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Maternal fish consumption exposes the fetus to beneficial nutrients and potentially adverse neurotoxicants. The current study investigated associations between maternal fish consumption and child neurodevelopmental outcomes. Maternal fish consumption was assessed in the Seychelles Child Development Study Nutrition Cohort 1 (n 229) using 4-day food diaries. Neurodevelopment was evaluated at 9 and 30 months, and 5 and 9 years with test batteries assessing twenty-six endpoints and covering multiple neurodevelopmental domains. Analyses used multiple linear regression with adjustment for covariates known to influence child neurodevelopment. This cohort consumed an average of 8 fish meals/week and the total fish intake during pregnancy was 106·8 (sd 61·9) g/d. Among the twenty-six endpoints evaluated in the primary analysis there was one beneficial association. Children whose mothers consumed larger quantities of fish performed marginally better on the Kaufman Brief Intelligence Test (a test of nonverbal intelligence) at age 5 years (β 0·003, 95 % CI (0, 0·005)). A secondary analysis dividing fish consumption into tertiles found no significant associations when comparing the highest and lowest consumption groups. In this cohort, where fish consumption is substantially higher than current global recommendations, maternal fish consumption during pregnancy was not beneficially or adversely associated with children’s neurodevelopmental outcomes.

Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data (n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores (n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation.

Cancer-related fatigue is a prevalent, debilitating condition, and preliminary evidence suggests a relationship between higher diet quality and lower fatigue. Serum-based carotenoids, Vitamin A, and Vitamin E are biomarkers of fruit and vegetable intake and therefore diet quality. To further elucidate the link between diet quality and cancer-related fatigue, associations were assessed between these serum-based nutrients and fatigue among American adults with special attention to cancer history. Data were analyzed from the United States 2005–2006 National Health and Nutrition Examination Survey dataset. Ten carotenoids, vitamin A, vitamin E, and γ-tocopherol were measured from fasting blood samples and fatigue was patient-reported. Associations between carotenoid concentration and fatigue were estimated using ordinal logistic regression models. Adjusted models included a diagnosis of cancer (with the exception on nonmelanoma skin cancer, yes/no), age, body mass index, race/ethnicity, education, and exercise habits as covariates, and additional models included a cancer × nutrient interaction. Of 4,091 participants, 272 (8.0%) reported a history of cancer. Greater fatigue was associated with lower serum trans-lycopene, retinyl palmitate, and retinyl stearate (all P < 0.05) in separate models adjusting for potential confounders. For these nutrients, a one-SD increase in nutrient was associated with a 6.8%–9.9% lower risk of greater fatigue. Among cancer survivors only (n = 272), statistically significant associations were not observed between any of the nutrients and fatigue. In conclusion, greater serum concentrations of carotenoid biomarkers were associated with less fatigue. These results support further exploration into relationships between carotenoid intake, diet quality, and persistent fatigue. Significance: Cancer-related fatigue often persists for years into survivorship, reduces quality of life, and prevents people from returning to their lives before cancer. Interventions to address cancer-related fatigue are much needed. Herein, serum carotenoids were associated with lower fatigue, thereby supporting further development of nutritional interventions to address fatigue in survivorship.

BACKGROUND AND OBJECTIVE For febrile infants, predictive models to detect bacterial infections are available, but clinical adoption remains limited by implementation barriers. There is a need for predictive models using widely available predictors. Thus, we previously derived 2 novel predictive models (machine learning and regression) by using demographic and clinical factors, plus urine studies. The objective of this study is to refine and externally validate the predictive models. METHODS This is a cross-sectional study of infants initially evaluated at one pediatric emergency department from January 2011 to December 2018. Inclusion criteria were age 0 to 90 days, temperature ≥38°C, documented gestational age, and insurance type. To reduce potential biases, we derived models again by using derivation data without insurance status and tested the ability of the refined models to detect bacterial infections (ie, urinary tract infection, bacteremia, and meningitis) in the separate validation sample, calculating areas-under-the-receiver operating characteristic curve, sensitivities, and specificities. RESULTS Of 1419 febrile infants (median age 53 days, interquartile range = 32–69), 99 (7%) had a bacterial infection. Areas-under-the-receiver operating characteristic curve of machine learning and regression models were 0.92 (95% confidence interval [CI] 0.89–0.94) and 0.90 (0.86–0.93) compared with 0.95 (0.91–0.98) and 0.96 (0.94–0.98) in the derivation study. Sensitivities and specificities of machine learning and regression models were 98.0% (94.7%–100%) and 54.2% (51.5%–56.9%) and 96.0% (91.5%–99.1%) and 50.0% (47.4%–52.7%). CONCLUSIONS Compared with the derivation study, the machine learning and regression models performed similarly. Findings suggest a clinical-based model can estimate bacterial infection risk. Future studies should prospectively test the models and investigate strategies to optimize clinical adoption.

Cancer-related fatigue is a prevalent, debilitating condition, and preliminary evidence suggests a relationship between higher diet quality and lower fatigue. Serum-based carotenoids, Vitamin A, and Vitamin E are biomarkers of fruit and vegetable intake and therefore diet quality. To further elucidate the link between diet quality and cancer-related fatigue, associations were assessed between these serum-based nutrients and fatigue among American adults with special attention to cancer history. Data were analyzed from the United States 2005–2006 National Health and Nutrition Examination Survey dataset. Ten carotenoids, vitamin A, vitamin E, and γ-tocopherol were measured from fasting blood samples and fatigue was patient-reported. Associations between carotenoid concentration and fatigue were estimated using ordinal logistic regression models. Adjusted models included a diagnosis of cancer (with the exception on nonmelanoma skin cancer, yes/no), age, body mass index, race/ethnicity, education, and exercise habits as covariates, and additional models included a cancer × nutrient interaction. Of 4,091 participants, 272 (8.0%) reported a history of cancer. Greater fatigue was associated with lower serum trans-lycopene, retinyl palmitate, and retinyl stearate (all P < 0.05) in separate models adjusting for potential confounders. For these nutrients, a one-SD increase in nutrient was associated with a 6.8%–9.9% lower risk of greater fatigue. Among cancer survivors only (n = 272), statistically significant associations were not observed between any of the nutrients and fatigue. In conclusion, greater serum concentrations of carotenoid biomarkers were associated with less fatigue. These results support further exploration into relationships between carotenoid intake, diet quality, and persistent fatigue.Significance:Cancer-related fatigue often persists for years into survivorship, reduces quality of life, and prevents people from returning to their lives before cancer. Interventions to address cancer-related fatigue are much needed. Herein, serum carotenoids were associated with lower fatigue, thereby supporting further development of nutritional interventions to address fatigue in survivorship.

Suppl. Table 1. Results of crude and adjusted models describing the association between carotenoid concentrations and fatigue: all model output. For body mass index, estimates are compared to normal weight (18.5-Suppl. Table 2. Results of adjusted model with the nutrient×cancer interaction term to explore the associations between carotenoids and cancer-related fatigue: all model output.Suppl. Table 3. Adjusted odds ratios and 95% confidence intervals for the effects of the nutrient×cancer interaction on fatigue. Models are adjusted for age, body mass index, race/ethnicity, education, physical activity, history of a cancer diagnosis, and nutrient concentration.Suppl. Table 4. Results of adjusted models (no interaction term) describing the association between carotenoid concentrations and fatigue only among cancer survivors: all model output; estimates for race/ethnicity are compared to non-Hispanic Whites, 1=Mexican American, 2=Other Hispanic, 4=non-Hispanic Black American, 5=Other non-Hispanic race, including multi-racial; estimates for body mass index are compared to those of normal weight; and estimates for education are compared to those with at least a college education. Exercise is estimated from metabolic equivalents (MET hours) per week as a continuous variable. Age, Years since Diagnosis, and carotenoid concentration are treated as continuous variables. (n=272)

Background: Identifying those at risk for suboptimal breastfeeding outcomes remains critical for improving maternal and child health. Prenatal breastfeeding motivation may be a key predictor useful for identifying those who would benefit from additional breastfeeding support. Research Aims: To (1) validate a breastfeeding-specific adaptation of the Treatment Self-Regulation Questionnaire (TSRQ-BF); and (2) determine if breastfeeding motivation predicts prenatal breastfeeding intentions and early breastfeeding outcomes. Methods: Participants in their third trimester of pregnancy ( N = 150) completed several instruments, including the TSRQ-BF and infant feeding intention, and could opt to participate in an assessment of early breastfeeding outcomes (by medical record review). TSRQ-BF subscales were derived from factor analysis, and multivariable regression was used to evaluate the association between TSRQ-BF subscale scores and breastfeeding intention and outcomes during the birth hospitalization. Results: Autonomous (related to personal values/beliefs regarding self) and Autonomous-Baby (values/benefits for the infant) subscale scores were positively associated with intended exclusivity (aOR [95% CI]: 2.22 [1.57, 3.30], 4.94 [2.49, 11.07], respectively) while higher scores on these subscales predicted longer time to planned cessation (aHR [95% CI]: 0.72 [0.61, 0.84],0.52 [0.34, 0.81]). Higher Amotivation (lack of motivation) scores were negatively associated with intended exclusivity (0.45 [0.26, 0.74]). Higher scores on Autonomous, Autonomous-Baby, and Controlled (avoidance of negative feelings/punishment or gaining reward) subscales were associated with greater odds of hospital exclusivity (aOR [95% CI]: 3.39 [1.75, 8.00], 3.44 [1.66, 9.04] and 6.05 [1.88, 29.04]) and lower odds of 2-day formula supplementation (aOR [95% CI]: 0.31 [0.14, 0.59],0.28 [0.11, 0.59], 0.19 [0.04, 0.62]). Conclusions: The TSRQ-BF predicted breastfeeding intent and outcomes, and may be helpful for identifying patients at risk for suboptimal breastfeeding outcomes before delivery.

Objective Mild to moderate iodine deficiency during pregnancy has been associated with adverse neurodevelopmental outcomes in offspring. Few research studies to date combine assessment of urinary iodine (UIC and/or ICr), biomarkers that best reflect dietary intake, with reported dietary intake of iodine rich foods in their assessment of iodine deficiency. Thus, a systematic review was conducted to incorporate both these important measures. Design Using PRISMA guidelines, a comprehensive search was conducted in three electronic databases (EMBASE®, MedLine® and Web of Science®) from January 1970–March 2021. Quality assessment was undertaken using the Newcastle Ottawa Scale. Eligible studies included reported assessment of iodine status through urinary iodine (UIC and/or ICr) and/or dietary intake measures in pregnancy alongside neurodevelopmental outcomes measured in the children. Data extracted included study author, design, sample size, country, gestational age, child age at testing, cognitive tests, urinary iodine assessment (UIC in μg/L and/or ICr in μg/g), dietary iodine intake assessment and results of associations for the assessed cognitive outcomes. Results Twelve studies were included with nine reporting women as mild-moderately iodine deficient based on World Health Organization (WHO) cut-offs for urinary iodine measurements Conclusion The majority of studies classified pregnant women to be mild-moderately iodine deficient based on urinary iodine assessment (UIC and/or ICr) and/or dietary intakes, with subsequent offspring neurodevelopment implications identified. Although a considerable number of studies did not report an adverse association with neurodevelopmental outcomes, these findings are still supportive of ensuring adequate dietary iodine intakes and urinary iodine monitoring throughout pregnancy due to the important role iodine plays within foetal neurodevelopment. This review suggests that dietary intake data may indicate a stronger association with cognitive outcomes than urinary iodine measurements alone. The strength of this review distinguishes results based on cognitive outcome per urinary iodine assessment strategy (UIC and/or ICr) with dietary data. Future work is needed respecting the usefulness of urinary iodine assessment (UIC and/or ICr) as an indicator of deficiency whilst also taking account of dietary intakes.

BACKGROUND: Fish is a primary source of protein and n-3 PUFA but also contains methylmercury (MeHg), a naturally occurring neurotoxicant to which, at sufficient exposure levels, the developing fetal brain is particularly sensitive. OBJECTIVES: To examine the association between prenatal MeHg and maternal status of n-3 and n-6 PUFA with neurodevelopment, and to determine whether PUFA might modify prenatal MeHg associations with neurodevelopment. METHODS: We examined the Seychelles Child Development Study Nutrition Cohort 2 (NC2) at age 7 y. We used a sophisticated and extensive neurodevelopmental test battery that addressed 17 specific outcomes in multiple neurodevelopmental domains: cognition, executive and psychomotor function, language development, behavior, scholastic achievement, and social communication. Analyses were undertaken on 1237 mother-child pairs with complete covariate data (after exclusions) and a measure of at least 1 outcome. We examined the main and interactive associations of prenatal MeHg exposure (measured as maternal hair mercury) and prenatal PUFA status (measured in maternal serum at 28 weeks' gestation) on child neurodevelopmental outcomes using linear regression models. We applied the Bonferroni correction to account for multiple comparisons and considered P values

Purpose Long-chain polyunsaturated fatty acids (LCPUFA) can be synthesised endogenously from linoleic acid (LA) and α-linolenic acid (ALA) in a pathway involving the fatty acid desaturase (FADS) genes. Endogenous synthesis is inefficient; therefore, dietary intake of preformed LCPUFA from their richest source of fish is preferred. This study investigated the effect of fish consumption on PUFA concentrations in women of childbearing age while stratifying by FADS genotype. The influence of fish consumption on lipid profile, and markers of inflammation and oxidative stress was also examined. Methods Healthy women (n = 49) provided a buccal swab which was analysed for FADS2 genotype (rs3834458; T/deletion). Participants were stratified according to genotype and randomised to an intervention group to receive either no fish (n = 18), 1 portion (n = 14) or 2 portions (n = 17) (140 g per portion) of fish per week for a period of 8 weeks. Serum PUFA was analysed at baseline and post-intervention. Lipid profile, and markers of inflammation and oxidative stress were also analysed. Results Participants consuming 2 portions of fish per week had significantly higher concentrations of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and total n-3 PUFA, and a lower n-6:n-3 ratio compared to those in the no fish or 1 portion per week group (all p Conclusion Consumption of 2 portions of fish per week has beneficial effects on biological n-3 PUFA concentrations in women of childbearing age; however, no effects on oxidative stress, inflammation or lipid profile were observed. This trial was registered at www.clinicaltrials.gov (NCT03765580), registered December 2018.

BACKGROUND: Maternal status of long-chain PUFAs (LC-PUFAs) may be related to fetal growth. Maternal fish consumption exposes the mother to the neurotoxicant methylmercury (MeHg), which, in contrast, may restrict fetal growth. OBJECTIVE: Our aim was to examine relations between maternal LC-PUFA status at 28 wk and birth outcomes (birth weight, length, and head circumference), controlling for MeHg exposure throughout pregnancy, in the Seychelles Child Development Study Nutrition Cohort 2. Our secondary aim was to examine the influence of maternal variation in genes regulating the desaturation of LC-PUFAs [fatty acid desaturase (FADS)] on birth outcomes. METHODS: From nonfasting blood samples collected at 28 wk of gestation, we measured serum total LC-PUFA concentrations and FADS1 (rs174537, rs174561), FADS1-FADS2rs3834458, and FADS2rs174575 genotypes, with hair total mercury concentrations assessed at delivery. Data were available for n = 1236 mother-child pairs. Associations of maternal LC-PUFAs, MeHg, and FADS genotype with birth outcomes were assessed by multiple linear regression models, adjusting for child sex, gestational age, maternal age, BMI, alcohol use, socioeconomic status, and parity. RESULTS: In our cohort of healthy mothers, neither maternal LC-PUFA status nor MeHg exposure were significant determinants of birth outcomes. However, when compared with major allele homozygotes, mothers who were heterozygous for the minor allele of FADS1 (rs174537 and rs174561, GT compared with TT, β = 0.205, P = 0.03; TC compared with CC, β = 0.203, P = 0.04) and FADS1-FADS2 (rs3834458, Tdel compared with DelDel, β = 0.197, P = 0.04) had infants with a greater head circumference (all P < 0.05). Homozygosity for the minor allele of FADS2 (rs174575) was associated with a greater birth weight (GG compared with CC, β = 0.109, P = 0.04). CONCLUSIONS: In our mother-child cohort, neither maternal LC-PUFA status nor MeHg exposure was associated with birth outcomes. The observed associations of variation in maternal FADS genotype with birth outcomes should be confirmed in other populations. (Less)

We compared anxiety symptoms in youth with and without tic disorders by comparing scores on the Multidimensional Anxiety Scale for Children (MASC) in youth with tic disorders to those in a concurrent community control group and in a group of treatment-seeking anxious youth from the Child/Adolescent Anxiety Multimodal Study (CAMS). Data from 176 youth with tic disorders, 93 control subjects, and 488 CAMS participants were included. Compared to youth with tic disorders, controls had lower total MASC scores (p

PURPOSE: Methylmercury (MeHg) is a known neurodevelopmental toxicant in sufficient dosage and is universally found in fish. Current fish advisories for children are based on epidemiology studies examining prenatal exposure with a premise that MeHg exposure resulting from children eating fish could also be neurotoxic and have long-term consequences. However, the evidence that this assumption is true is limited. We investigated postnatal MeHg exposure from regular fish consumption using time weighted Hg measurements to determine if there are neurotoxic consequences. METHODS: We examined 85 neurodevelopmental outcomes measured from ages 9 to 24 years in the Seychelles Child Development Study Main Cohort (n=312–550) and examined their association with time-weighted measures of postnatal MeHg exposure in childhood and early adulthood. Postnatal MeHg exposure measured in the first cm of participants’ hair samples collected at seven evaluations were used to create two time-weighted (TW) average MeHg exposure metrics, one for childhood (TW-C) and the other for early adulthood (TW-A). TW-C was based on Hg measures at three ages between 6 months and 5.5 years, and TW-A was based on Hg measured at up to four ages between 17 and 24 years. We examined the association between each of these exposure metrics and the neurodevelopmental outcomes using linear regression with adjustment for covariates known to influence neurodevelopmental outcomes. RESULTS: There were 14 statistically significant associations between a postnatal metric and an endpoint. Six were associated with the TW-C and eight with the TW-A. Thirteen were adverse. Only the TW-C association at 9 years with the Bender Gestalt error score showed improvement. TW-C was adversely associated at 9 years with the Continuous Performance Task risk score, at 22 years with the Boston Naming Test (BNT) total and no cues scores, and at 24 years with the Test of Variables of Attention (TOVA) auditory response time variability and visual response time mean on the logarithmic scale. TW-A was adversely associated at 17 years with the Wisconsin Card Sorting Test % total errors, the Woodcock-Johnson passage comprehension, and the CANTAB rapid visual information processing false alarms, and at 22 years with the BNT total and no cue scores, the CANTAB rapid visual information processing false alarms and the intra-extra dimensional shift total errors and trials. CONCLUSION: These findings suggest that postnatal MeHg exposure may be adversely associated with neurodevelopmental outcomes in early adulthood. However, the associations are statistical and of unknown, if any, clinical significance. The results need confirmation in other cohorts.

In many studies of the health effects of toxicants, exposure is measured once even though exposure may be continuous. However, some studies collect repeated measurements on participants over an extended time with the goal of determining a long-term metric that captures the average or cumulative exposure. This can be challenging, especially when exposure is measured at irregular intervals and has some missing values. Here we describe a method for determining a measure of long-term exposure using data on postnatal mercury (Hg) from the Seychelles Child Development Study (SCDS) Main Cohort as a model. In this cohort (n = 779), we incorporate postnatal Hg values that were measured on most study participants at seven ages, three between 6 months and 5.5 years ("childhood"), and an additional four between 17 and 24 years ("early adulthood"). We develop time-weighted measures of average exposure during the childhood and the early adulthood periods and compare the strengths and weaknesses of our metric to two standard measures: overall average and cumulative exposure. We account for missing values through an imputation method that uses information about age- and sex-specific Hg means and the participant's Hg values at similar ages to estimate subject-specific missing Hg values. We compare our method to the implicit imputation assumed by these two standard methods, and to Fully Conditional Specification (FCS), an alternative method of imputing missing data. To determine the accuracy of our imputation method we use data from participants with no missing Hg values in the relevant time window. The imputed values from our proposed method are substantially closer to the observed values on average than the average or cumulative exposure, while also performing slightly better than FCS. In conclusion, time-weighted long-term exposure appears to offer advantages over cumulative exposure in longitudinal studies with repeated measures where the follow-up period for a toxicant is similar for all participants. Additionally, our method to impute missing values maximizes the number of participants for whom the overall exposure metric can be calculated and should provide a more accurate long-term exposure metric than standard methods when exposure has missing values. Our method is applicable to any study of long-term toxicant effects when longitudinal exposure measurements are available but have missing values.

Objective Cancer survivors face numerous physical and mental health challenges even after treatment completion. However, few studies have examined mental health in cancer survivors who received curative treatment during the transition out of active treatment and into survivorship. The current study describes the prevalence of mental health outcomes and their correlates in cancer survivors treated with curative intent during the first year of survivorship. Methods A total of 120 cancer survivors of any cancer type completed a survey that assessed depression, anxiety, death ideation, alcohol and substance use, and demographic characteristics. Data regarding cancer type and treatment were extracted from the medical record. Results Approximately 15% of the sample reported depression symptoms. Fifteen percent also reported anxiety symptoms in the past two weeks. 10 percent of the sample reported experiencing death ideation since their treatment ended and 7.5% reported death ideation in the past two weeks. Younger age, previous psychiatric diagnosis, and current substance use were associated with reports of depression symptoms, anxiety symptoms, and death ideation. Conclusion Cancer survivors entering survivorship after curative treatment experience elevated prevalence of depressive symptoms, anxiety symptoms, and death ideation. Younger cancer survivors and those with previous psychiatric diagnoses or substance use may be at particular risk for mental health problems during the first year of survivorship. Future research should further examine modifiable risk factors for depression, anxiety, and death ideation in cancer survivors at the transition into survivorship after curative treatment in order to improve survivorship care within both oncology and primary care.

Background Inflammation may contribute to cognitive difficulties in patients with breast cancer. We tested 2 hypotheses: inflammation is elevated in patients with breast cancer vs noncancer control participants and inflammation in patients is associated with worse attention and processing speed over the course of chemotherapy. Methods Serum cytokines (interleukin [IL]–4, 6, 8, 10; tumor necrosis factor [TNF]–α) and soluble receptors [sTNFRI, II]) were measured in 519 females with breast cancer before and after chemotherapy and 338 females without cancer serving as control participants. Attention and processing speed were measured by Rapid Visual Processing (RVP), Backward Counting (BCT), and Trail Making-A (TMT-A) tests. Linear regression models examined patient vs control cytokines and receptor levels, adjusting for covariates. Linear regression models also examined relationships between patient cytokines and receptor levels and test performance, adjusting for age, body mass index, anxiety, depression, cognitive reserve, and chemotherapy duration. Statistical tests were 2-sided (α = .05). Results sTNFRI and sTNFRII increased over time in patients relative to controls, whereas IL-4, IL-6, and IL-10 decreased. Prechemotherapy, higher IL-8 associated with worse BCT (β = 0.610, SE = 0.241, P = .01); higher IL-4 (β = −1.098, SE = 0.516, P = .03) and IL-10 (β = −0.835, SE = 0.414, P = .04) associated with better TMT-A. Postchemotherapy, higher IL-8 (β = 0.841, SE = 0.260, P = .001), sTNFRI (β = 6.638, SE = 2.208, P = .003), and sTNFRII (β = 0.913, SE = 0.455, P = .045) associated with worse BCT; higher sTNFRII also associated with worse RVP (β = −1.316, SE = 0.587, P = .03). At prechemotherapy, higher IL-4 predicted RVP improvement over time (β = 0.820, SE = 0.336, P = .02); higher sTNFRI predicted worse BCT over time (β = 5.566, SE = 2.367, P = .02). Longitudinally, increases in IL-4 associated with BCT improvement (β = −0.564, SE = 0.253, P = .03). Conclusions Generally, worse attention and processing speed were associated with higher inflammatory cytokines and receptors and lower anti-inflammatory cytokines in patients; future confirmatory studies are needed.

Background Maternal thyroid hormones facilitate optimal foetal neurodevelopment, however the exact role of the thyroid hormones on specific cognitive outcomes is unknown. Objectives This study aimed to investigate associations between maternal thyroid function and neurodevelopmental outcomes at 20 months in the Seychelles Child Development Study (SCDS, n=1535). Methods Maternal free thyroid hormones (fT3, fT4 and fTSH) were assessed at 28 weeks gestation with a range of child cognitive outcomes analysed at 20 months. Dietary iodine intake was analysed for a subset of women through a Food Frequency Questionnaire (FFQ) (n=422), with a median iodine intake of 233µg/d, slightly below the recommended iodine intake for pregnancy as advised by the WHO (>250µg/d). Linear regression analysis was used to test associations between serum concentrations of fT3, fT4 and fTSH and child cognitive outcomes. Thyroid hormones were analysed both as continuous data and also categorised as quintiles. 95% of mothers had optimal thyroid function based on their TSH concentrations. Results Results show that maternal fT3, fT4 and TSH were not significantly associated with any cognitive outcomes at 20 months in this high fish-eating population. However, a positive association, using quintiles for fT3, was reported for Motor Development Index (MDI; a subtest of the Bayley’s Scales of Infant Development), between Q3 vs Q4 (β 0.073; p 0.043) and for Q3 vs Q5 (β value 0.086; p 0.018). Conclusions Thus, it is possible mothers in our cohort, who largely have optimal thyroid function and iodine intakes, are able to regulate thyroid function throughout pregnancy to meet neurodevelopmental needs. However, it is likely that minor imbalances of fT3, as indicated from our quintile analysis, may impact offspring neurodevelopment. Thus, further investigation is warranted, particularly focusing on thyroid hormone fluctuation throughout pregnancy in relation to possible associations with infant neurodevelopment.

OBJECTIVE: To determine if cesarean delivery is adversely associated with child neurodevelopment as measured at 20 months and 7 years. METHODS: In a prospective cohort study (n = 1,328) in the Republic of Seychelles, we examined the association between mode of delivery and 22 measures of child neurodevelopment spanning multiple domains: cognition, executive and psychomotor function, language development, behavior, scholastic achievement, and social communication. Using multivariable linear regression, we evaluated the relationship between delivery mode (Cesarean/vaginal delivery) and each developmental outcome, while controlling for relevant covariates including child sex and age, maternal age, maternal IQ, whether both parents lived with the child, and Hollingshead socioeconomic status. RESULTS: At 20 months, children born via cesarean delivery had slightly higher scores (β = 0.11, 95% confidence interval: 0.00, 0.21) on the Infant Behavior Questionnaire–Revised Positive Affectivity/Surgency subtest, a measure of infant temperament, as compared to vaginal delivery. Delivery mode was not associated with any of the 7-year developmental outcomes. CONCLUSIONS FOR PRACTICE: Our study does not support the notion that cesarean delivery is associated with child neurodevelopmental outcomes.

BACKGROUND: Damage to the insula disrupts nicotine-induced cravings and is associated with greater odds of cessation. The role of laterality in regulating these changes is unclear. Neuroimaging studies in cigarette smokers show left hemispheric activation during a period of forced withdrawal and right hemispheric activation after having just smoked. Among current smokers hospitalized for stroke involving their insula, we compared left versus right insular damage and its effect on smoking outcomes. METHODS: A total of 37 smokers hospitalized with unilateral insular strokes (14 right, 23 left) were administered questionnaires to assess urge (Questionnaire on Smoking Urges) before (retrospectively) and during hospitalization and 3 months post-stroke, withdrawal during hospitalization (Wisconsin Smoking Withdrawal Scale), and prolonged abstinence at 3 months post-stroke. Crude and adjusted linear regression models were performed controlling for baseline covariates. RESULTS: Right and left insular-damaged smokers experienced a significant decrease in urge from baseline to hospitalization and three-month follow-up (p

The association between mental health symptoms and the quantity of green space surrounding the homes of people who recently experienced a cardiovascular event were examined while also assessing pla...

Background: Previous work reported increased rates of acute cardiovascular hospitalizations associated with increased PM2.5 concentrations in the previous few days across urban centers in New York State from 2005 to 2016. These relative rates were higher after air quality policies and economic changes resulted in decreased PM2.5 concentrations and changes in PM composition (e.g. increased secondary organic carbon), compared to before and during these changes. Changes in PM composition and sources may explain this difference. Objectives: To estimate the rate of acute cardiovascular hospitalizations associated with increases in source specific PM2.5 concentrations. Methods: Using source apportioned PM2.5 concentrations at the same NYS urban sites, a time-stratified case-crossover design, and conditional logistic regression models adjusting for ambient temperature and relative humidity, we estimated the rate of these acute cardiovascular hospitalizations associated with increases in mean source specific PM2.5 concentrations in the previous 1, 4, and 7 days. Results: Interquartile range (IQR) increases in spark-ignition emissions (GAS) concentrations were associated with increased excess rates of cardiac arrhythmia hospitalizations (2.3%; 95% CI = 0.4%, 4.2%; IQR = 2.56 μg/m3) and ischemic stroke hospitalizations (3.7%; 95% CI = 1.1%, 6.4%; 2. 73 μg/m3) over the next day. IQR increases in diesel (DIE) concentrations were associated with increased rates of congestive heart failure hospitalizations (0.7%; 95% CI = 0.2% 1.3%; 0.51 μg/m3) and ischemic heart disease hospitalizations (0.8%; 95% CI = 0.3%, 1.3%; 0.60 μg/m3) over the next day, as hypothesized. However, secondary sulfate PM2.5 (SS) was not. Increased acute cardiovascular hospitalization rates were also associated with IQR increases in concentrations of road dust (RD), residual oil (RO), and secondary nitrate (SN) over the previous 1, 4, and 7 days, but not other sources. Conclusions: These findings suggest a role of several sources of PM2.5 in New York State (i.e. traffic emissions, non-traffic emissions such as brake and tire wear, residual oil, and nitrate that may also reflect traffic emissions) in the triggering of acute cardiovascular events. Keywords: Cardiovascular hospitalizations, Air pollution, Source apportionment, Traffic emissions

Background: Fish contains methylmercury (MeHg) which can cause oxidative stress and neurodevelopmental toxicity at sufficiently high doses. Fish also contains polyunsaturated fatty acids (PUFA) which have both antioxidant (n-3) and oxidant (n-6) properties. Mitochondrial DNA (mtDNA) is sensitive to oxidative stress but has not been previously studied in relation to MeHg exposure or PUFA status. Objective: To investigate the associations between MeHg exposure and PUFA status during pregnancy with relative mitochondrial DNA copy number (RmtDNAcn) in mothers and their newborns. Methods: In total, 1488 mother-child pairs from the Seychelles Child Development Study Nutrition Cohort 2 were included in this study. Total Hg was measured in maternal blood collected at 28 weeks' gestation, maternal hair at delivery, and in fetal cord blood. PUFA (n-3 and n-6) were measured only in maternal blood. RmtDNAcn was measured by qPCR in both maternal and cord blood. Results: Increasing maternal blood Hg (β = 0.001, 95%CI: 0.000, 0.002) and n-3 PUFA concentrations (β = 0.183, 95%CI: 0.048, 0.317) were associated with higher maternal RmtDNAcn. Increasing maternal n-6 PUFA (β = −0.103, 95%CI: −0.145, −0.062) and n-6/n-3 ratio (β = −0.011, 95%CI: −0.017, −0.004) were associated with lower maternal RmtDNAcn. Increasing fetal cord blood Hg was associated with lower fetal RmtDNAcn (β = −0.002, 95%CI: −0.004, −0.000). Neither maternal blood Hg nor PUFA status was associated with fetal RmtDNAcn. Conclusions: Our findings suggest that MeHg and PUFA may influence mitochondrial homeostasis although the magnitude of these associations are small. Future studies should confirm the findings and explore the underlying mechanisms. Keywords: Mitochondrial DNA, Methylmercury, Mercury, Polyunsaturated fatty acids

Specific health-risk behaviors are present in older adolescents and young adults wtih Tourette syndrome (TS), but little is known about health-risk behaviors in youth with TS.We compared responses on the Youth Risk Behavior Surveillance System (YRBS) in youth with TS with those in a concurrent community control group. The YRBS evaluates risk behaviors most closely associated with morbidity and mortality in young people. Tic severity, presence of comorbid attention-deficit/hyperactivity disorder (ADHD), measures of ADHD symptom severity, and whether or not the individual had been bullied in school were also compared between the groups.Data from 52 youth with TS and 48 control youth were included. We did not detect any differences between control youth and youth with TS in the reporting of risky behaviors. Tic severity was not significantly associated with high-risk behavior. However, ADHD was significantly more common in youth with TS (P 0.0002), and youth with TS who identified themselves as victims of bullying had significantly higher ADHD symptom severity scores (P = 0.04) compared with those who were not bullied.Risk behaviors are not reliably or clinically different in youth with TS compared with control youth. ADHD severity, but not tic severity, was associated with being bullied in youth with TS.

Drug addiction is a public health crisis for which new treatments are urgently needed. In rare cases, regional brain damage can lead to addiction remission. These cases may be used to identify therapeutic targets for neuromodulation. We analyzed two cohorts of patients addicted to smoking at the time of focal brain damage (cohort 1 n = 67; cohort 2 n = 62). Lesion locations were mapped to a brain atlas and the brain network functionally connected to each lesion location was computed using human connectome data (n = 1,000). Associations with addiction remission were identified. Generalizability was assessed using an independent cohort of patients with focal brain damage and alcohol addiction risk scores (n = 186). Specificity was assessed through comparison to 37 other neuropsychological variables. Lesions disrupting smoking addiction occurred in many different brain locations but were characterized by a specific pattern of brain connectivity. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula and negative connectivity to the medial prefrontal and temporal cortex. This circuit was reproducible across independent lesion cohorts, associated with reduced alcohol addiction risk, and specific to addiction metrics. Hubs that best matched the connectivity profile for addiction remission were the paracingulate gyrus, left frontal operculum, and medial fronto-polar cortex. We conclude that brain lesions disrupting addiction map to a specific human brain circuit and that hubs in this circuit provide testable targets for therapeutic neuromodulation.

Optimal maternal long-chain PUFA (LCPUFA) status is essential for the developing fetus. The fatty acid desaturase (FADS) genes are involved in the endogenous synthesis of LCPUFA. The minor allele of various FADS SNP have been associated with increased maternal concentrations of the precursors linoleic acid (LA) and α-linolenic acid (ALA), and lower concentrations of arachidonic acid (AA) and DHA. There is limited research on the influence of FADS genotype on cord PUFA status. The current study investigated the influence of maternal and child genetic variation in FADS genotype on cord blood PUFA status in a high fish-eating cohort. Cord blood samples (n 1088) collected from the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2) were analysed for total serum PUFA. Of those with cord PUFA data available, maternal (n 1062) and child (n 916), FADS1 (rs174537 and rs174561), FADS2 (rs174575), and FADS1-FADS2 (rs3834458) were determined. Regression analysis determined that maternal minor allele homozygosity was associated with lower cord blood concentrations of DHA and the sum of EPA + DHA. Lower cord blood AA concentrations were observed in children who were minor allele homozygous for rs3834458 (β = 0·075; P = 0·037). Children who were minor allele carriers for rs174537, rs174561, rs174575 and rs3834458 had a lower cord blood AA:LA ratio (P < 0·05 for all). Both maternal and child FADS genotype were associated with cord LCPUFA concentrations, and therefore, the influence of FADS genotype was observed despite the high intake of preformed dietary LCPUFA from fish in this population.

Experimental and epidemiological evidence suggests that environmental toxicants may influence susceptibility to influenza and respiratory syncytial virus (RSV). The objective of the present study was to estimate the association between blood lead concentrations and the odds of child influenza or RSV infection. A test-negative, case-control study was conducted among 617 children, &lt, 4 years of age, tested for influenza/RSV from 2012&ndash, 2017 in Rochester, NY. There were 49 influenza cases (568 controls) and 123 RSV cases (494 controls). Blood lead concentrations reported in children&rsquo, s medical records were linked with influenza/RSV lab test results. Covariables were collected from medical records, birth certificates, and U.S. census data. In this sample, evidence of an association between blood lead levels and RSV or influenza diagnosis was not observed. Children with a lead level &ge, 1 &mu, g/dL vs. &lt, g/dL had an adjusted odds ratio (aOR) and 95% confidence limit of 0.95 (0.60, 1.49) for RSV and 1.34 (0.65, 2.75) for influenza. In sex-specific analyses, boys with lead concentrations &ge, g/dL had an aOR = 1.89 (1.25, 2.86) for influenza diagnosis, while the estimates were inconsistent for girls. These results are suggestive of sex-specific associations between blood lead levels and the risk of influenza, although the sample size was small.

PURPOSE: Long-term exposure to ambient fine particle (PM(2.5)) concentrations has been associated with an increased rate or risk of neurodegenerative conditions but individual PM sources have not been previously examined in relation to neurodegenerative diseases. METHODS: Using the Statewide Planning and Research Cooperative System database, we studied 63,287 hospital admissions with a primary diagnosis of either Alzheimer’s disease (AD), dementia, or Parkinson’s disease (PD) for New York State (NYS) residents living within 15 miles from six PM(2.5) monitoring sites. In addition to PM(2.5) concentrations, we studied seven specific PM(2.5) sources: secondary sulfate, secondary nitrate, biomass burning, diesel, spark-ignition emissions, pyrolyzed organic rich, and road dust. We estimated the rate of neurodegenerative hospital admissions associated with increased concentration of PM(2.5) and individual PM(2.5) sources average concentrations in the previous 0–29, 0–179, and 0–364 days. RESULTS: Increases in ambient PM(2.5) concentrations were not consistently associated with increased hospital admissions rates. Increased source-specific PM2.5 concentrations were associated with both increased (e.g., secondary sulfates and diesel emissions) and decreased rates (e.g., secondary nitrate and spark-ignition vehicular emissions) of neurodegenerative admissions. CONCLUSIONS: We did not observe clear associations between overall ambient PM(2.5) concentrations or source apportioned ambient PM(2.5) contributions and rates of neurologic disease hospitalizations.

PURPOSE: Androgen deprivation therapy (ADT) is commonly used to treat patients with advanced prostate cancer but is associated with functional decline. Bioelectrical impedance analysis (BIA)-derived phase angle may reflect frailty and functional decline in cancer patients. High-dose vitamin D supplementation may improve phase angle values and physical function. METHODS: We conducted an exploratory analysis from a phase II randomized controlled trial investigating the efficacy of high-dose vitamin D supplementation in prostate cancer patients (age ≥ 60 yrs). Fifty-nine patients were randomized to high-dose vitamin D (600 IU/day plus 50,000 IU/week) or low-dose: RDA for vitamin D (600 IU/day plus placebo weekly) for 24 weeks. Phase angle was measured by BIA. Physical function measures included handgrip strength, 6-minute walk test, Short Performance Physical Battery and leg extension. All testing was completed at baseline, week 12 and week 24. RESULTS: Phase angle values were wider over the entire study in the high-dose vitamin D arm indicating healthier muscle cells. The low-dose vitamin D arm had phase angle values consistent with frailty cutoffs in older men (< 5.7°). CONCLUSION: Patients in the high-dose vitamin D arm experienced wider phase angle values over the course of the study which may indicate less frailty. ClinicalTrials.gov ID: NCT02064946.

Background Methylmercury (MeHg) is present in fish and is a neurotoxicant at sufficiently high levels. One potential mechanism of MeHg toxicity early in life is epigenetic dysregulation that may affect long-term neurodevelopment. Altered DNA methylation of nervous system-related genes has been associated with adult mental health outcomes. Objective To assess associations between prenatal MeHg exposure and DNA methylation (at the cytosine of CG dinucleotides, CpGs) in three nervous system-related genes, encoding brain-derived neurotropic factor (BDNF), glutamate receptor subunit NR2B (GRIN2B), and the glucocorticoid receptor (NR3C1), in children who were exposed to MeHg in utero. Methods We tested 406 seven-year-old Seychellois children participating in the Seychelles Child Development Study (Nutrition Cohort 2), who were prenatally exposed to MeHg from maternal fish consumption. Total mercury in maternal hair (prenatal MeHg exposure measure) collected during pregnancy was measured using atomic absorption spectroscopy. Methylation in DNA from the children’s saliva was measured by pyrosequencing. To assess associations between prenatal MeHg exposure and CpG methylation at seven years of age, we used multivariable linear regression models adjusted for covariates. Results We identified associations with prenatal MeHg exposure for DNA methylation of one GRIN2B CpG and two NR3C1 CpGs out of 12 total CpG sites. Higher prenatal MeHg was associated with higher methylation for each CpG site. For example, NR3C1 CpG3 had an expected increase of 0.03-fold for each additional 1 ppm of prenatal MeHg (B = 0.030, 95% CI 0.001, 0.059; p = 0.047). Several CpG sites associated with MeHg are located in transcription factor binding sites and the observed methylation changes are predicted to lead to lower gene expression. Conclusions In a population of people who consume large amounts of fish, we showed that higher prenatal MeHg exposure was associated with differential DNA methylation at seven years of age at specific CpG sites that may influence neurodevelopment and mental health.

Objective To develop a novel predictive model using primarily clinical history factors and compare performance to the widely used Rochester Low Risk (RLR) model. Study design In this cross-sectional study, we identified infants brought to one pediatric emergency department from January 2014 to December 2016. We included infants age 0-90 days, with temperature ≥38°C, and documented gestational age and illness duration. The primary outcome was bacterial infection. We used 10 predictors to develop regression and ensemble machine learning models, which we trained and tested using 10-fold cross-validation. We compared areas under the curve (AUCs), sensitivities, and specificities of the RLR, regression, and ensemble models. Results Of 877 infants, 67 had a bacterial infection (7.6%). The AUCs of the RLR, regression, and ensemble models were 0.776 (95% CI 0.746, 0.807), 0.945 (0.913, 0.977), and 0.956 (0.935, 0.975), respectively. Using a bacterial infection risk threshold of .01, the sensitivity and specificity of the regression model was 94.6% (87.4%, 100%) and 74.5% (62.4%, 85.4%), compared with 95.5% (87.5%, 99.1%) and 59.6% (56.2%, 63.0%) using the RLR model. Conclusions Compared with the RLR model, sensitivities of the novel predictive models were similar whereas AUCs and specificities were significantly greater. If externally validated, these models, by producing an individualized bacterial infection risk estimate, may offer a targeted approach to young febrile infants that is noninvasive and inexpensive.

Author(s): Myers, Gary; van Wijngaarden, Edwin; Lasley, Stephen M; Cranmer, Joan M; Lein, Pamela J; Westerink, Remco HS

Cancer-related cognitive impairment (CRCI) has not been objectively assessed in chronic lymphocytic leukemia (CLL). It is currently unclear how much of CRCI is attributable to disease, treatment, or both. We used CLL as a novel model to study the differential roles of disease and treatment in CRCI. 150 CLL patients (100 treatment-naïve and 50 chemotherapy-treated) including 84 patients with higher-risk of CLL progression completed objective neuropsychological tests. Sociodemographic-adjusted linear regression models examined cognitive outcomes in relation to risk and treatment. Higher-risk patients recalled 2 fewer words on a memory task (β=−1.8, 95%CI-3.3,−0.3) and took 15 seconds longer on an executive function task (β=15.4, 95%CI 3.1,27.6) than lower-risk patients, independent of treatment. Treated patients reported greater cognitive difficulties than treatment-naive patients (β=−6.1, 95%CI-10.1,−2.2) but did not perform worse on objective measures. Higher-risk patients experienced impairments in executive function and memory suggesting that disease biology contributes to CRCI independent of treatment.

Background Maternal fish consumption increases infant methylmercury (MeHg) exposure and polyunsaturated fatty acid (PUFA) concentrations. The n-3 PUFA are regulators of inflammation while MeHg may impact the cord cytokine profile and, subsequently, contribute to immune mediated outcomes. This study aimed to investigate associations between infant MeHg exposure and cord cytokine concentrations while adjusting for cord PUFA. Methods We studied participants in the Seychelles Child Development Study (SCDS) Nutrition Cohort 2 (NC2), a large birth cohort in a high fish-eating population. Whole blood MeHg, serum PUFA and serum cytokine concentrations (IFN-γ, IL-1β, IL-2, IL-12p70, TNF-α, IL-4, IL-10, IL-13, IL-6 and IL-8) were measured in cord blood collected at delivery (n = 878). Linear regression examined associations between infant MeHg exposure and cord cytokines concentrations, with and without adjustment for cord PUFA. An interaction model examined cord MeHg, cytokines and tertiles of the n-6:n-3 ratio (low/medium/high). Results There was no overall association between cord MeHg (34.08 ± 19.98 μg/L) and cytokine concentrations, with or without adjustment for PUFA. Increased total n-3 PUFA (DHA, EPA and ALA) was significantly associated with lower IL-10 (β = −0.667; p = 0.007) and lower total Th2 (IL-4, IL-10 and IL-13) (β = −0.715; p = 0.036). In the interaction model, MeHg and IL-1β was positive and significantly different from zero in the lowest n-6:n-3 ratio tertile (β = 0.002, p = 0.03). Conclusion Methylmercury exposure from fish consumption does not appear to impact markers of inflammation in cord blood. The association of cord n-3 PUFA with lower IL-10 and total Th2 cytokines suggests that they may have a beneficial influence on the regulation of the inflammatory milieu. These findings are important for public health advice and deserve to be investigated in follow up studies.