Manouchehr Hessabi

Concentration of Lead, Mercury, Cadmium, Aluminum, Arsenic and Manganese in Umbilical Cord Blood of Jamaican Newborns

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 < 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 < 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.

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.

Methodological issues for designing and conducting a multicenter, international clinical trial in Acute Stroke: Experience from ARTSS-2 trial

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 Fishers 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.

Maternal Exposures Associated with Autism Spectrum Disorder in Jamaican Children

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.

The Diagnosis of Autism and Autism Spectrum Disorder in Low- and Middle-Income Countries: Experience from Jamaica.

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 < 0.01). Despite a high level of agreement of the Childhood Autism Rating Scale with the Autism Diagnostic Observation Schedule, Autism Diagnostic Observation Schedule, Second Edition, and Autism Diagnostic Interview–Revised, the Childhood Autism Rating Scale should be evaluated further with a broader range of autism spectrum disorder symptomatology, and by clinicians with varying experience before recommendation for use in low- and middle-income countries.

Concentrations of Polychlorinated Biphenyls and Organochlorine Pesticides in Umbilical Cord Blood Serum of Newborns in Kingston, Jamaica

To date much of the biomonitoring related to exposure to polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides is from middle to high income countries, including the U.S., Canada and Europe, but such data are lacking for the majority of low to middle income countries. Using data from 64 pregnant mothers who were enrolled in 2011, we aimed to assess the concentrations of the aforementioned toxins in umbilical cord blood serum of 67 Jamaican newborns. For 97 of the 100 PCB congeners and 16 of the 17 OC pesticides, all (100%) concentrations were below their respective limits of detection (LOD). Mean (standard deviation (SD)) lipid-adjusted concentrations in cord blood serum for congeners PCB-153, PCB-180, PCB-206 and total PCB were 14.25 (3.21), 7.16 (1.71), 7.30 (1.74) and 28.15 (6.03) ng/g-lipid, respectively. The means (SD) for the 4,4′-dichlorodiphenyldichloroethylene (DDE)-hexane fraction and total-DDE were 61.61 (70.78) and 61.60 (70.76) ng/g-lipid, respectively. Compared to the U.S. and Canada, the concentrations of these toxins were lower in cord-blood serum of Jamaican newborns. We discuss that these differences could be partly due to differences in dietary patterns in these countries. Despite limitations in our dataset, our results provide information on the investigated toxins in cord blood serum that could serve as a reference for Jamaican newborns.

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.

Interaction between manganese and GSTP1 in relation to autism spectrum disorder while controlling for exposure to mixture of lead, mercury, arsenic, and cadmium

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.

Harmonization, data management, and statistical issues related to prospective multicenter studies in Ankylosing spondylitis (AS): Experience from the Prospective Study Of Ankylosing Spondylitis (PSOAS) cohort

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.

Environmental Exposure to Dioxins, Dibenzofurans, Bisphenol A, and Phthalates in Children with and without Autism Spectrum Disorder Living near the Gulf of Mexico

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 (<20% difference) MEP, MBZP, MEOHP, and MCPP concentrations. We also conducted a preliminary investigation of dietary exposures and found that the consumption of certain types of fish may be associated with higher OCDD concentrations, and the consumption of soft drinks and juices may be associated with lower BPA and MEOHP concentrations, respectively.