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Background: The Japan Environment and Children's Study (JECS) is a nationwide birth cohort study investigating environmental effects on children's health and development. A Sub-Cohort Study has begun, conducting extended exposure and outcome measurements by targeting a subgroup randomly selected from the JECS Main Study. We report the Sub-Cohort Study methodology and participants' baseline profiles., Methods: Of 100,148 children in the JECS Main Study, children born after April 1, 2013 who met eligibility criteria ([1] all questionnaire and medical record data from children and their mothers collected from the first trimester to 6 months of age, [2] biospecimens [except umbilical cord blood] from children and their mothers collected at first to second/third trimester and delivery) were randomly selected for each Regional Centre at regular intervals. Face-to-face assessment of neuropsychiatric development, body measurement, paediatrician's examination, blood/urine collection for clinical testing and chemical analysis, and home visits (ambient and indoor air measurement and dust collection) are conducted. Participants are followed up at 1.5 and 3 years old for home visits, and 2, 4, 6, and 8 years old for developmental/medical examination. The details of protocols after age 10 are under discussion., Results: Of 10,302 selected children, 5,017 participated. The profiles of the participating mothers, fathers and children did not substantially differ between the Main Study and Sub-Cohort Study., Conclusion: The JECS Sub-Cohort Study offers a platform for investigating associations between environmental exposure and outcomes.

The occurrence of anorectal malformations (ARM) is thought to be reduced with sufficient folate intake. However, there is no apparent evidence. We focused on enzyme cofactors for one-carbon metabolism, including folate (vitamin B9), vitamin B6 and vitamin B12, and explored the association between maternal combined intake of these B vitamins and the risk of ARM. Using baseline data from a Japanese nationwide birth cohort study between 2011 and 2014, we analysed data of 89 235 women (mean age at delivery = 31·2 years) who delivered singleton live births without chromosomal anomalies. Information on dietary intake was obtained via a FFQ focused on early pregnancy and used to estimate B vitamin intake. We also collected information on the frequency of folic acid supplement use. ARM occurrence was ascertained from medical records. We identified forty-three cases of ARM diagnosed up to the first month after birth (4·8 per 10 000 live births). In terms of individual intake of the respective B vitamins, high vitamin B6 intake was non-significantly associated with reduced odds of ARM. Compared with women in the low combined B vitamin intake group, the OR of having an infant with ARM was 0·4 (95 % CI 0·2, 1·0) in the high intake group (folate ≥400 μg/d, and upper half of vitamin B6 and/or vitamin B12). In conclusion, our cohort analysis suggested an inverse association between the combined intake of one-carbon metabolism-related B vitamins in early pregnancy and ARM occurrence.

Objective: For several observational studies that have reported the factors related to gastroschisis, the target population in these studies was mainly residents of Europe or the US, and there is little data on the Asian population. In this study, we summarised characteristics of Japanese women who delivered infants with gastroschisis, particularly focusing on the pre-pregnancy body mass index (BMI), which was found to be inversely associated with gastroschisis in past studies, because the distribution of BMI is clearly different in Asia and the West., Results: We used data from a nationwide birth cohort study which recruited pregnant women between 2011 and 2014. Among 92,796 women who delivered singleton live births, the frequency of underweight (pre-pregnancy BMI < 18.5 kg/m 2 ) was 16.2%, reference weight (18.5-24.9 kg/m 2 ) 73.1%, and overweight (≥ 25.0 kg/m 2 ) 10.6%. We identified only 9 infants with gastroschisis, 2 of whose women were underweight (frequency of gastroschisis = 0.01%), 5 were in the reference group (0.01%), and 2 were overweight (0.02%). Of these 9 women, none were aged < 20 years, 2 were aged 20-29 years (frequency = 0.01%), and 7 were aged 30-39 years (0.01%). No reduction in the occurrence of gastroschisis was apparent among Japanese women who were overweight before pregnancy.

The pathogenesis of congenital diaphragmatic hernia (CDH) is largely unknown; however, vitamin A seems to play a role in diaphragmatic development. Previous case-control studies reported that maternal dietary vitamin A intake was inversely associated with the risk of CDH. To our knowledge, however, there is no prospective evidence regarding this association. Our aim was to examine whether maternal intake of vitamin A was associated with CDH occurrence. Baseline data, from the Japan nationwide birth cohort study (2011-2014) of 89 658 mothers (mean age at delivery = 31·2 years) who delivered singleton live births, were analysed. We assessed dietary habits using an FFQ focused on the first trimester and estimated the daily intake of total vitamin A (retinol activity equivalents), retinol, provitamin A carotenoids and vegetables. The occurrence of CDH was ascertained from medical records. A total of forty cases of CDH were documented. The adjusted OR of CDH occurrence for the high total vitamin A intake category (median = 468 μg/d) was 0·6 (95 % CI 0·3, 1·2) with reference to the low intake category (230 μg/d). When we restricted to mothers with a prepregnancy BMI of 18·5-24·9 kg/m2, vitamin A intake was inversely associated with the risk of their children being born with CDH (OR 0·5, 95 % CI 0·2, 1·0). Even given the limited number of cases in the study, our findings provide additional evidence to link vitamin A with CDH.

Objective: To explore the association between isoflavone intake in early pregnancy (the critical window of masculinisation) and hypospadias. Since oestrogen is likely to contribute to the differentiation of male external genitalia, dietary intake of isoflavone, which has a similar structure to human oestrogen, may be associated with the occurrence of hypospadias. However, there has been little evidence of this association., Materials and Methods: We used data of a nationwide birth cohort study, which recruited women as early in pregnancy as possible throughout Japan between 2011 and 2014. From the response to a self-administered food-frequency questionnaire, the daily intake of genistein (as a representative for isoflavone) was estimated. Information on hypospadias cases that were diagnosed until the first month after birth was obtained from medical records. Odds ratios (ORs) of hypospadias were estimated using a logistic regression model., Results: Among 41,578 mothers, who delivered singleton live male births, the median genistein intake was 15.3 mg/day, and a total of 51 cases of hypospadias were identified. Compared with mothers in the reference group (genistein intake 11th-89th percentiles), those in the low intake group (≤10th percentile) had an elevated risk of their sons having hypospadias (multivariable-adjusted OR = 2.8, 95% confidence interval = 1.4-5.8). Adverse or beneficial effects of genistein on hypospadias were not observed in the high intake group (≥90th percentile) (OR = 0.9, 95% confidence interval = 0.4-2.4)., Conclusion: Low maternal intake of isoflavone in early pregnancy was associated with an elevated risk of hypospadias., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Current evidence suggests that the aetiology of congenital gastrointestinal (GI) tract atresia is multifactorial, and not based solely on genetic factors. However, there are no established modifiable risk factors for congenital GI tract atresia. We used data from a Japanese nationwide birth cohort study launched in 2011, and examined whether fish consumption in early pregnancy was associated with congenital GI tract atresia. We analysed data of 89 495 women (mean age at delivery=31·2 years) who delivered singleton live births without chromosomal anomalies. Based on the results of the FFQ, we estimated the daily intake of fish and n-3 PUFA consumption in early pregnancy. We defined a composite outcome (oesophageal atresia, duodenal atresia, jejunoileal atresia and/or anorectal malformation) as congenital GI tract atresia. In this population, median fish intake was 31·9 g/d, and seventy-four cases of congenital GI tract atresia were identified. Fish consumption in early pregnancy was inversely associated with the composite outcome (multivariable-adjusted OR for the high v. low consumption category=0·5, 95 % CI 0·3, 1·0). For all the specific types of atresia, decreased OR were observed in the high consumption category, although not statistically significant. Reduced atresia occurrence was observed even beyond the US Food and Drug Administration's recommended consumption of no more than 340 g/week. Also, n-3 PUFA-rich fish and n-3 PUFA consumptions tended to be inversely associated with atresia. Fish consumption in early pregnancy may be a preventive factor for congenital GI tract atresia.

Background: The Japan Environment and Children's Study (JECS) is a nation-wide birth cohort study investigating environmental effects on children's health and development. In this study, the exposure characteristics of the JECS participating mothers were summarized using two questionnaires administered during pregnancy., Methods: Women were recruited during the early period of their pregnancy. We intended to administer the questionnaire during the first trimester (MT1) and the second/third trimester (MT2). The total number of registered pregnancies was 103,099., Results: The response rates of the MT1 and MT2 questionnaires were 96.8% and 95.1%, respectively. The mean gestational ages (SDs) at the time of the MT1 and MT2 questionnaire responses were 16.4 (8.0) and 27.9 (6.5) weeks, respectively. The frequency of participants who reported "lifting something weighing more than 20 kg" during pregnancy was 5.3% for MT1 and 3.9% for MT2. The Cohen kappa scores ranged from 0.07 to 0.54 (median 0.31) about the occupational chemical use between MT1 and MT2 questionnaires. Most of the participants (80%) lived in either wooden detached houses or steel-frame collective housing. More than half of the questionnaire respondents answered that they had "mold growing somewhere in the house". Insect repellents and insecticides were used widely in households: about 60% used "moth repellent for clothes in the closet," whereas 32% applied "spray insecticide indoors" or "mosquito coil or an electric mosquito repellent mat.", Conclusions: We summarized the exposure characteristics of the JECS participants using two maternal questionnaires during pregnancy.

Background: The Japan Environment and Children's Study (JECS), known as Ecochil-Chosa in Japan, is a nationwide birth cohort study investigating the environmental factors that might affect children's health and development. We report the baseline profiles of the participating mothers, fathers, and their children., Methods: Fifteen Regional Centres located throughout Japan were responsible for recruiting women in early pregnancy living in their respective recruitment areas. Self-administered questionnaires and medical records were used to obtain such information as demographic factors, lifestyle, socioeconomic status, environmental exposure, medical history, and delivery information. In the period up to delivery, we collected bio-specimens, including blood, urine, hair, and umbilical cord blood. Fathers were also recruited, when accessible, and asked to fill in a questionnaire and to provide blood samples., Results: The total number of pregnancies resulting in delivery was 100,778, of which 51,402 (51.0%) involved program participation by male partners. Discounting pregnancies by the same woman, the study included 95,248 unique mothers and 49,189 unique fathers. The 100,778 pregnancies involved a total of 101,779 fetuses and resulted in 100,148 live births. The coverage of children in 2013 (the number of live births registered in JECS divided by the number of all live births within the study areas) was approximately 45%. Nevertheless, the data on the characteristics of the mothers and children we studied showed marked similarity to those obtained from Japan's 2013 Vital Statistics Survey., Conclusions: Between 2011 and 2014, we established one of the largest birth cohorts in the world.

Introduction: One of the ethical issues surrounding birth cohort studies is how to obtain informed assent from children as they grow up. What and how parents tell their children affects children's future choices about the study, yet few studies have focused on parents' influence on children., Objective: This study examines parents' attitudes towards telling their children about their participation in a specific birth cohort study., Methods: We conducted surveys and in-depth interviews with the parents of children who participated in the "Japan Environment and Children's Study" (JECS), which follows children from the foetal stage to age 13., Results: Forty-four mothers and 23 fathers answered the survey, and 11 mothers and 3 fathers participated in in-depth interviews. Parents' attitudes towards "telling" were categorized into 3 communication styles depending on their perception of the risk/benefits for their children. Most parents predicted that the study would benefit their children and preferred "directive telling," which we divided into "empowered telling" (provides children with a positive identity as participants) and "persuasive telling" (attempts to persuade children even if they express reluctance as they grow). A few parents, weighing the study's potential risk, preferred "non-directive telling," which respects children's choices even if that means withdrawing from the study., Discussion: While "directive telling" may lead children to have positive associations with the study, children should also be told about the risks. Investigators can provide materials that support parents and give children age-appropriate information about their participation, as well as ensure opportunities for children to express their feelings., (© 2017 The Authors Health Expectations Published by John Wiley & Sons Ltd.)

Pain management for needle-related procedures is poor in Japan. In many countries the use of lidocaine/prilocaine cream for the relief of pain associated with venipuncture has been approved. In children, a psychological approach has also been shown to be effective in reducing pain with venipuncture. We developed a multidisciplinary procedure that combines a cream (2.5% lidocaine and 2.5% prilocaine) and pharmacological approaches such as preparation, education, positioning and distraction. We evaluated the feasibility and acceptability of the procedure for young children. Among 132 pediatric participants, 58.3% did not cry during venipuncture. According to caregiver questionnaire, 71.9% felt that the multidisciplinary procedure eliminated the fear of needle-related procedures in the children; 90.9% were satisfied with it and 75.8% thought it should be applied to all children undergoing venipuncture. The present results suggest that the multidisciplinary procedure is feasible, acceptable and suitable for use in children undergoing venipuncture., (© 2015 Japan Pediatric Society.)

Background: The Japan Environment and Children's Study (JECS) is an ongoing nationwide birth cohort study launched in January 2011. In this progress report, we present data collected in the first year to summarize selected maternal and infant characteristics., Methods: In the 15 Regional Centers located throughout Japan, the expectant mothers were recruited in early pregnancy at obstetric facilities and/or at local government offices issuing pregnancy journals. Self-administered questionnaires were distributed to the women during their first trimester and then again during the second or third trimester to obtain information on demographic factors, physical and mental health, lifestyle, occupation, environmental exposure, dwelling conditions, and socioeconomic status. Information was obtained from medical records in the first trimester and after delivery on medical history, including gravidity and related complications, parity, maternal anthropometry, and infant physical examinations., Results: We collected data on a total of 9819 expectant mothers (mean age = 31.0 years) who gave birth during 2011. There were 9635 live births. The selected infant characteristics (singleton births, gestational age at birth, sex, birth weight) in the JECS population were similar to those in national survey data on the Japanese general population., Conclusions: Our final birth data will eventually be used to evaluate the national representativeness of the JECS population. We hope the JECS will provide valuable information on the impact of the environment in which our children live on their health and development.

We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations.

With the advent of dense maps of human genetic variation, it is now possible to detect positive natural selection across the human genome. Here we report an analysis of over 3 million polymorphisms from the International HapMap Project Phase 2 (HapMap2). We used 'long-range haplotype' methods, which were developed to identify alleles segregating in a population that have undergone recent selection, and we also developed new methods that are based on cross-population comparisons to discover alleles that have swept to near-fixation within a population. The analysis reveals more than 300 strong candidate regions. Focusing on the strongest 22 regions, we develop a heuristic for scrutinizing these regions to identify candidate targets of selection. In a complementary analysis, we identify 26 non-synonymous, coding, single nucleotide polymorphisms showing regional evidence of positive selection. Examination of these candidates highlights three cases in which two genes in a common biological process have apparently undergone positive selection in the same population:LARGE and DMD, both related to infection by the Lassa virus, in West Africa;SLC24A5 and SLC45A2, both involved in skin pigmentation, in Europe; and EDAR and EDA2R, both involved in development of hair follicles, in Asia.

The International HapMap Consortium has developed the HapMap, a resource that describes the common patterns of human genetic variation (haplotypes). Processes of community/public consultation and individual informed consent were implemented in each locality where samples were collected to understand and attempt to address both individual and group concerns. Perceptions about the research varied, but we detected no critical opposition to the research. Incorporating community input and responding to concerns raised was challenging. However, the experience suggests that approaching genetic variation research in a spirit of openness can help investigators better appreciate the views of the communities whose samples they seek to study and help communities become more engaged in the science., (Copyright 2007 S. Karger AG, Basel.)

The inhibitory activity of a new peptidyl collagenase inhibitor, FN-439 or tetrapeptidyl hydroxamic acid (H2N-C6H4-CO-Gly-L-Pro-D-Leu-D-Ala-NHOH), was determined against vertebrate collagenases derived from human fibroblast, human polymorphonuclear leukocyte (PMN) and tadpole skin. In addition, the effect of FN-439 in inhibiting corneal ulceration was also investigated with alkali-burned rabbit corneas. FN-439 can block the active site of collagenase, and hydroxamic acid can chelate Zn2+ which is essential for collagenase activity. Furthermore, this compound contains D-amino acids to resist nonspecific host-derived degradative enzymes. In our experiments, corneal ulceration occurred in 5 of the 9 control eyes, but in none of the 9 eyes treated with FN-439 (P < 0.01). The only cellular elements observed at the ulcerated area were PMNs and monocytes. FN-439 appeared to act against PMN collagenase. In addition, we compared the change in the concentration of FN-439 (D-peptide) and the L-form of FN-439 (L-peptide) in aqueous humor aspirated from the rabbit eyes burned with alkali. After incubation for 3 hours, the concentration of the D-peptide was decreased by 3%, while that of the L-peptide was decreased by 60%. FN-439 may be useful for treating noninfectious corneal ulcers because of its potent activity (IC50 = 1 microM) and chemical and biological stabilities.