Factors associated with blood mercury concentrations and their interactions with three glutathione S-transferase genes (GSTT1, GSTM1, and GSTP1): an exposure assessment study of typically developing Jamaican children.

BACKGROUND: Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms. METHODS: In this exposure assessment study we used data from 375 typically developing (TD) 2-8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general linear models (GLMs). RESULTS: We identified the child's age, consumption of saltwater fish, canned fish (sardine, mackerel), string beans, grain, and starches (pasta, macaroni, noodles) as the environmental factors significantly associated with BHgCs (all P < 0.05). A significant interaction between consumption of canned fish (sardine, mackerel) and GSTP1 in relation to BHgC using either a co-dominant or recessive genetic model (overall interaction P = 0.01 and P < 0.01, respectively) indicated that consumption of canned fish (sardine, mackerel) was significantly associated with higher mean BHgC only among children with the GSTP1 Ile105Val, Ile/Ile [Ratio of mean Hg (95% CI) = 1.59 (1.09, 2.32), P = 0.02] and Ile/Val [Ratio of mean Hg (95% CI) = 1.46 (1.12, 1.91), P = 0.01] genotypes. CONCLUSIONS: Since this is the first study from Jamaica to report these findings, replication in other populations is recommended.

Fungi: Friend or Foe? A Mycobiome Evaluation in Children With Autism and Gastrointestinal Symptoms.

ABSTRACT: Gastrointestinal (GI) symptoms often affect children with autism spectrum disorders (ASD) and GI symptoms have been associated with an abnormal fecal microbiome. There is limited evidence of Candida species being more prevalent in children with ASD. We enrolled 20 children with ASD and GI symptoms (ASD + GI), 10 children with ASD but no GI symptoms (ASD - GI), and 20 from typically developing (TD) children in this pilot study. Fecal mycobiome taxa were analyzed by Internal Transcribed Spacer sequencing. GI symptoms (GI Severity Index [GSI]), behavioral symptoms (Social Responsiveness Scale -2 [SRS-2]), inflammation and fungal immunity (fecal calprotectin and serum dectin-1 [ELISA]) were evaluated. We observed no changes in the abundance of total fungal species (alpha diversity) between groups. Samples with identifiable Candida spp. were present in 4 of 19 (21%) ASD + GI, in 5 of 9 (56%) ASD - GI, and in 4 of 16 (25%) TD children (overall P = 0.18). The presence of Candida spp. did not correlate with behavioral or GI symptoms (P = 0.38, P = 0.5, respectively). Fecal calprotectin was normal in all but one child. Finally, there was no significance in serum dectin-1 levels, suggesting no increased fungal immunity in children with ASD. Our data suggest that fungi are present at normal levels in the stool of children with ASD and are not associated with gut inflammation.

Construct validity for the self-reported competency and sub-construct associated characteristics of Romanian physicians in autism spectrum disorder.

BACKGROUND: Lack of physicians' knowledge regarding mental health, including Autism Spectrum Disorder (ASD) could have adverse effects on affected individuals' health and quality of life. The purpose of this study was to provide construct validity for a modified questionnaire in order to determine the self-reported competency for underlying sub-constructs in ASD, make inferences on perceived competence in ASD based on a sample of Romanian physicians, and identify physicians' characteristics associated with these sub-domains of competency. METHODS: For this survey, we modified a questionnaire that was used in Pakistan and Turkey, and administered it to a sample of 383 practicing physicians in Romania to assess their perceived competency regarding ASD. Exploratory factor analysis on 12 knowledge questions revealed five sub-domains: stigma, potential causes, children's behavior, misconceptions, and educational needs associated with ASD knowledge. Using General Linear Models, we determined physicians' characteristics that predict the total competency score and various competency sub-scores. RESULTS: Seventy-five percent of the responding physicians were female and 30% had over 30 years practicing medicine. The majority (73-94%) of physicians have correctly responded to some basic questions regarding knowledge about ASD. We also found that younger physicians were more knowledgeable about potential causes of ASD than older physicians (Adjusted Mean Score (AMS): 2.90 vs. 2.18, P < 0.01), while older physicians knew more about the behavior of children with ASD (AMS: 0.64 vs. 0.37, P = 0.02). We found a significant interaction (P < 0.01) between television as source of ASD knowledge and city where the clinic is located in relation to knowledge of the physicians regarding stigma related to ASD. However, the total score was not associated with the variables associated with sub-domains. CONCLUSION: Using factor analysis, we demonstrated construct validity of five sub-domains related to Romanian physicians' knowledge about ASD that include stigma, potential causes, behavior in ASD children, special education needs, and misconceptions related to ASD. The lack of significant association of the knowledge of physicians on ASD neither with the Psychiatry nor the Pediatric ward rotations at medical school may support the need for improving the curriculum on ASD in Romanian medical schools.

Correlation between concentrations of four heavy metals in cord blood and childhood blood of Jamaican children.

This study investigated whether the concentrations of four metals [lead (Pb), mercury (Hg), manganese (Mn), and aluminum (Al)] are correlated in cord blood and childhood blood samples from Jamaican children. Cord blood samples were obtained from 21 pregnant women enrolled in the second Jamaican Birth Cohort Study from July 1, 2011 to September 30, 2011, and blood samples were drawn from their children who participated in a follow up study when the children were 4-8 years old. Correlations were assessed by the Pearson or the Spearman's rank correlation coefficient. The mean ages of children at the childhood visit and their mother at the child's birth were 5.5 years and 29.8 years, respectively. About 47.6% of children were male. Statistically significant correlations between cord blood and childhood blood concentrations of Pb (rSpearman =0.45; P = 0.04) and Mn (rPearson=0.48; P = 0.03) were found, and these remained significant when adjusted for the child's sex, age, or both. For Al and Hg, rSpearman=0.29 and 0.08, respectively, but the correlations were not statistically significant (both P ≥ 0.20). A significant correlation between cord blood and childhood blood Pb concentrations for children 4-8 years old has not been previously reported.

Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized, Placebo-Controlled, Double-Blind Pilot Study.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with antioxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. OBJECTIVE: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM. METHODS AND RESULTS: HALT-HCM (Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy) is a double-blind, randomized, sex-matched, placebo-controlled single-center pilot study in patients with HCM. Patients with HCM, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated ≤2.4 g per day. Clinical evaluation, blood chemistry, and 6-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging, the latter whenever not contraindicated, before and after 12 months of treatment. Eighty-five of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographic, echocardiographic, and cardiac magnetic resonance imaging phenotypes at the baseline between the 2 groups were similar. WSE in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC group and 11 in the placebo group completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and cardiac magnetic resonance imaging indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement-a surrogate for fibrosis-were small. CONCLUSIONS: Treatment with NAC for 12 months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01537926.

A generalized weighted quantile sum approach for analyzing correlated data in the presence of interactions.

A weighted quantile sum (WQS) regression has been used to assess the associations between environmental exposures and health outcomes. However, the currently available WQS approach, which is based on additive effects, does not allow exploring for potential interactions of exposures with other covariates in relation to a health outcome. In addition, the current WQS cannot account for clustering, thus it may not be valid for analysis of clustered data. We propose a generalized WQS approach that can assess interactions by estimating stratum-specific weights of exposures in a mixture, while accounting for potential clustering effect of matched pairs of cases and controls as well as censored exposure data due to being below the limits of detection. The performance of the proposed method in identifying interactions is evaluated through simulations based on various scenarios of correlation structures among the exposures and with an outcome. We also assess how well the proposed method performs in the presence of the varying levels of censoring in exposures. Our findings from the simulation study show that the proposed method outperforms the traditional WQS, as indicated by higher power of detecting interactions. We also find no strong evidence that the proposed method falsely identifies interactions when there are no true interactive effects. We demonstrate application of the proposed method to real data from the Epidemiological Research on Autism Spectrum Disorder (ASD) in Jamaica (ERAJ) by examining interactions between exposure to manganese and glutathione S-transferase family gene, GSTP1 in relation to ASD.

Lactobacillus reuteri for Infants with Colic: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

OBJECTIVE: To assess the safety of probiotic Lactobacillus reuteri strain Deutsche Sammlung von Mikroorganismen (DSM) 17938 with daily administration to healthy infants with colic and to determine the effect of L reuteri strain DSM 17938 on crying, fussing, inflammatory, immune, and microbiome variables. STUDY DESIGN: We performed a controlled, double-blinded, phase 1 safety and tolerability trial in healthy breast-fed infants with colic, aged 3 weeks to 3 months, randomly assigned to L reuteri strain DSM 17938 (5 × 108 colony-forming units daily) or placebo for 42 days and followed for 134 days. RESULTS: Of 117 screened infants, 20 were randomized to L reuteri strain DSM 17938 or placebo (sunflower oil) (in a 2:1 ratio) with 80% retention. Eleven of the 20 (55%) presented with low absolute neutrophil counts (<1500/mm3), which resolved in all subjects by day 176. L reuteri strain DSM 17938 produced no severe adverse events and did not significantly change crying time, plasma bicarbonate, or inflammatory biomarkers. Fecal calprotectin decreased rapidly in both groups. In the infants with dominant fecal gram negatives (Klebsiella, Proteus, and Veillonella), resolution of colic was associated with marked decreases in these organisms. CONCLUSIONS: Daily administration of L reuteri strain DSM 17938 appears to be safe in newborn infants with colic, including those with neutropenia, which frequently coexists. A placebo response of 66% suggests that many infants with colic will have resolution within 3 weeks. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01849991.

Factors associated with blood lead concentrations of children in Jamaica.

Lead is a heavy metal known to be detrimental to neurologic, physiologic, and behavioral health of children. Previous studies from Jamaica reported that mean lead levels in soil are four times that of lead levels in some other parts of the world. Other studies detected lead levels in fruits and root vegetables, which were grown in areas with lead contaminated soil. In this study, we investigate environmental factors associated with blood lead concentrations in Jamaican children. The participants in this study comprised 125 typically developing (TD) children (ages 2-8 years) who served as controls in an age- and sex-matched case-control study that enrolled children from 2009-2012 in Jamaica. We administered a questionnaire to assess demographic and socioeconomic information as well as potential exposures to lead through food. Using General Linear Models (GLMs), we identified factors associated with blood lead concentrations in Jamaican children. The geometric mean blood lead concentration (GMBLC) in the sample of children in this study was 2.80 µg dL(-1). In univariable GLM analyses, GMBLC was higher for children whose parents did not have education beyond high school compared to those whose parents had attained this level (3.00 µg dL(-1) vs. 2.31 µg dL(-1); P = 0.05), children living near a high traffic road compared to those who did not (3.43 µg dL(-1) vs. 2.52 µg dL(-1); P < 0.01), and children who reported eating ackee compared to those who did not eat this fruit (2.89 µg dL(-1) vs. 1.65 µg dL(-1); P < 0.05). In multivariable analysis, living near a high traffic road was identified as an independent risk factor for higher adjusted GMBLC (3.05 µg dL(-1) vs. 2.19 µg dL(-1); P = 0.01). While our findings indicate that GMBLC in Jamaican children has dropped by at least 62% during the past two decades, children living in Jamaica still have GMBLC that is twice that of children in more developed countries. In addition, we have identified significant risk factors for higher blood lead concentrations in Jamaican children. We believe increasing awareness among parents regarding these risk factors could potentially lead to a lower level of lead exposure in Jamaican children.

Blood manganese concentrations in Jamaican children with and without autism spectrum disorders.

BACKGROUND: Manganese is an essential element for human health and development. Previous studies have shown neurotoxic effects in children exposed to higher levels of manganese. Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impairs social interaction and communication. Several studies have hypothesized that ASD is caused through environmental exposures during crucial stages in brain development. We investigated the possible association between blood manganese concentrations (BMC) and ASD. We also identified factors associated with BMC in typically developing (TD) Jamaican children. METHODS: We used data from 109 ASD cases with their 1:1 age- and sex-matched TD controls to compare mean BMC in Jamaican children (2-8 years of age) with and without ASD. We administered a pre-tested questionnaire to assess demographic and socioeconomic information, medical history, and potential exposure to manganese. Finally, we collected 2 mL of whole blood from each child for analysis of manganese levels. Using General Linear Models (GLM), we assessed the association between BMC and ASD status. Furthermore, we used two independent sample t-tests to identify factors associated with BMC in TD children. RESULTS: In univariable GLM analysis, we found no significant association between BMC and ASD, (10.9 µg/L for cases vs. 10.5 µg/L for controls; P = 0.29). In a multivariable GLM adjusting for paternal age, parental education, place of child's birth (Kingston parish), consumption of root vegetables, cabbage, saltwater fish, and cakes/buns, there was still no significant association between BMC and ASD status, (11.5 µg/L for cases vs. 11.9 µg/L for controls; P = 0.48). Our findings also indicated TD children who ate fresh water fish had a higher BMC than children who did not (11.0 µg/L vs. 9.9 µg/L; P = 0.03) as younger TD children (i.e., 2 ≤ age ≤4), (12.0 µg/L vs. 10.2 µg/L; P = 0.01). CONCLUSIONS: While these results cannot be used to assess early exposure at potentially more susceptible time period, our findings suggest that there is no significant association between manganese exposures and ASD case status in Jamaica. Our findings also indicate that BMC in Jamaican children resemble those of children in the developed world and are much lower than those in the developing countries.

Metabolomic profiles in Jamaican children with and without autism spectrum disorder.

Background: Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a wide range of behavioral and cognitive impairments. While genetic and environmental factors are known to contribute to its etiology, the underlying metabolic perturbations associated with ASD which can potentially connect genetic and environmental factors, remain poorly understood. Therefore, we conducted a metabolomic case-control study and performed a comprehensive analysis to identify significant alterations in metabolite profiles between children with ASD and typically developing (TD) controls. Objective: To elucidate potential metabolomic signatures associated with ASD in children and identify specific metabolites that may serve as biomarkers for the disorder. Methods: We conducted metabolomic profiling on plasma samples from participants in the second phase of Epidemiological Research on Autism in Jamaica (ERAJ-2), which was a 1:1 age (±6 months)-and sex-matched cohort of 200 children with ASD and 200 TD controls (2-8 years old). Using high-throughput liquid chromatography-mass spectrometry techniques, we performed a targeted metabolite analysis, encompassing amino acids, lipids, carbohydrates, and other key metabolic compounds. After quality control and imputation of missing values, we performed univariable and multivariable analysis using normalized metabolites while adjusting for covariates, age, sex, socioeconomic status, and child's parish of birth. Results: Our findings revealed unique metabolic patterns in children with ASD for four metabolites compared to TD controls. Notably, three of these metabolites were fatty acids, including myristoleic acid, eicosatetraenoic acid, and octadecenoic acid. Additionally, the amino acid sarcosine exhibited a significant association with ASD. Conclusions: These findings highlight the role of metabolites in the etiology of ASD and suggest opportunities for the development of targeted interventions.

CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health-sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion. METHODS: All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. RESULTS: Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5-29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%-64%) complete and 2 of 20 (10%; 95% confidence interval, 1%-32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%-82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%-49) patients had a modified Rankin scale of 0 to 1. CONCLUSIONS: Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356.

The University of Texas Houston Stroke Registry (UTHSR): implementation of enhanced data quality assurance procedures improves data quality.

BACKGROUND: Limited information has been published regarding standard quality assurance (QA) procedures for stroke registries. We share our experience regarding the establishment of enhanced QA procedures for the University of Texas Houston Stroke Registry (UTHSR) and evaluate whether these QA procedures have improved data quality in UTHSR. METHODS: All 5093 patient records that were abstracted and entered in UTHSR, between January 1, 2008 and December 31, 2011, were considered in this study. We conducted reliability and validity studies. For reliability and validity of data captured by abstractors, a random subset of 30 records was used for re-abstraction of select key variables by two abstractors. These 30 records were re-abstracted by a team of experts that included a vascular neurologist clinician as the "gold standard". We assessed inter-rater reliability (IRR) between the two abstractors as well as validity of each abstractor with the "gold standard". Depending on the scale of variables, IRR was assessed with Kappa or intra-class correlations (ICC) using a 2-way, random effects ANOVA. For assessment of validity of data in UTHSR we re-abstracted another set of 85 patient records for which all discrepant entries were adjudicated by a vascular neurology fellow clinician and added to the set of our "gold standard". We assessed level of agreement between the registry data and the "gold standard" as well as sensitivity and specificity. We used logistic regression to compare error rates for different years to assess whether a significant improvement in data quality has been achieved during 2008-2011. RESULTS: The error rate dropped significantly, from 4.8% in 2008 to 2.2% in 2011 (P < 0.001). The two abstractors had an excellent IRR (Kappa or ICC ≥ 0.75) on almost all key variables checked. Agreement between data in UTHSR and the "gold standard" was excellent for almost all categorical and continuous variables. CONCLUSIONS: Establishment of a rigorous data quality assurance for our UTHSR has helped to improve the validity of data. We observed an excellent IRR between the two abstractors. We recommend training of chart abstractors and systematic assessment of IRR between abstractors and validity of the abstracted data in stroke registries.

Detoxification Role of Metabolic Glutathione S-Transferase (GST) Genes in Blood Lead Concentrations of Jamaican Children with and without Autism Spectrum Disorder.

Glutathione S-transferases (GST) are involved in the detoxification of exogenous chemicals including lead (Pb). Using data from 344 pairs of autism spectrum disorder (ASD) cases and age- and sex-matched typically developing (TD) controls (2−8 years old) from Jamaica, we investigated the interaction between three GST genes and ASD status as determinants of blood Pb concentrations (BPbCs). We found that ASD cases had lower geometric mean BPbCs than TD children (1.74 vs. 2.27 µg/dL, p < 0.01). Using a co-dominant genetic model, ASD cases with the Ile/Val genotype for the GSTP1 Ile105Val polymorphism had lower GM BPbCs than TD controls, after adjusting for a known interaction between GSTP1 and GSTT1, child's parish, socioeconomic status, consumption of lettuce, fried plantains, and canned fish (Ile/Val: 1.78 vs. 2.13 µg/dL, p = 0.03). Similarly, among carriers of the I/I or I/D (I*) genotype for GSTT1 and GSTM1, ASD cases had lower adjusted GM BPbCs than TD controls (GSTT1 I*: 1.61 vs. 1.91 µg/dL, p = 0.01; GSTM1 I*: 1.71 vs. 2.04 µg/dL, p = 0.01). Our findings suggest that genetic polymorphisms in GST genes may influence detoxification of Pb by the enzymes they encode in Jamaican children with and without ASD.

Interactions between Environmental Factors and Glutathione S-Transferase (GST) Genes with Respect to Detectable Blood Aluminum Concentrations in Jamaican Children.

Aluminum (Al) is a metallic toxicant at high concentrations following natural or unnatural exposures. Dietary intake is considered as the main source of aluminum exposure in children. We used data from 366 typically developing (TD) children (ages 2−8 years) who participated as controls in an age- and sex-matched case−control study in Jamaica. We investigated additive and interactive associations among environmental factors and children's genotypes for glutathione S-transferase (GST) genes (GSTT1, GSTM1, GSTP1), in relation to having a detectable blood aluminum concentration (BAlC) of >5.0 µg/L, using multivariable logistic regression models. Findings from interactive models revealed that the odds of having a detectable BAlC was significantly higher among children who ate string beans (p ≤ 0.01), whereas about 40% lower odds of having a detectable BAlC was observed in children with higher parental education level, (p = 0.02). A significant interaction between consumption of saltwater fish and GSTP1 in relation to having a detectable BAlC using either co-dominant or dominant genetic models (overall interaction p = 0.02 for both models) indicated that consumption of saltwater fish was associated with higher odds of having a detectable BAlC only among children with the GSTP1 Ile105Val Ile/Ile genotype using either co-dominant or dominant models [OR (95% CI) = 2.73 (1.07, 6.96), p = 0.04; and OR (95% CI) = 2.74 (1.08, 6.99), p = 0.03]. Since this is the first study from Jamaica that reports such findings, replication in other populations is warranted.

Younger age of stroke in low-middle income countries is related to healthcare access and quality.

Stroke is the second leading cause of mortality globally with higher burden and younger age in low-middle income countries (LMICs) than high-income countries (HICs). However, it is unclear to what extent differences in healthcare access and quality (HAQ) and prevalence of risk factors between LMICs and HICs contribute to younger age of stroke in LMICs. In this systematic review, we conducted meta-analysis of 67 articles and compared the mean age of stroke between LMICs and HICs, before and after adjusting for HAQ index. We also compared the prevalence of main stroke risk factors between HICs and LMICs. The unadjusted mean age of stroke in LMICs was significantly lower than HICs (63.1 vs. 68.6), regardless of gender (63.9 vs. 66.6 among men, and 65.6 vs. 70.7 among women) and whether data were collected in population- (64.7 vs. 69.5) or hospital-based (62.6 vs. 65.9) studies (all p < 0.01). However, after adjusting for HAQ index, the difference in the mean age of stroke between LMICs and HICs was not significant (p ≥ 0.10), except among women (p = 0.048). In addition, while the median prevalence of hypertension in LMICs was 23.4% higher than HICs, the prevalence of all other risk factors was lower in LMICs than HICs. Our findings suggest a much larger contribution of HAQ to the younger mean age of stroke in LMICs, as compared with other potential factors. Additional studies on stroke care quality and accessibility are needed in LMICs.

Additive and Interactive Associations of Environmental and Sociodemographic Factors with the Genotypes of Three Glutathione S-Transferase Genes in Relation to the Blood Arsenic Concentrations of Children in Jamaica.

Arsenic (As) is a metalloid that has been classified as a xenobiotic with toxic effects on human beings, especially on children. Since the soil in Jamaica contains As, dietary intake is considered the main source of As exposure in Jamaicans. In addition, glutathione S-transferase (GST) genes, including GSTT1, GSTP1, and GSTM1, play an important role in the metabolism of xenobiotics including As in humans. Using data from 375 typically developing children (2-8 years) in Jamaica, we investigated the environmental and sociodemographic factors, as well as their possible interactions with the children's genotype for GST genes in relation to having a detectable level of blood As concentration (i.e., >1.3 µg/L). Using multivariable logistic regression, we have identified environmental factors significantly associated with blood As concentrations that include a child's age, parental education levels, and the consumption of saltwater fish, cabbage, broad beans, and avocado (all p < 0.01). Based on the multivariable analysis including gene x environment interactions, we found that among children with the Ile/Ile genotype for GSTP1 Ile105Val, children who consumed avocado had higher odds of having a detectable blood As concentration compared to children who did not eat avocado.

Additive or Interactive Associations of Food Allergies with Glutathione S-Transferase Genes in Relation to ASD and ASD Severity in Jamaican Children.

To investigate additive and interactive associations of food allergies with three glutathione S-transferase (GST) genes in relation to ASD and ASD severity in Jamaican children. Using data from 344 1:1 age- and sex-matched ASD cases and typically developing controls, we assessed additive and interactive associations of food allergies with polymorphisms in GST genes (GSTM1, GSTP1 and GSTT1) in relation to ASD by applying conditional logistic regression models, and in relation to ASD severity in ASD cases as measured by the Autism Diagnostic Observation Schedule-2nd Edition (ADOS-2) total and domains specific comparison scores (CSs) by fitting general linear models. Although food allergies and GST genes were not associated with ASD, ASD cases allergic to non-dairy food had higher mean ADOS-2 Restricted and Repetitive Behaviors (RRB) CS (8.8 vs. 8.0, P = 0.04). In addition, allergy to dairy was associated with higher mean RRB CS only among ASD cases with GSTT1 DD genotype (9.9 vs. 7.8, P < 0.01, interaction P = 0.01), and GSTP1 Val/Val genotype under a recessive genetic model (9.8 vs. 7.8, P = 0.02, interaction P = 0.06). Our findings are consistent with the role for GST genes in ASD and food allergies, though require replication in other populations.

Associations of Metabolic Genes (GSTT1, GSTP1, GSTM1) and Blood Mercury Concentrations Differ in Jamaican Children with and without Autism Spectrum Disorder.

We investigated interactive roles of three metabolic glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1) and autism spectrum disorder (ASD) status in relation to blood Hg concentrations (BHC) of Jamaican children. We used data from 266 children (2-8 years) with ASD and their 1:1 age- and sex-matched typically developing (TD) controls. After adjusting General Linear Models for child's age, socioeconomic status, consumption of leafy vegetables, fried plantain, canned fish, and the interaction between GSTP1 and GSTT1, we found significant interactions between GSTP1 and ASD status in relation to BHC either in a co-dominant or dominant genetic model for GSTP1(P < 0.001, P = 0.007, respectively). In the co-dominant model for the Ile105Val GSTP1 polymorphism, geometric mean (GM) BHC in ASD cases with genotype Ile/Ile were significantly higher than in cases with the Ile/Val genotype (0.73 vs. 0.48 µg/L, P = 0.01). In contrast, in TD controls with the Ile/Val genotype GM BHC were significantly higher than in those with the Ile/Ile genotype (0.72 vs. 0.49 µg/L, P = 0.03) or the Val/Val genotype (0.72 vs. 0.51 µg/L, P = 0.04). Although our findings are consistent with the role of GSTP1 in detoxification of Hg, replication in other populations is warranted.

Interaction of Blood Manganese Concentrations with GSTT1 in Relation to Autism Spectrum Disorder in Jamaican Children.

Using data from 266 age- and sex-matched pairs of Jamaican children with autism spectrum disorder (ASD) and typically developing (TD) controls (2-8 years), we investigated whether glutathione S-transferase theta 1 (GSTT1) modifies the association between blood manganese concentrations (BMC) and ASD. After adjusting conditional logistic regression models for socioeconomic status and the interaction between GSTT1 and GSTP1 (glutathione S-transferase pi 1), using a recessive genetic model for GSTT1 and either a co-dominant or dominant model for GSTP1, the interaction between GSTT1 and BMC was significant (P = 0.02, P = 0.01, respectively). Compared to controls, ASD cases with GSTT1-DD genotype had 4.33 and 4.34 times higher odds of BMC > 12 vs. ≤ 8.3 µg/L, respectively. Replication in other populations is warranted.

Concentrations of Lead, Mercury, Arsenic, Cadmium, Manganese, and Aluminum in the Blood of Pakistani Children with and without Autism Spectrum Disorder and Their Associated Factors.

BACKGROUND: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder with early onset in utero or childhood. Environmental exposure to six metals (Pb, Hg, As, Cd, Mn, Al) is believed to be associated with ASD directly or interactively with genes. Objective: To assess the association of ASD among Pakistani children with the six metals and genotype frequencies of three GST genes (GSTP1, GSTM1, GSTT1). METHODS: We enrolled 30 ASD cases, age 2-12 years old, and 30 age- and sex-matched typically developing (TD) controls in Karachi, Pakistan. We assessed associations of ASD status with various factors using Conditional Logistic Regression models. We also used General Linear Models to assess possible interaction of blood Mn and Pb concentrations with the three GST genes in relation to ASD status. RESULTS: The unadjusted difference between ASD and TD groups in terms of geometric mean blood Pb concentrations was marginally significant (p = 0.05), but for Al concentrations, the adjusted difference was marginally significant (p = 0.06). CONCLUSIONS: This is the first study reporting six blood metal concentrations of Pakistani children with ASD. Estimates provided for possible interactions of GST genes with Mn and Pb in relation to ASD status are valuable for designing future similar studies.