surgical procedure was completed), and 12 hours postoperatively. Cyclohexanone and the molar sum of its metabolites were examined at each point and as a geometric mean of all 3 points. Main Outcomes and Measures: Neurodevelopment was assessed at age 12 months with the Bayley Scales of Infant and Toddler Development III, assessing cognitive, language, and motor function composite scores standardized to a population mean (SD) of 100 (15). Linear regression models were used to determine covariate-adjusted differences in 12-month cognitive, language, and motor composite scores per interquartile range increase in cyclohexanone level or summed metabolite molar concentrations. Results: Among 85 included neonates, mean (SD) age at surgical treatment was 9.7 (5.3) days, 49 (58%) were boys, and 54 (64%) underwent corrective repair. Mean (SD) Bayley Scales of Infant and Toddler Development III composite scores were 108.2 (12.2) for cognitive function, 104.7 (11.0) for language function, and 94.7 (15.7) for motor function. Median (interquartile range) cyclohexanone levels increased approximately 3-fold from immediately prior to surgical treatment to immediately after surgical treatment (572 [389-974] vs 1744 [1469-2291] µg/L; P = .001). In adjusted analyses, higher geometric mean cyclohexanone levels were associated with significantly lower composite scores for cognitive (-4.23; 95% CI, -7.39 to -1.06; P = .01) and language (-3.65; 95% CI, -6.41 to -0.88; P = .01) function. The difference in composite scores for motor function among infants with higher geometric mean cyclohexanone levels was not statistically significant(-3.93, 95% CI: -8.19 to 0.33, P = .07). Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that infants who underwent neonatal cardiac surgical treatment with cardiopulmonary bypass had substantial cyclohexanone levels, which were associated with adverse neurodevelopmental function at age 12 months. Trial Registration: ClinicalTrials.gov identifier: NCT01579513.

Combined effect of polymorphisms of MTHFR and MTR and arsenic methylation capacity on developmental delay in preschool children in Taiwan.

Polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase (MTR) are related to cognitive dysfunction and mental disability. These genes, along with folate and vitamin B12 levels, are regulators of one-carbon metabolism, which synthesizes S-adenosylmethionine (SAM) as a methyl donor for arsenic methylation. The aim of this study was to explore whether polymorphisms of MTHFR and MTR influence arsenic methylation capacity and plasma folate and vitamin B12 levels and if these influences cause developmental delay in preschool children. A total of 178 children with developmental delay and 88 without developmental delay were recruited from August 2010 to March 2014. A high-performance liquid chromatography-hydride generator and atomic absorption spectrometer were used to determine urinary arsenic species. Plasma folate and vitamin B12 concentrations were measured by SimulTRAC-SNB radioassay. Polymorphisms of MTHFR C677T, MTHFR A1298C, and MTR A2756G were examined by polymerase chain reaction and restriction fragment length variation. The results show that MTHFR C677T C/T and T/T genotypes had a lower risk of developmental delay than the C/C genotype (odds ratio [OR] = 0.47; 95% confidence interval, 0.26-0.85). Subjects with the MTHFR C677T C/C genotype had significantly lower plasma folate and vitamin B12 levels than those with the MTHFR C677T C/T and T/T genotype. The MTHFR C677T C/C genotype combined with high total urinary arsenic and poor arsenic methylation capacity indices significantly increased the OR of developmental delay in a dose-response manner. This is the first study to show the combined effect of MTHFR C677T genotype and poor arsenic methylation capacity on developmental delay.

Impact of anesthesia exposure in early development on learning and sensory functions.

Each year, millions of children undergo anesthesia, and both human and animal studies have indicated that exposure to anesthesia at an early age can lead to neuronal damage and learning deficiency. However, disorders of sensory functions were not reported in children or animals exposed to anesthesia during infancy, which is surprising, given the significant amount of damage to brain tissue reported in many animal studies. In this review, we discuss the relationship between the systems in the brain that mediate sensory input, spatial learning, and classical conditioning, and how these systems could be affected during anesthesia exposure. Based on previous reports, we conclude that anesthesia can induce structural, functional, and compensatory changes in both sensory and learning systems. Changes in myelination following anesthesia exposure were observed as well as the neurodegeneration in the gray matter across variety of brain regions. Disproportionate cell death between excitatory and inhibitory cells induced by anesthesia exposure can lead to a long-term shift in the excitatory/inhibitory balance, which affects both learning-specific networks and sensory systems. Anesthesia may directly affect synaptic plasticity which is especially critical to learning acquisition. However, sensory systems appear to have better ability to compensate for damage than learning-specific networks.

Immune network dysregulation associated with child neurodevelopmental delay: modulatory role of prenatal alcohol exposure.

BACKGROUND: Evidence suggests that cytokine imbalances may be at the root of deficits that occur in numerous neurodevelopmental disorders, including schizophrenia and autism spectrum disorder. Notably, while clinical studies have demonstrated maternal cytokine imbalances with alcohol consumption during pregnancy-and data from animal models have identified immune disturbances in alcohol-exposed offspring-to date, immune alterations in alcohol-exposed children have not been explored. Thus, here we hypothesized that perturbations in the immune environment as a result of prenatal alcohol exposure will program the developing immune system, and result in immune dysfunction into childhood. Due to the important role of cytokines in brain development/function, we further hypothesized that child immune profiles might be associated with their neurodevelopmental status. METHODS: As part of a longitudinal study in Ukraine, children of mothers reporting low/no alcohol consumption or moderate-to-heavy alcohol consumption during pregnancy were enrolled in the study and received neurodevelopmental assessments. Group stratification was based on maternal alcohol consumption and child neurodevelopmental status resulting in the following groups: A/TD, alcohol-consuming mother, typically developing child; A/ND, alcohol-consuming mother, neurodevelopmental delay in the child; C/TD, control mother (low/no alcohol consumption), typically development child; and C/ND, control mother, neurodevelopmental delay in the child. Forty cytokines/chemokines were measured in plasma and data were analyzed using regression and constrained principle component analysis. RESULTS: Analyses revealed differential cytokine network activity associated with both prenatal alcohol exposure and neurodevelopmental status. Specifically, alcohol-exposed children showed activation of a cytokine network including eotaxin-3, eotaxin, and bFGF, irrespective of neurodevelopmental status. However, another cytokine network was differentially activated based on neurodevelopmental outcome: A/TD showed activation of MIP-1ß, MDC, and MCP-4, and inhibition of CRP and PlGF, with opposing pattern of activation/inhibition detected in the A/ND group. By contrast, in the absence of alcohol-exposure, activation of a network including IL-2, TNF-ß, IL-10, and IL-15 was associated with neurodevelopmental delay. CONCLUSIONS: Taken together, this comprehensive assessment of immune markers allowed for the identification of unique immune milieus that are associated with alcohol exposure as well as both alcohol-related and alcohol-independent neurodevelopmental delay. These findings are a critical step towards establishing unique immune biomarkers for alcohol-related and alcohol-independent neurodevelopmental delay.

Leveraging complementary computational models for prioritizing chemicals of developmental and reproductive toxicity concern: an example of food contact materials.

The evaluation of developmental and reproductive toxicity of food contact materials (FCMs) is an important task for food safety. Since traditional experiments are both time-consuming and labor-intensive, only a small number of FCMs have sufficient toxicological data for evaluating their effects on human health. While computational methods such as structural alerts and quantitative structure-activity relationships can serve as first-line tools for the identification of chemicals of high toxicity concern, models with binary outputs and unsatisfied accuracy and coverage prevent the use of computational methods for prioritizing chemicals of high concern. This study proposed a genetic algorithm-based method to develop a weight-of-evidence (WoE) model leveraging complementary methods of structural alerts, quantitative structure-activity relationships and in silico toxicogenomics models for chemical prioritization. The WoE model was applied to evaluate 623 food contact chemicals and identify 26 chemicals of high toxicity concern, where 13 chemicals have been reported to be developmental or reproductive toxic and further experiments are suggested for the remaining 13 chemicals without toxicity data related to developmental and reproductive effects. The proposed WoE model is potentially useful for prioritizing chemicals of high toxicity concern and the methodology may be applied to toxicities other than developmental and reproductive toxicity.

Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes.

INTRODUCTION: Fetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential. METHODS: We reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service. RESULTS: Seven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10). CONCLUSIONS: This study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.

Developmental outcomes following prenatal exposure to methamphetamine: A Western Australian perspective.

AIM: To describe neurodevelopmental outcomes among a cohort of Western Australian infants exposed to maternal methamphetamine use during pregnancy and to determine whether the Ages and Stages Questionnaire is a reliable screening tool for this population. METHODS: Methamphetamine-using women were approached for participation when referred to the state-wide perinatal specialist drug and alcohol service for pregnancy care. Drug use during pregnancy was self-reported in each trimester using a standardised questionnaire. Ages and Stages Questionnaires were completed by infant care givers at 4 and 12 months, and development was formally assessed at 12 months using the Griffiths Mental Development Scales. Griffiths results for term-born infants in our cohort were compared to a Western Australian historical cohort of 443 healthy 1-2-year-olds. RESULTS: A total of 112 methamphetamine-using pregnant women participated in the study, who gave birth to 110 live-born infants. Ages and Stages Questionnaires were completed for 89 (81%) and 78 (71%) of the infants at 4 and 12 months, respectively. The Ages and Stages assessment identified 30 infants (33.7%) as having a potential developmental delay at 4 months and 29 infants (38.7%) as having a potential developmental delay at 12 months. Griffiths assessments were performed on 64 (58%) of the infants, with a mean general quotient of 92.7. This was significantly lower in term-born babies compared to the historical cohort (who had a median general quotient of 113.0). There was a weak correlation between 12-month Ages and Stages scores and Griffiths general quotients (r = 0.322) and no correlation between 4-month Ages and Stages Questionnaire scores and later Griffiths results. CONCLUSIONS: Infants born to women reporting methamphetamine use during pregnancy are at increased risk of developmental delay and may warrant enhanced developmental follow-up. However, they are a challenging group to follow due to complex psychosocial factors. Ages and Stages Questionnaires at 4 and 12 months were not helpful in screening for infants who had a developmental delay at 12 months.

Prenatal exposure to antiepileptic drugs and early processing of emotionally relevant sounds.

INTRODUCTION: Prenatal exposure to antiepileptic drugs (AEDs) is associated with developmental compromises in verbal intelligence and social skills in childhood. Our aim was to evaluate whether a multifeature Mismatch Negativity (MMN) paradigm assessing semantic and emotional components of linguistic and emotional processing would be useful to detect possible alterations in early auditory processing of newborns with prenatal AED exposure. MATERIAL AND METHODS: Data on AED exposure, pregnancy outcome, neuropsychological evaluation of the mothers, information on maternal epilepsy type, and a structured neurological examination of the newborn were collected prospectively. Blinded to AED exposure, we compared a cohort of 36 AED-exposed with 46 control newborns at the age of two weeks by measuring MMN with a multifeature paradigm with six linguistically relevant deviant sounds and three emotionally uttered sounds. RESULTS: Frontal responses for the emotionally uttered stimulus Happy differed significantly in the exposed newborns compared with the control newborns. In addition, responses to sounds with or without emotional component differed in newborns exposed to multiple AEDs compared with control newborns or to newborns exposed to only one AED. CONCLUSIONS: These preliminary findings suggest that prenatal AED exposure may alter early processing of emotionally and linguistically relevant sound information.