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Economical production of lignin-based jet fuel (LJF) can improve the sustainability of sustainable aviation fuels (SAFs) as well as can reduce the overall greenhouse gas emissions. However, the challenge lies in converting technical lignin polymer from biorefinery directly to jet fuel in a continuous operation. In this work, we demonstrate a simultaneous depolymerization and hydrodeoxygenation (SDHDO) process to produce lignin-based jet fuel from the alkali corn stover lignin (ACSL) using engineered Ru-HY-60-MI catalyst in a continuous flow reactor, for the first time. The maximum carbon yield of LJF of 17.9 wt% was obtained, and it comprised of 60.2 wt% monocycloalkanes, and 21.6 wt% polycycloalkanes. Catalyst characterization of Ru-HY-60-MI suggested there was no significant change in HY zeolite structure and its crystallinity after catalyst engineering. Catalyst characterizations performed post the SDHDO experiments indicate presence of carbon and K content in the catalyst. K content presence in the spent catalyst was due to K+ ion was exchanged between lignin solution and HY-60 while carbon presence validated the SDHDO chemistry on the catalyst surface. Tier α fuel property testing indicates that LJF production using SDHDO chemistry can produce SAF with high compatibility, good sealing properties, low emissions, and high energy density for aircraft.

The dielectric constant of aviation turbine fuel is leveraged by aircraft fuel quantity indicator systems (FQISs) using the Clausius–Mossotti relation, which assumes no significant dipole moments. For fossil-derived jet fuel containing relatively consistent fractions of polar aromatic molecules, this is appropriate. However, the interest in sustainable aviation fuels (SAFs) to reduce the carbon intensity of commercial aviation has brought attention to the uncertainty of the FQISs’ compatibility for low- or zero-aromatic fuels exhibiting dielectric constant values outside of the conventional Jet-A range. A dielectric constant model accounting for the varying dipole moments of both aromatic and non-aromatic jet-range hydrocarbons improves the community’s understanding of fuel composition on FQISs’ operability and provides a tool suitable for fuel performance property optimizations while maintaining compatibility with current aircraft systems. Here, the Clausius–Mossotti relation is first evaluated against a training dataset of 240 dielectric constant and density measurements (48 neat hydrocarbons each measured at five temperatures). Then, the dipole moment is calculated for each species of interest using open-source computational chemistry software, and a second-degree binomial regression is performed over the training data to correct for the error in the Clausius–Mossotti relation. The Clausius–Mossotti relation exhibited an R2 value of 0.54, which increased to 0.92 when terms for the dipole correction were added to the model. The improved accuracy from this model establishes a computationally inexpensive framework for modeling theoretical fuel compositions that demonstrate improved performance characteristics (sooting propensity, thermal management, aircraft efficiency, etc.) while remaining within key limiting property constraints, such as the dielectric constant.

Covert measures of the family system can tap concepts and discover patterns of which family members themselves are unaware and can avoid social desirability bias. Covert measures can be particularly useful in cross-cultural research and can avoid many pitfalls of language and translation. Three such measures which have been used cross-culturally are described. The first is a method of measuring triangulation of children by the parents based on patterns of agreement in a true-false questionnaire describing the family. The second is a projective measure in which family members as a group create a picture of their family distinguishing relationships between individuals and boundaries within and around the family. The third is a global coding scheme used to evaluate family processes from taped interaction.

Atom probe tomography is a well-established analytical instrument for imaging the 3D structure and composition of materials with high mass resolution, sub-nanometer spatial resolution and ppm elemental sensitivity. Thanks to recent hardware developments in Atom Probe Tomography (APT), combined with progress on site-specific focused ion beam (FIB)-based sample preparation methods and improved data treatment software, complex materials can now be routinely investigated. From model samples to complex, usable porous structures, there is currently a growing interest in the analysis of catalytic materials. APT is able to probe the end state of atomic-scale processes, providing information needed to improve the synthesis of catalysts and to unravel structure/composition/reactivity relationships. This review focuses on the study of catalytic materials with increasing complexity (tip-sample, unsupported and supported nanoparticles, powders, self-supported catalysts and zeolites), as well as sample preparation methods developed to obtain suitable specimens for APT experiments.

Abstract Background A growing body of epidemiologic and toxicologic literature indicates that fine airborne particulate matter (PM2.5) pollution is neurotoxic and threatens children’s neurobehavioral development, resulting in reduced cognitive function. Understanding the magnitude of this effect is critical for establishing public health policies that will protect children’s health, preserve human capital, and support societal progress. Objective To quantify the association between ambient PM2.5 air pollution and loss of cognitive function in children, as measured by Intelligence Quotient (IQ) scores, through a systematic literature review and meta-analysis. Methods Following PRISMA guidelines, we conducted a systematic literature search across seven databases: Agricultural and Environmental Science, BIOSIS Citation Index, Embase, GreenFILE, PubMed, Scopus, and Web of Science to identify original scientific studies that investigated the impact of PM2.5 exposure during pre-and postnatal periods on IQ loss during childhood. Using data from studies included for final review, we conducted a meta-analysis, using a random effects model to compute a beta coefficient that quantifies the overall effect of PM2.5 exposure on Full-Scale IQ (FSIQ), Performance IQ (PIQ), and Verbal IQ (VIQ). Findings Of the 1,107 unique publications identified, six studies met the inclusion criteria for final review, representing 4,860 children across three continents (North America, Europe, and Asia). The mean PM2.5 concentration across all studies was 30.4 ± 24.4 µg/m3. Exposure timing ranged from the prenatal period to mid-childhood. Children were an average of 8.9 years old at the time of cognitive testing. We found that each 1 µg/m3 increase in PM2.5 concentration is associated with a -0.27 point change in FSIQ (p

Background: Epidemiologic studies on health effects of parental preconception exposures are limited despite emerging evidence from toxicological studies suggesting that such exposures, including to environmental chemicals, may affect offspring health. Objective: We investigated whether maternal and paternal preconception and maternal pregnancy urinary phthalate metabolite and bisphenol A (BPA) concentrations were associated with child behavior. Methods: We analyzed data from the Preconception Environmental exposure And Childhood health Effects (PEACE) Study, an ongoing prospective cohort study of children aged 6–11 years whose parent(s) previously enrolled in the prospective preconception Environment and Reproductive Health (EARTH) study. Using linear mixed models, we estimated covariate-adjusted associations of 11 urinary phthalate metabolite and BPA concentrations collected prior to conception and during pregnancy with Behavioral Assessment System for Children-3 (BASC-3) T-scores (higher scores indicate more problem behaviors). Results: This analysis included 134 mothers, 87 fathers and 157 children (24 sets of twins); parents were predominantly non-Hispanic white (mothers and fathers86%). Higher maternal preconception or pregnancy monobenzyl phthalate (MBzP) concentrations were related to higher mean externalizing problems T-scores in their children (β = 1.3 per 1-loge unit increase; 95 % CI: −0.2, 2.4 and β = 2.1, 95 % CI: 0.7, 3.6, respectively). Higher maternal preconception monocarboxyoctyl phthalate (MCOP) was suggested to be related to lower mean externalizing problems T-scores (β = -0.9; 95 % CI: −1.8, 0.0). Higher paternal preconception MCOP was suggestively associated with lower internalizing problems (β = -0.9; 95 %CI:-1.9, 0.1) and lower Behavioral Symptoms Index (BSI) T-scores (β = -1.3; 95 % CI: −2.1, −0.4). Conclusion: In this cohort, higher maternal preconception and pregnancy MBzP were associated with worse parent-reported child behavior, while higher maternal and paternal preconception MCOP concentrations were related to lower BASC-3 scores.

IntroductionHigh-level prenatal and childhood arsenic (As) exposure characteristic of several regions in Asia (e.g., Bangladesh), may impact motor function. However, the relationship between lower-level arsenic exposure (characteristic of other regions) and motor development is largely unstudied, despite the potential for deficient motor skills in childhood to have adverse long-term consequences. Thus, we sought to investigate the association between prenatal As exposure and motor function among 395 children in the New Hampshire Birth Cohort Study, a rural cohort from northern New England.MethodsPrenatal exposure was estimated by measuring maternal urine speciated As at 24–28 weeks of gestation using high-performance liquid chromatography (HPLC) inductively coupled plasma mass spectrometry (ICP-MS) and summing inorganic As, monomethylarsonic acid, and dimethylarsinic acid to obtain total urinary As (tAs). Motor function was assessed with the Bruininks-Oseretsky Test of Motor Proficiency, 2nd Edition (BOT-2) at a mean (SD) age of 5.5 (0.4) years.ResultsChildren who completed this exam were largely reported as white race (97%), born to married mothers (86%) with a college degree or higher (67%). The median (IQR) gestational urine tAs concentration was 4.0 (5.0) µg/L. Mean (SD) BOT-2 scores were 48.6 (8.4) for overall motor proficiency and 48.2 (9.6) for fine manual control [standard score = 50 (10)], and were 16.3 (5.1) for fine motor integration and 12.5 (4.1) for fine motor precision [standard score = 15 (5)]. We found evidence of a non-linear dose response relationship and used a change-point model to assess the association of tAs with overall motor proficiency and indices of fine motor integration, fine motor precision, and their composite, fine manual control, adjusted for age and sex. In models adjusted for potential confounders, each doubling of urine tAs decreased overall motor proficiency by –3.3 points (95% CI: –6.1, –0.4) for tAs concentrations greater than the change point of 9.5 µg/L and decreased fine motor integration by –4.3 points (95% CI: –8.0, –0.6) for tAs concentrations greater than the change point of 17.0 µg/L.DiscussionIn summary, we found that levels of prenatal As exposure above an empirically-derived threshold (i.e., the change point) were associated with decrements in childhood motor development in a US population.

Background: Developmental exposure to airborne particulate matter (PM) may increase children’s risk of developing autism spectrum disorder. We quantified the impact of reducing PM exposure during pregnancy on the development of autistic traits in children. We also assessed associations between indoor fine PM (PM2.5) concentrations during pregnancy and autistic traits. Methods: In this parallel-group randomized controlled trial, we randomized 540 non-smoking pregnant women to receive HEPA filter air cleaners or to a control group, which did not receive air cleaners. We administered the Social Responsiveness Scale (SRS-2) to caregivers when children were a median of 48 months (range: 48 to 51 months). Our primary outcome was the SRS-2 total T-score. We imputed missing data using multiple imputation with chained equations and our primary analysis was by intention to treat. In secondary analyses, we estimated associations between full pregnancy and trimester-specific indoor PM2.5 concentrations and T-scores. Results: We enrolled participants at a median of 11 weeks’ gestation. Our analysis included 478 children (233 control, 245 intervention). The intervention reduced average indoor PM2.5 concentrations by 29 % (95 % CI: 21, 37 %). The mean SRS-2 total T-score was 0.5 units lower (95 % CI: −2.5, 1.5) among intervention participants, with evidence of larger benefits for children at the high end of the T-score distribution. An interquartile range (9.6 µg/m3) increase in indoor PM2.5 during pregnancy was associated with 1.8-unit (95 % CI: 0.3, 3.2) increase in mean SRS-2 total T-score. Effect estimates for PM2.5 concentrations by trimester were smaller and confidence intervals spanned no effect. Conclusion: Reducing indoor PM during pregnancy had little impact on mean autism-related behavior scores in children. However, indoor PM2.5 concentrations during pregnancy were associated with higher scores. Exposure to particulate matter during pregnancy may influence the development of autistic traits in childhood.Trial registration: ClinicalTrials.gov: NCT01741051.

Dramatic advances in the management of congenital heart disease (CHD) have improved survival to adulthood from less than 10% in the 1960s to over 90% in the current era, such that adult CHD (ACHD) patients now outnumber their pediatric counterparts. ACHD patients demonstrate domain-specific neurocognitive deficits associated with reduced quality of life that include deficits in educational attainment and social interaction. Our hypothesis is that ACHD patients exhibit vascular brain injury and structural/physiological brain alterations that are predictive of specific neurocognitive deficits modified by behavioral and environmental enrichment proxies of cognitive reserve (e.g., level of education and lifestyle/social habits). This technical note describes an ancillary study to the National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Heart Network (PHN) “Multi-Institutional Neurocognitive Discovery Study (MINDS) in Adult Congenital Heart Disease (ACHD)”. Leveraging clinical, neuropsychological, and biospecimen data from the parent study, our study will provide structural–physiological correlates of neurocognitive outcomes, representing the first multi-center neuroimaging initiative to be performed in ACHD patients. Limitations of the study include recruitment challenges inherent to an ancillary study, implantable cardiac devices, and harmonization of neuroimaging biomarkers. Results from this research will help shape the care of ACHD patients and further our understanding of the interplay between brain injury and cognitive reserve.

Abstract Background Developmental exposure to particulate matter (PM) air pollution may impair children’s behaviors. Our objectives were to quantify the impact of reducing indoor PM using portable HEPA filter air cleaners during pregnancy on behavioral problems in children and to assess associations between indoor fine PM (PM2.5) concentrations during pregnancy and children’s behavior. Methods This is a secondary analysis of a single-blind parallel-group randomized controlled trial in which we randomly assigned 540 non-smoking pregnant women to receive 1 or 2 HEPA filter air cleaners or no air cleaners. We administered the Behavior Assessment System for Children (BASC-3) to caregivers when children were a mean age of 23 months, and again at a mean age of 48 months. Primary outcomes were the four BASC-3 composite scales: externalizing problems, internalizing problems, adaptive skills, and the behavioral symptoms index. We imputed missing data using multiple imputation with chained equations. The primary analysis was by intention-to-treat. In a secondary analysis, we evaluated associations between BASC-3 composite indices and modeled trimester-specific PM2.5 concentrations inside residences. Results We enrolled participants at a median of 11 weeks gestation. After excluding miscarriages, still births and neonatal deaths, our analysis included 478 children (233 control and 245 intervention). We observed no differences in the mean BASC-3 scores between treatment groups. An interquartile increase (20.1 µg/m3) in first trimester PM2.5 concentration was associated with higher externalizing problem scores (2.4 units, 95% CI: 0.7, 4.1), higher internalizing problem scores (2.4 units, 95% CI: 0.7, 4.0), lower adaptive skills scores (-1.5 units, 95% CI: -3.0, 0.0), and higher behavior symptoms index scores (2.3 units, 95% CI: 0.7, 3.9). Third trimester PM2.5 concentrations were also associated with some behavioral indices at age 4, but effect estimates were smaller. No significant associations were observed with PM2.5 concentrations during the second trimester or for any of the BASC indices when children were 2 years old. Conclusion We found no benefit of reducing indoor particulate air pollution during pregnancy on parent-reported behaviors in children. Associations between indoor PM2.5 concentrations in the first trimester and behavioral scores among 4-year old children suggest that it may be necessary to intervene early in pregnancy to protect children, but these exploratory findings should be interpreted cautiously. Trial registration ClinicalTrials.gov: NCT01741051

Patients with hypoplastic left heart syndrome who have been palliated with the Fontan procedure are at risk for adverse neurodevelopmental outcomes, lower quality of life, and reduced employability. We describe the methods (including quality assurance and quality control protocols) and challenges of a multi-center observational ancillary study, SVRIII (Single Ventricle Reconstruction Trial) Brain Connectome. Our original goal was to obtain advanced neuroimaging (Diffusion Tensor Imaging and Resting-BOLD) in 140 SVR III participants and 100 healthy controls for brain connectome analyses. Linear regression and mediation statistical methods will be used to analyze associations of brain connectome measures with neurocognitive measures and clinical risk factors. Initial recruitment challenges occurred that were related to difficulties with: (1) coordinating brain MRI for participants already undergoing extensive testing in the parent study, and (2) recruiting healthy control subjects. The COVID-19 pandemic negatively affected enrollment late in the study. Enrollment challenges were addressed by: (1) adding additional study sites, (2) increasing the frequency of meetings with site coordinators, and (3) developing additional healthy control recruitment strategies, including using research registries and advertising the study to community-based groups. Technical challenges that emerged early in the study were related to the acquisition, harmonization, and transfer of neuroimages. These hurdles were successfully overcome with protocol modifications and frequent site visits that involved human and synthetic phantoms.

Abstract Background Many children in Bangladesh experience poor nutritional status and environmental lead exposure, both of which are associated with lower scores on neurodevelopmental assessments. Recent studies have suggested that part of lead’s adverse effects on neurodevelopment are caused in part by lead’s effect on growth. New statistical methods are now available to evaluate potential causal pathways in observational studies. This study used a novel statistical method to test the hypothesis that stunting, a measure of linear growth related to poor nutrition, is a mediator and/or an effect modifier of the lead exposure’s adverse effect on cognitive development. Methods Participants were 734 children from a longitudinal birth cohort established in rural Bangladesh to study the health effects of prenatal and early childhood environmental metal exposures. Lead exposure was estimated using umbilical cord blood samples obtained at birth and blood obtained via venipuncture at age 20–40 months. Stunting was determined using the World Health Organization’s standards. Neurodevelopment was assessed at age 20–40 months years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). We evaluated the effect of lead on stunting and whether the effect of lead on cognitive scores is modified by stunting status in multivariable regression analyses. We then conducted a novel 4-way mediation analysis that allows for exposure-mediator interaction to assess how much of the effect of lead on cognitive scores is explained by the pathway through stunting (mediation) and how much is explained by the interaction between lead and stunt (effect modification). Results Stunting was not a mediator of the effect of lead in our analyses. Results suggested effect modification by stunting. In an area of Bangladesh with lower lead exposures (median umbilical cord blood lead concentration, 1.7 μg/dL), stunting modified the relationship between prenatal blood lead concentrations and cognitive score at age 2–3 years. A 1-unit increase in natural log cord blood lead concentration in the presence of stunting was associated with a 2.1-unit decrease in cognitive scores (β = − 2.10, SE = 0.71, P = 0.003). This interaction was not found in a second study site where lead exposures were higher (median umbilical cord blood lead concentration, 6.1 μg/dL, β = − 0.45, SE = 0.49, P = 0.360). Conclusions We used a novel method of mediation analysis to test whether stunting mediated the adverse effect of prenatal lead exposure on cognitive outcomes in Bangladesh. While we did not find that stunting acted as mediator of lead’s effect on cognitive development, we found significant effect modification by stunting. Our results suggest that children with stunting are more vulnerable to the adverse effects of low-level lead exposure.

Abstract Background Low-dose mercury (Hg) exposure has been associated with cardiovascular diseases, diabetes, and obesity in adults, but it is unknown the metabolic consequence of in utero Hg exposure. This study aimed to investigate the association between in utero Hg exposure and child overweight or obesity (OWO) and to explore if adequate maternal folate can mitigate Hg toxicity. Methods This prospective study included 1442 mother-child pairs recruited at birth and followed up to age 15 years. Maternal Hg in red blood cells and plasma folate levels were measured in samples collected 1–3 days after delivery (a proxy for third trimester exposure). Adequate folate was defined as plasma folate ≥ 20.4 nmol/L. Childhood OWO was defined as body mass index ≥ 85% percentile for age and sex. Results The median (interquartile range) of maternal Hg levels were 2.11 (1.04–3.70) μg/L. Geometric mean (95% CI) of maternal folate levels were 31.1 (30.1–32.1) nmol/L. Maternal Hg levels were positively associated with child OWO from age 2–15 years, independent of maternal pre-pregnancy OWO, diabetes, and other covariates. The relative risk (RR = 1.24, 95% CI 1.05–1.47) of child OWO associated with the highest quartile of Hg exposure was 24% higher than those with the lowest quartile. Maternal pre-pregnancy OWO and/or diabetes additively enhanced Hg toxicity. The highest risk of child OWO was found among children of OWO and diabetic mothers in the top Hg quartile (RR = 2.06; 95% CI 1.56–2.71) compared to their counterparts. Furthermore, adequate maternal folate status mitigated Hg toxicity. Given top quartile Hg exposure, adequate maternal folate was associated with a 34% reduction in child OWO risk (RR = 0.66, 95% CI 0.51–0.85) as compared with insufficient maternal folate. There was a suggestive interaction between maternal Hg and folate levels on child OWO risk (p for interaction = 0.086). Conclusions In this US urban, multi-ethnic population, elevated in utero Hg exposure was associated with a higher risk of OWO in childhood, and such risk was enhanced by maternal OWO and/or diabetes and reduced by adequate maternal folate. These findings underscore the need to screen for Hg and to optimize maternal folate status, especially among mothers with OWO and/or diabetes.

Abstract Background Humans are exposed to mixtures of chemicals across their lifetimes, a concept sometimes called the “exposome.” Mixtures likely have temporal “critical windows” of susceptibility like single agents and measuring them repeatedly might help to define such windows. Common approaches to evaluate the effects of chemical mixtures have focused on their effects at a single time point. Our goal is to expand upon these previous techniques and examine the time-varying critical windows for metal mixtures on subsequent neurobehavior in children. Methods We propose two methods, joint weighted quantile sum regression (JWQS) and meta-weighted quantile sum regression (MWQS), to estimate the effects of chemical mixtures measured across multiple time points, while providing data on their critical windows of exposure. We compare the performance of both methods using simulations. We also applied both techniques to assess second and third trimester metal mixture effects in predicting performance in the Rapid Visual Processing (RVP) task from the Cambridge Neuropsychological Test Automated Battery (CANTAB) assessed at 6–9 years in children who are part of the PROGRESS (Programming Research in Obesity, GRowth, Environment and Social Stressors) longitudinal cohort study. The metals, arsenic, cadmium (Cd), cesium, chromium, lead (Pb) and antimony (Sb) were selected based on their toxicological profile. Results In simulations, JWQS and MWQS had over 80% accuracy in classifying exposures as either strongly or weakly contributing to an association. In real data, both JWQS and MWQS consistently found that Pb and Cd exposure jointly predicted longer latency in the RVP and that second trimester exposure better predicted the results than the third trimester. Additionally, both JWQS and MWQS highlighted the strong association Cd and Sb had with lower accuracy in the RVP and that third trimester exposure was a better predictor than second trimester exposure. Conclusions Our results indicate that metal mixtures effects vary across time, have distinct critical windows and that both JWQS and MWQS can determine longitudinal mixture effects including the cumulative contribution of each exposure and critical windows of effect.

BackgroundPrevalence of antenatal depression in low and middle income countries is high. However studies examining the association between maternal antenatal depression and early childhood development from these countries are scarce. The objective of the study was to examine the association between antenatal depressive symptoms assessed serially during pregnancy and child neurodevelopment outcomes in mother–child dyads part of a randomized control trial of maternal B12 supplementation during pregnancy.MethodSubjects were 203 women who had participated in the placebo-controlled, randomized trial of vitamin B12 supplementation during pregnancy and 6 weeks post-partum on whom serial assessments of depressive symptoms in each of the trimesters were available. Cognitive, receptive language, expressive language, fine motor skills and gross motor skills were assessed at 30 months using the Bayley’s Scale of Infant Development-3rd edition (BSID-III). Antenatal depressive symptoms were assessed at three trimesters using the Kessler’s 10 Psychological Distress Scale (K10). Women were classified into three categories: not depressed (K10

Abstract The purpose of this commentary is to consider whether the methods of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) can provide accurate estimates of the impact of developmental neurotoxicant exposures on population health. The discussion focuses on two concerns. First, GBD implicitly largely endorses a “high risk” or “disease” approach to estimating health loss rather than a “population-based” approach. Exposure to many developmental neurotoxicants is highly prevalent but, for most individuals, it does not affect functional health to such an extent that diagnostic criteria for a disease are met. Nevertheless, the impacts are real and can be substantial when viewed in terms of the aggregate impact on a population. Second, in GBD the disability weights used for the most common sequelae of developmental neurotoxicant exposures, based on judgments provided by general population respondents, are not commensurate with the import that these sequelae have for an individual’s lifelong well-being, including their ability to fulfill educational, occupational, and social potential. It would be unfortunate if priorities were set or policy decisions made based on how developmental neurotoxicants compare to other risk factors using the current GBD methods.

Cognitive flexibility, the ability to smoothly adapt to changing circumstances, is a skill that is vital to higher-level executive functions such as problem-solving, planning, and reasoning. As it undergoes substantial development during adolescence, decrements in cognitive flexibility may not become apparent until this time. There is evidence that prenatal exposure to individual chemicals may adversely impact executive functions in children, but few studies have explored the association of co-exposure to multiple chemicals with cognitive flexibility specifically among adolescents. We investigated this association among a diverse group of adolescents living near a Superfund site in New Bedford, Massachusetts. Specifically, using Bayesian kernel machine regression (BKMR) and multivariable regression analyses, we investigated the association of biomarkers of prenatal exposure to organochlorines (DDE, HCB, PCBs) and metals (lead, manganese) with cognitive flexibility, measured with four subtests of the Delis-Kaplan Executive Function System. In BKMR models, we observed adverse joint associations of the chemical mixture with two of the four cognitive flexibility subtests. In covariate-adjusted linear regression models, a two-fold increase in cord blood Mn was associated with poorer performance on two of the subtests: Trail-Making (scaled score difference = −0.60; 95% CI: −1.16, −0.05 points) and Color-Word Interference (scaled score difference = −0.53; 95% CI: −1.08, 0.01 points). These adverse Mn-cognitive flexibility associations were supported by the results of the BKMR. There was little evidence of effect modification by sex and some evidence of effect modification by a measure of social disadvantage, particularly for the associations between HCB and cognitive flexibility. This study is among the first to provide evidence of an adverse association of prenatal exposure to a chemical mixture with cognitive flexibility in adolescence.

Inhibition, one of the building blocks of executive function, is the ability to focus one’s attention despite interference from external stimuli. It undergoes substantial development during adolescence and may be susceptible to adverse impacts of prenatal exposure to chemical mixtures, yet few studies have explored this association. The New Bedford Cohort (NBC) is a birth cohort of residents living near the New Bedford Harbor Superfund site in Massachusetts. Among adolescents from the NBC, we investigated the association of biomarkers of prenatal exposure to organochlorines (DDE, HCB, PCBs) and metals (Pb, Mn) with inhibition, assessed with the Delis–Kaplan Executive Function System Design Fluency (non-verbal task) and Color–Word Interference (verbal task) subtests. An exploratory mixtures analysis using Bayesian kernel machine regression (BKMR) informed a traditional multivariable regression approach. NBC adolescents are diverse with 29% non-white and 31% in a low-income household at birth. Cord serum organochlorine concentrations and cord blood metals concentrations were generally similar to other birth cohorts. In BKMR models, we observed a suggestive adverse association of the chemical mixture with Color–Word Interference but not Design Fluency. In covariate-adjusted linear regression models including all five chemical exposure measures, a doubling of cord blood Mn was associated with poorer Color–Word Interference completion time scaled scores (difference = −0.74; 95% CI: −1.34, −0.14). This study provided evidence of an adverse joint association between prenatal exposure to a five-chemical mixture and verbal inhibition in adolescence with exposure to Mn potentially driving this overall association.

Background: Manganese is an essential nutrient, but in excess, can be a potent neurotoxicant. We previously reported findings from two cross-sectional studies on children, showing that higher concentrations of manganese in drinking water were associated with deficits in IQ scores. Despite the common occurrence of this neurotoxic metal, its concentration in drinking water is rarely regulated. Objective: We aimed to apply a benchmark concentration analysis to estimate water manganese levels associated with pre-defined levels of cognitive impairment in children, i.e. drop of 1%, 2% and 5% in Performance IQ scores. Methods: Data from two studies conducted in Canada were pooled resulting in a sample of 630 children (ages 5.9–13.7 years) with data on tap water manganese concentration and cognition, as well as confounders. We used the Bayesian Benchmark Dose Analysis System to compute weight-averaged median estimates for the benchmark concentration (BMC) of manganese in water and the lower bound of the credible interval (BMCL), based on seven different exposure-response models. Results: The BMC for manganese in drinking water associated with a decrease of 1% Performance IQ score was 133 μg/L (BMCL, 78 μg/L); for a decrease of 2%, this concentration was 266 μg/L (BMCL, 156 μg/L) and for a decrease of 5% it was 676 μg/L (BMCL, 406 μg/L). In sex-stratified analyses, the manganese concentrations associated with a decrease of 1%, 2% and 5% Performance IQ in boys were 185, 375 and 935 μg/L (BMCLs, 75, 153 and 386 μg/L) and 78, 95, 192 μg/L (BMCLs, 9, 21 and 74 μg/L) for girls. Conclusion: Studies suggest that a maximum acceptable concentration for manganese in drinking water should be set to protect children, the most vulnerable population, from manganese neurotoxicity. The present risk analysis can guide decision-makers responsible for developing these standards. Keywords: Drinking water, Manganese, IQ, Neurodevelopmental toxicity, Benchmark-concentration analysis

Patients with congenital heart disease (CHD) are at risk for neurocognitive impairments. Little is known about the impact of CHD on the organization of large-scale brain networks. We applied graph analysis techniques to diffusion tensor imaging (DTI) data obtained from 49 adolescents with dextro-transposition of the great arteries (d-TGA) repaired with the arterial switch operation in early infancy and 29 healthy referent adolescents. We examined whether differences in neurocognitive functioning were related to white matter network topology. We developed mediation models revealing the respective contributions of peri-operative variables and network topology on cognitive outcome. Adolescents with d-TGA had reduced global efficiency at a trend level (p = 0.061), increased modularity (p = 0.012), and increased small-worldness (p = 0.026) as compared to controls. Moreover, these network properties mediated neurocognitive differences between the d-TGA and referent adolescents across every domain assessed. Finally, structural network topology mediated the neuroprotective effect of longer duration of core cooling during reparative neonatal cardiac surgery, as well as the detrimental effects of prolonged hospitalization. Taken together, worse neurocognitive function in adolescents with d-TGA is mediated by global differences in white matter network topology, suggesting that disruption of this configuration of large-scale networks drives neurocognitive dysfunction. These data provide new insights into the interplay between perioperative factors, brain organization, and cognition in patients with complex CHD.

All people need food. Unsafe foods; however, may cause diseases ranging from diarrhea to cancer. Chemicals in food are a worldwide health concern. In 2006, the World Health Organization (WHO) organized a consultation on the global burden of foodborne diseases. Work to estimate this burden began in 2007 and was carried out by the WHO Foodborne Disease Burden Epidemiology Reference Group (FERG), which included a Chemical and Toxins Disease Task Force. The results of 8 years of work were released in December 2015.

Experimental studies suggest a myriad of mechanisms by which inorganic arsenic can interfere with central nervous system development, and, indeed, epidemiological studies published in the last dozen years suggest that exposure to arsenic impairs children’s cognitive development. Most of the studies have been conducted in developing countries (e.g., Bangladesh, India, Mexico), where exposure to arsenic is thought to be considerably higher than it is in developed countries. This review summarizes the results of these studies, focusing in particular on issues pertinent to risk assessment, including the existence of critical windows of vulnerability, characteristics of the dose-effect relationships (e.g., the lowest adverse effect level, the functional form), the most sensitive neurodevelopmental endpoints, and potential effect modifiers such as host characteristics (e.g., methylation efficiency, sex) and co-exposures to other neurotoxicants (e.g., lead, manganese). At present, the epidemiological data do not permit firm conclusions to be drawn regarding these issues. Several factors that complicate an effort to compare the results of studies are identified, including use of a variety of indices of external and internal exposure, and inconsistency in the measurement of important potential confounders for neurodevelopmental outcomes.

This review surveys the recent literature on the neurodevelopmental impacts of chemical exposures during pregnancy. The review focuses primarily on chemicals of recent concern, including phthalates, bisphenol-A, polybrominated diphenyl ethers, and perfluorinated compounds, but also addresses chemicals with longer histories of investigation, including air pollutants, lead, methylmercury, manganese, arsenic, and organophosphate pesticides. For some chemicals of more recent concern, the available literature does not yet afford strong conclusions about neurodevelopment toxicity. In such cases, points of disagreement among studies are identified and suggestions provided for approaches to resolution of the inconsistencies, including greater standardization of methods for expressing exposure and assessing outcomes.

Background Few studies have described the neuropsychological outcomes and frequency of structural brain or genetic abnormalities in adolescents with single ventricle who underwent the Fontan procedure. Methods and Results In a cross‐sectional, single‐center study, we enrolled 156 subjects with single ventricle, mean age 14.5±2.9 years, who had undergone the Fontan procedure. Scores in the entire cohort on a standard battery of neuropsychological tests were compared with those of normative populations or to those of a group of 111 locally recruited healthy adolescents. They also underwent brain magnetic resonance imaging and were evaluated by a clinical geneticist. Genetic abnormalities were definite in 16 subjects (10%) and possible in 49 subjects (31%). Mean Full‐Scale IQ was 91.6±16.8, mean Reading Composite score was 91.9±17.2, and mean Mathematics Composite score was 92.0±22.9, each significantly lower than the population means of 100±15. Mean scores on other neuropsychological tests were similarly lower than population norms. In multivariable models, risk factors for worse neuropsychological outcomes were longer total support and circulatory arrest duration at first operation, presence of a genetic abnormality, more operations and operative complications, more catheterization complications, and seizure history. The frequency of any abnormality on magnetic resonance imaging was 11 times higher among Fontan adolescents than referents (66% versus 6%); 19 (13%) patients had evidence of a stroke, previously undiagnosed in 7 patients (40%). Conclusions The neuropsychological deficits and high frequencies of structural brain abnormalities in adolescents who underwent the Fontan procedure highlight the need for research on interventions to improve the long‐term outcomes in this high‐risk group.

In December 2015, the World Health Organization (WHO) published the first ever report on the estimates of the global burden of foodborne diseases, which included diseases related to chemical exposures in foods such as peanut allergy. In the report, the burden of disease related to peanut allergies was measured for the European, American and West Pacific Regions. The report showed that unlike other food-related chemical exposures, peanut allergies are far more common in the European and American Regions than in the West Pacific Region. In this commentary we tried to inform physicians and public health workers, and to raise awareness about peanut allergies to facilitate future discussions. Although the WHO report on the estimates of the global burden of foodborne diseases indicates a possible geographical difference in global peanut allergy prevalence, further studies need to compare the relative risk of peanut allergies among individuals of different racial backgrounds in one defined population.

With this inaugural issue, Toxics begins its life as a peer-reviewed, open access journal focusing on all aspects of toxic chemicals. We are interested in publishing papers that present a wide range of perspectives on toxicants and naturally occurring toxins, including exposure, biomarkers, kinetics, biological effects, fate and transport, treatment, and remediation. Toxics differs from many other journals in the absence of a page or word limit on contributions, permitting authors to present their work in as much detail as they wish. Toxics will publish original research papers, conventional reviews, meta-analyses, short communications, theoretical papers, case reports, commentaries and policy perspectives, and book reviews (Book reviews will be solicited and should not be submitted without invitation). Toxins and toxicants concern individuals from a wide range of disciplines, and Toxics is interested in receiving papers that represent the full range of approaches applied to their study, including in vitro studies, studies that use experimental animal or non-animal models, studies of humans or other biological populations, and mathematical modeling. We are excited to get underway and look forward to working with authors in the scientific and medical communities and providing them with a novel venue for sharing their work. [...]

Iron storage proteins are essential for cellular iron homeostasis and redox balance. Ferritin proteins are the major storage units for bioavailable forms of iron. Some organisms lack ferritins, and it is not known how they store iron. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment from Quasibacillus thermotolerans. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo and show interactions underlying cargo-shell co-assembly. This compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. Our results reveal a new approach for survival in diverse habitats with limited or fluctuating iron availability via an iron storage system able to store 10 to 20 times more iron than ferritin.