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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.

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.

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.

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.

Soon after commencement of the SARS-CoV-2 disease outbreak of 2019 (COVID-19), it became evident that the receptor-binding domain of the viral spike protein is the target of neutralizing antibodies that comprise a critical element of protective immunity to the virus. This study addresses the relative lack of information regarding actual antibody concentrations in convalescent plasma samples from COVID-19 patients and extends these analyses to post-vaccination samples to estimate protective IgG antibody (Ab) levels. Both sample populations were similar and a protective Ab level of 7.5 µg/ml was determined, based on 95% of the normal distribution of the post-vaccination population. The results of this study have implications for future vaccine development, projection of protective efficacy duration, and understanding of the immune response to SARS-CoV-2 infection.One-Sentence SummaryUsing two quantitative immunoassays, we have found similar IgG antibody responses to the SARS-CoV-2 spike protein in populations of COVID-19 survivors and vaccine recipients that indicate a protective antibody concentration.

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 P = 0.02). We found a significant interaction (P 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.

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 (r(Spearman)= 0.45; P = 0.04) and Mn (r(Pearson) = 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, r(Spearman)= 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.

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.

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.

Mode of delivery, preterm birth, and low birth weight (LBW) are hypothesized to be associated with Autism Spectrum Disorder (ASD) in the offspring. Using data from 343 ASD cases (2–8 years) and their age- and sex-matched typically developing controls in Jamaica we investigated these hypotheses. Our statistical analyses revealed that the parish of residence could modify the association between cesarean delivery and ASD, with a difference found in this relationship in Kingston parish [matched odds ratio (MOR) (95% confidence interval (CI)): 2.30 (1.17–4.53)] and other parishes [MOR (95% CI): 0.87 (0.48–1.59)]. Although the associations of LBW and preterm birth with ASD were not significant, we observed a significant interaction between LBW and the household socioeconomic status. These findings require replication.

Background An inadequate level of general knowledge of physicians regarding mental health, including Autism Spectrum Disorder (ASD) not only could have adverse effects on affected individuals’ health and quality of life, but also could further delay its diagnosis and initiation of timely interventions. The purpose of this survey was to assess the level of knowledge, attitudes, and practices (KAP) of physicians regarding ASD in Romania and identify their associated factors. Methods For conducting this cross-sectional survey, investigators in the US collaborated with faculty at “Carol Davila” University of Medicine and Pharmacy (UMF) and developed a questionnaire by modifying similar questionnaires used in Pakistan and Turkey, to assess KAP of physicians and specialists regarding ASD in Romania. The Questionnaire was administered to a convenient sample of 383 practicing physicians or specialists. Exploratory Factor Analysis on 12 variables revealed five composite sub-scores: stigma, potential causes, children’s behavior, misconceptions, and educational needs associated with ASD knowledge. We determined the variables associated additively or interactively with KAP regarding ASD by applying General Linear Models to the five sub-scores as dependent variables. Results Approximately 75% of the responding physicians were female and more than 80% were over the age of 30 years. The majority (73%-94%) of physicians in Romania have correctly responded to some basic questions regarding knowledge about ASD. We also found that younger physicians (age P = 0.04, adjusted for the “type of medical school attended” and “city where the clinic is located”), while older physicians knew more about the behavior of children with ASD (P = 0.02). We found a significant interaction between source of ASD knowledge and (city where the clinic is located) in relation to knowledge of the physicians’ regarding stigma related to ASD. There were no significant interactions in relation to the physician’s knowledge of behaviors of children with ASD. Conclusion Though Romanian physicians are knowledgeable about ASD, greater attention is needed on symptoms, causes, and awareness of stigma and misconceptions surrounding ASD.

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 &lt, 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.

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.

BACKGROUND: Exposure to many environmental chemicals, including metals, often does not occur in isolation, hence requires assessment of the associations between exposure to mixtures of chemicals and human health. OBJECTIVES: To investigate associations of a metal mixture of lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) in children with autism spectrum disorder (ASD), additively or interactively with each of three glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1). METHOD: Using data from 266 case-control pairs of Jamaican children (2–8 years old), we fitted negative and positive generalized weighted quantile sum (gWQS) regression models to assess the aforementioned associations. RESULTS: Based on additive and interactive negative gWQS models adjusted for maternal age, parental education, child’s parish, and seafood consumption, we found inverse associations of the overall mixture score with ASD [MOR (95% CI): 0.70 (0.49, 0.99); P < 0.05) and [MOR (95%CI): 0.46 (0.25, 0.84); P = 0.01], respectively. In an unadjusted negative gWQS model, we found a marginally significant interaction between GSTP1 and a mixture of three metals (Pb, Hg, and Mn) (P = 0.07) while the association was no longer significant after adjustment for the same covariates (P = 0.24). CONCLUSIONS: Differences in diet between ASD and control groups may play a role in the inverse associations we found. The possible interactive association between Mn and GSTP1 in ASD based on gWQS is consistent with our previous reports. However, possible interaction of GSTP1 with Pb and Hg in ASD requires further investigation and replication.

Ankylosing spondylitis (AS) is characterized by inflammation of the spine and sacroiliac joints causing pain and stiffness and, in some patients, ultimately new bone formation, and progressive joint ankyloses. The classical definition of AS is based on the modified New York (mNY) criteria. Limited data have been reported regarding data quality assurance procedure for multicenter or multisite prospective cohort of patients with AS. Since 2002, 1272 qualified AS patients have been enrolled from five sites (4 US sites and 1 Australian site) in the Prospective Study Of Ankylosing Spondylitis (PSOAS). In 2012, a Data Management and Statistical Core (DMSC) was added to the PSOAS team to assist in study design, establish a systematic approach to data management and data quality, and develop and apply appropriate statistical analysis of data. With assistance from the PSOAS investigators, DMSC modified Case Report Forms and developed database in Research Electronic Data Capture (REDCap). DMSC also developed additional data quality assurance procedure to assure data quality. The error rate for various forms in PSOAS databases ranged from 0.07% for medications data to 1.1% for arthritis activity questionnaire-Global pain. Furthermore, based on data from a sub study of 48 patients with AS, we showed a strong level (90.0%) of agreement between the two readers of X-rays with respect to modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). This paper not only could serve as reference for future publications from PSOAS cohort but also could serve as a basic guide to ensuring data quality for multicenter clinical studies. Keywords: Ankylosing spondylitis, Data quality, Harmonization, PSOAS cohort, Reliability of data

Environmental exposure to lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) has been associated with neurodevelopmental disorders including autism spectrum disorder (ASD). We conducted a pilot study during May 2015&ndash, May 2107 to estimate blood concentrations of six metals (Pb, Hg, As, Cd, Mn, and Al) and identify their associated factors for children with ASD or suspected of having ASD in Romania. Sixty children, age 2&ndash, 8 years, were administered versions of ADOS or ADI-R translated from English to Romanian. After assessment, 2&ndash, 3 mL of blood was obtained and analyzed for the concentrations of the six metals. The mean age of children was 51.9 months and about 90% were male. More than half (65%) of the children were born in Bucharest. Over 90% of concentrations of As and Cd were below limits of detection. Geometric mean concentrations of Pb, Mn, Al, and Hg were 1.14 &mu, g/dL, 10.84 &mu, g/L, 14.44 &mu, g/L, and 0.35 &mu, g/L, respectively. Multivariable linear regression analysis revealed that children who were female, had less educated parents, exhibited pica, and ate cold breakfast (e.g., cereal), watermelon, and lamb had significantly higher concentrations of Pb compared to their respective referent categories (all p &lt, 0.05 except for eating lamb, which was marginally significant, p = 0.053). Although this is the first study that provides data on concentrations of the six metals for Romanian children with ASD, the findings from this study could be useful for designing future epidemiologic studies for investigating the role of these six metals in ASD in Romanian children.

Background Exposure to many environmental chemicals, including metals, often does not occur in isolation, hence requires assessment of the associations between exposure to mixtures of chemicals and human health. Objectives To investigate associations of a metal mixture of lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) in children with autism spectrum disorder (ASD), additively or interactively with each of three glutathione S-transferase (GST) genes (GSTP1, GSTT1, and GSTM1). Method Using data from 266 case-control pairs of Jamaican children (2–8 years old), we fitted negative and positive generalized weighted quantile sum (gWQS) regression models to assess the aforementioned associations. Results Based on additive and interactive negative gWQS models adjusted for maternal age, parental education, child’s parish, and seafood consumption, we found inverse associations of the overall mixture score with ASD [MOR (95 % CI) = 0.70 (0.49, 0.99); P Conclusions Differences in diet between ASD and control groups may play a role in the inverse associations we found. The possible interactive association between Mn and GSTP1 in ASD based on gWQS is consistent with our previous reports. However, possible interaction of GSTP1 with Pb and Hg in ASD requires further investigation and replication.

IntroductionThis randomized controlled trial investigated community-clinical intervention strategies for a Mexican American population who had not demonstrated control of their diabetes. We tested a control program (Salud y Vida 1.0) supporting diabetes management versus an enhanced version (Salud y Vida 2.0) for reductions in HbA1c at 12 months.Research design and methodsAdults with uncontrolled diabetes (n=353) were enrolled if they had an HbA1c≥9.0% during a program or doctor’s visit between 6 and 36 months of their receipt of SyV 1.0 services, were patients at one of two clinics in local counties, and had an HbA1c≥8.0% at SyV 2.0 baseline enrollment. The control and intervention arms were coordinated by community health workers and the intervention arm included the control program enhanced with medication therapy management; behavioral health services; peer-led support groups; and additional community-based lifestyle programs also open to the family.ResultsAt 12 months, both study arms improved HbA1c (mean, (CI), Control (−0.47 (-0.74 to –0.20)) and intervention (−0.48 (-0.76 to –0.19)). The intervention group maintained HbA1c levels after month 6, whereas control group HbA1c levels slightly increased (adjusted mean from 9.83% at month 6%–9.90% at month 12). Also, HbA1c was examined by level of participant engagement. The high engagement group showed a decreasing trend over the study period, while control and lower engagement groups failed to maintain HbA1c levels at month 12.ConclusionsImproved HbA1c was found among a population that had not demonstrated diabetes management prior; however, mean HbA1c values were above clinical guideline recommendations. The randomized control trial findings provide additional evidence that extended time and intervention supports may be needed for populations experiencing inequities in social determinants of health.Trial registration numberNCT04035395.

BACKGROUND: We previously reported a significant interactive association between polymorphisms of GSTP1 and blood manganese concentrations (BMC) with autism spectrum disorder (ASD) in Jamaican children. In this paper, we investigate the same interactive association with ASD while adjusting for the mixture of four metals (lead, mercury, cadmium, and arsenic). METHOD: We used data from 163 case-control pairs of children 2–8 years of age from our autism project in Jamaica, in which we collected blood for heavy metals analysis at enrollment. To minimize potential multicollinearity between concentrations of the four metals, we generated a mixture index using generalized weighted quantile sum regression, which was used in conditional logistic regression models to control for the four metals while assessing the interactive association between GSTP1 and BMC with ASD. RESULTS: Similar to the findings we reported previously, we found that in co-dominant and dominant models for GSTP1, among children with the Ile/Ile genotype, those with BMC > 12μg/L had 4.6 and 4.27 times higher odds of ASD compared to those with BMC < 12μg/L (adjusted Matched Odds Ratio (MOR) = 4.6, 95% CI: 1.21 – 17.42 and adjusted MOR = 4.27, 95% CI: 1.15 – 15.85, respectively). In the co-dominant model, for children with the Ile/Val and Val/Val genotypes, the adjusted MORs were 1.26 (95% CI: 0.32, 5.01) and 0.26 (95% CI: 0.05, 1.42), respectively. CONCLUSIONS: After adjusting for the mixture of four metals, the interactive association of BMC and GSTP1 with ASD remained significant with similar magnitude of associations. Results should be interpreted cautiously.

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.

Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder with poorly understood etiology. Many maternal exposures during pregnancy and breastfeeding potentially interfere with neurodevelopment. Using data from two age- and sex-matched case-control studies in Jamaica (n = 298 pairs), results of conditional logistic regression analyses suggest that maternal exposures to fever or infection (matched odds ratio (MOR) = 3.12, 95% CI: 1.74 – 5.60), physical trauma (MOR = 2.02, 95% CI: 1.01 – 4.05), and oil-based paints (MOR = 1.99, 95% CI: 1.14 – 3.46) may be associated with ASD. Additionally, maternal exposure to oil-based paints may modify the relationship between maternal exposure to pesticides and ASD, which deepens our understanding of the association between pesticides and ASD.

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.

Background We describe innovations in the study design and the efficient data coordination of a randomized multicenter trial of Argatroban in Combination with Recombinant Tissue Plasminogen Activator for Acute Stroke (ARTSS-2). Methods ARTSS-2 is a 3-arm, multisite/multiregional randomized controlled trials (RCTs) of two doses of Argatroban injection (low, high) in combination with recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke patients and rt-PA alone. We developed a covariate adaptive randomization program that balanced the study arms with respect to study site as well as hemorrhage after thrombolysis (HAT) score and presence of distal internal carotid artery occlusion (DICAO). We used simulation studies to validate performance of the randomization program before making any adaptations during the trial. For the first 90 patients enrolled in ARTSS-2, we evaluated performance of our randomization program using chi-square tests of homogeneity or extended Fisher's exact test. We also designed a four-step partly Bayesian safety stopping rule for low and high dose Argatroban arms. Results Homogeneity of the study arms was confirmed with respect to distribution of study site (UK sites vs. US sites, P = 0.98), HAT score (0–2 vs. 3–5, P = 1.0), and DICAO (N/A vs. No vs. Yes, P = 0.97). Our stopping thresholds for safety of low and high dose Argatroban were not crossed. Despite challenges, data quality was assured. Conclusions We recommend adaptive designs for randomization and Bayesian safety stopping rules for multisite Phase I/II RCTs for maintaining additional flexibility. Efficient data coordination could lead to improved data quality.

The objective of this study was to characterize the concentrations of lead, mercury, cadmium, aluminum, and manganese in umbilical cord blood of Jamaican newborns and to explore the possible association between concentrations of these elements and certain birth outcomes. Based on data from 100 pregnant mothers and their 100 newborns who were enrolled from Jamaica in 2011, the arithmetic mean (standard deviation) concentrations of cord blood lead, mercury, aluminum, and manganese were 0.8 (1.3 μg/dL), 4.4 (2.4 μg/L), 10.9 (9.2 μg/L), and 43.7 (17.7 μg/L), respectively. In univariable General Linear Models, the geometric mean cord blood aluminum concentration was higher for children whose mothers had completed their education up to high school compared to those whose mothers had any education beyond high school (12.2 μg/L vs. 6.4 μg/L, p &lt, 0.01). After controlling for maternal education level and socio-economic status (through ownership of a family car), the cord blood lead concentration was significantly associated with head circumference (adjusted p &lt, 0.01). Our results not only provide levels of arsenic and the aforementioned metals in cord blood that could serve as a reference for the Jamaican population, but also replicate previously reported significant associations between cord blood lead concentrations and head circumference at birth in other populations.

We investigated the role of glutathione S-transferase (GST) genes in Autism Spectrum Disorder (ASD). We used data from 111 pairs of age- and sex-matched ASD cases and typically developing (TD) controls between 2-8 years of age from Jamaica to investigate the role of GST pi 1 (GSTP1), GST theta 1 (GSTT1), and GST mu 1 (GSTM1) polymorphisms in susceptibility to ASD. In univariable conditional logistic regression models we did not observe significant associations between ASD status and GSTT1, GSTM1, or GSTP1 genotype (all P > 0.15). However, in multivariable conditional logistic regression models, we identified a significant interaction between GSTP1 and GSTT1 in relation to ASD. Specifically, in children heterozygous for the GSTP1 Ile105Val polymorphism, the odds of ASD was significantly higher in those with the null GSTT1 genotype than those with the other genotypes [Matched Odds Ratio (MOR) = 2.97, 95% CI (1.09, 8.01), P = 0.03]. Replication in other populations is warranted.

Environmental exposure to organic endocrine disrupting chemicals, including dioxins, dibenzofurans, bisphenol A (BPA), and phthalates has been associated with neurodevelopmental disorders, including autism spectrum disorder (ASD). We conducted a pilot monitoring study of 30 ASD cases and 10 typically developing (TD) controls ages 2–8 years from communities along the Gulf of Mexico near Alabama, which houses 14 Superfund sites, to assess the concentrations of dioxins and dibenzofurans in serum, and BPA and phthalate ester metabolites in urine. Based on General Linear Models, the lipid- or creatinine-adjusted geometric mean concentrations of the aforementioned chemicals did not differ between the ASD case and TD control groups (all p ≥ 0.27). We compared our findings to the adjusted means as reported by the National Health and Nutrition Examination Survey, survey years 2011–2012, and found that TD controls in our study had lower BPA (59%) and MEHHP (26%) concentrations, higher MBP (50%) concentration, and comparable (

The administration requirements of the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview–Revised, widely used in high-income countries, make them less feasible for diagnosis of autism spectrum disorder in low- and middle-income countries. The flexible administration requirements of the Childhood Autism Rating Scale have resulted in its use in both high-income countries and low- and middle-income countries. This study examines the agreement between assessments using the Childhood Autism Rating Scale with those using the Autism Diagnostic Observation Schedule or Autism Diagnostic Observation Schedule, Second Edition and Autism Diagnostic Interview–Revised in Jamaica. Children aged 2–8 years (n = 149) diagnosed with autism by an experienced clinician using the Childhood Autism Rating Scale were re-evaluated using the Autism Diagnostic Observation Schedule and Autism Diagnostic Interview–Revised. The proportion diagnosed with autism spectrum disorder using the Autism Diagnostic Observation Schedule, Autism Diagnostic Observation Schedule, Second Edition, and Autism Diagnostic Interview–Revised was determined and mean domain scores compared using analysis of variance (ANOVA). The mean age was 64.4 (standard deviation = 21.6) months; the male:female ratio was 6:1. The diagnostic agreement of the Childhood Autism Rating Scale with the Autism Diagnostic Observation Schedule and Autism Diagnostic Observation Schedule, Second Edition was 100.0% and 98.0%, respectively. Agreement with the Autism Diagnostic Interview–Revised was 94.6%. Domain scores were highest for children with more severe symptoms (p

© 2016 by the Association of American Medical Colleges. Purpose To learn the size, composition, and scholarly output of biostatistics, epidemiology, and research design (BERD) units in U.S. academic health centers (AHCs). Method Each year for four years, the authors surveyed all BERD units in U.S. AHCs that were members of the Clinical and Translational Science Award (CTSA) Consortium. In 2010, 46 BERD units were surveyed; in 2011, 55; in 2012, 60; and in 2013, 61. Results Response rates to the 2010, 2011, 2012, and 2013 surveys were 93.5%, 98.2%, 98.3%, and 86.9%, respectively. Overall, the size of BERD units ranged from 3 to 86 individuals. The median FTE in BERD units remained similar and ranged from 3.0 to 3.5 FTEs over the years. BERD units reported more availability of doctoral-level biostatisticians than doctoral-level epidemiologists. In 2011, 2012, and 2013, more than a third of BERD units provided consulting support on 101 to 200 projects. A majority of BERD units reported that between 25% and 75% (in 2011) and 31% to 70% (in 2012) of their consulting was to junior investigators. More than two-thirds of BERD units reported their contributions to the submission of 20 or more non-BERD grant or contract applications annually. Nearly half of BERD units reported 1 to 10 manuscripts submitted annually with a BERD practitioner as the first or corresponding author. Conclusions The findings regarding BERD units provide a benchmark against which to compare BERD resources and may be particularly useful for institutions planning to develop new units to support programs such as the CTSA.

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 ( 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 .

Aluminum is a neurotoxic metal with known health effects in animals and humans. Glutathione-S-transferase (GST) genes and enzymes play a major role in detoxification of several heavy metals. Besides a direct relationship with oxidative stress; aluminum decreases GST enzyme activities. Using data from 116 Jamaican children; age 2–8 years; with Autism Spectrum Disorder (ASD) and 116 sex- and age-matched typically developing (TD) children; we investigated the association of polymorphisms in three GST genes (GSTP1; GSTM1; and GSTT1) with mean blood aluminum concentrations in children with and without ASD. Using log-transformed blood aluminum concentration as the dependent variable in a linear regression model; we assessed the additive and interactive effects of ASD status and polymorphisms in the three aforementioned GST genes in relation to blood aluminum concentrations. Although none of the additive effects were statistically significant (all p > 0.16); we observed a marginally significant interaction between GSTP1 Ile105Val (rs1695) and ASD status (p = 0.07); even after controlling for parental education level and consumption of avocado; root vegetables; and tuna (canned fish). Our findings indicate a significantly lower (p < 0.03) adjusted geometric mean blood aluminum concentration for TD children who had the Val/Val genotype (14.57 µg/L); compared with those with Ile/Ile or Ile/Val genotypes who had an adjusted geometric mean of 23.75 µg/L. However; this difference was not statistically significant among the ASD cases (p = 0.76). Our findings indicate that ASD status may be a potential effect modifier when assessing the association between GSTP1 rs1695 and blood aluminum concentrations among Jamaican children. These findings require replication in other populations.

We used data from 100 age- and sex-matched case-control pairs (age 2-8 years) from Jamaica to investigate whether there is an interaction between glutathione-S-transferase (GST) genes and blood manganese concentrations (BMC) in relation to Autism Spectrum Disorder (ASD). Our findings, indicate that among children who had the Ile/Ile genotype for GST pi 1 (GSTP1), those with BMC ≥ 12µg/L had about 4 times higher odds of ASD than those with BMC < 12µg/L, (P=0.03) under a co-dominant genetic model. After adjusting for potential confounders, among the subgroup of children with genotype Ile/Ile, those with BMC ≥ 12µg/L had about six times higher odds of ASD than those with BMC < 12µg/L, (P=0.04). The results were similar when a recessive genetic model was used. These findings suggest a possible synergic effect of BMC and GSTP1 in ASD. Since our analysis included a variety of genetic models and was not adjusted for multiple testing, replication in other populations is warranted.

We investigated the role of glutathione S-transferase (GST) genes in Autism Spectrum Disorder (ASD). We used data from 111 pairs of age- and sex-matched ASD cases and typically developing (TD) controls between 2–8 years of age from Jamaica to investigate the role of GST pi 1 (GSTP1), GST theta 1 (GSTT1), and GST mu 1 (GSTM1) polymorphisms in susceptibility to ASD. In univariable conditional logistic regression models we did not observe significant associations between ASD status and GSTT1, GSTM1, or GSTP1 genotype (all P > 0.15). However, in multivariable conditional logistic regression models, we identified a significant interaction between GSTP1 and GSTT1 in relation to ASD. Specifically, in children heterozygous for the GSTP1 Ile105Val polymorphism, the odds of ASD was significantly higher in those with the null GSTT1 genotype than those with the other genotypes [Matched Odds Ratio (MOR) = 2.97, 95% CI (1.09, 8.01), P = 0.03]. Replication in other populations is warranted.

To investigate recruitment, retention, and estimates for effects of formula supplementation with Lactobacillus rhamnosus GG (LGG) on inflammatory biomarkers and fecal microbial community in infants with colic.A prospective, double-blind, placebo-controlled trial was conducted in otherwise healthy infants with colic. We screened 74 infants and randomized and analyzed results in 20 infants [9 receiving LGG (LGG+) and 11 not receiving LGG (LGG-)]. LGG was incorporated in the formula (Nutramigen(®)) (minimum of 3 × 10(7) CFU/d) in the LGG+ group. Fecal microbiota and inflammatory biomarkers, including fecal calprotectin (FC), plasma cytokines, circulating regulatory T cells (Tregs), and crying + fussing time were analyzed to determine optimal time points and effect sizes for a larger trial.Recruitment in this population was slow, with about 66% of eligible infants willing to enroll; subject retention was better (75%). These rates were influenced by parents' reluctance to volunteer their infant for a clinical trial and by their tendency to change formulas. The maximal difference of crying + fussing time was observed at day 14, comparing the 2 groups, with a mean difference of -91 (95%CI: -76, 259) min (P = NS). FC showed no significant difference, but the optimal time to determine a potential effect was at day 90 [with a mean difference of 121 (95%CI: -48, 291) μg/g stool], observing a lower level of FC in the LGG+ group. The fecal microbial communities were chaotic, as determined by Shannon's diversity index and not apparently influenced by the probiotic. No significant change was observed in plasma inflammatory cytokines or Tregs, comparing LGG+ to LGG- groups.Designing future colic trials involving a probiotic-supplemented formula for infants in the United States will require consideration for difficult enrollment. Infants with colic have major variations in feal microbiota and calprotectin, both of which improve with time, with optimal time points for measurement at days 14 and 90 after treatment.

Autism Spectrum Disorder ( ASD ) and Attention Deficit Hyperactivity Disorder (ADHD ) are neuro-devolepmental disorders which prevalence are increasing rapidly all over the world and in our country in recent years. Both disorders diagnosed at an early stage in the case of children studying in the same environment with their peers and have the opportunity to participate in social life. Primary health care services are most appropriate places to identify the children at high risk and follow-up them. Family physician to be equipped in this neurodevelopmental disorders and should refer them. This study aims to determine The Family Physician Resident’s Knowledge and Attitudes of Autism Spectrum Disorder and Attention Deficit Hyperactivity Disorders. The survey form have three part; (1) AHAs Information Form, (2) AHAs OSB Knowledge and Attitudes Scale ( Rahbar ) and ( 3) AHAs ADHD Knowledge and Attitudes Scale ( Ghanizadeh ) . OSB scale consisting of fifteen five-point Likert questions and ADHD scale consist binary twenty items. Volunaty 313 Family Medicine Resident participate the study form nine cities in Turkey. Descriptive statistics has made with Statistical Package for Social Sciences (SPSS) 21.0 software. A statistically significant result regarding gender, age and the period since graduation from medical faculty was found between the knowledge and attitude level about ADHD/ASD. A statistically significant difference in ASD knowledge levels was found between genders (0.04) has been found. The mean score for knowledge levels of female FMRs (6,4) was higher than that of male FMRs (5,5). When the relation between the ages and ASD knowledge levels of FMRs was examined, the statistically significant difference (0.03) between FMRs at 26 years of age and less and 35 years of age and over indicates that the ASD knowledge levels of FMRs at 35 years of age and over is lower. When the period since graduation from medical faculty of FMRs examined, a statistically (P-value 0.09) significant difference ADHD knowledge and attitudes between the earliest graduates (49+ months) with graduated 13-48 months ago. It is suggested that an interdisciplinary approach should be adopted, child developers with a bachelor’s degree should be appointed at FMCs and policy makers should attach priority to this topic.