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Objective: The possible effects of Assisted Reproductive Technology (ART) on sex ratio at birth are extremely significant. This study aimed to determine whether ART affects the sex ratio of infants born through in vitro fertilization and embryo transfer (IVF-ET)., Materials and Methods: We ran this retrospective study on 290 singleton infants born following IVF-ET from February 2014 to August 2018 at a single institution. We compared the sex ratios of these infants with respect to insemination versus intracytoplasmic sperm injection (ICSI), early-cleavage embryo versus blastocyst transfer, fresh versus frozen-thawed embryo transfer and normal sperm versus asthenospermia., Results: There were no significant differences in the sex ratio with respect to the fertilization method, transfer time, fresh embryo or frozen-thawed embryo transfer. In addition, the multiple logistic regression analysis revealed that these factors did not significantly affect the sex ratio., Conclusions: Our study indicated that the differences in the fertilization method transfer time and sperm motility rate did not affect the sex ratio of IVF live births. However, with increasing numbers of ICSI and blastocyst transfer cycles, factors possibly affecting the sex ratio need to be further investigated.

Epidemiologic studies investigating the association between birth season and risk of mortality in adulthood are limited and have yielded inconclusive results. We aimed to examine the relationship between birth month and all-cause and cause-specific mortality, after controlling for potential confounders, including lifestyle and medical factors, in a population-based cohort study in Japan. We included 28,884 subjects (13,262 men and 15,622 women) from Takayama City, aged 35 years or older without cancer, stroke, and ischemic heart disease, who were born in Japan at baseline. Participants who were enrolled in 1992 were followed up for over 16 years. Information including place of birth, lifestyles, and medical history was obtained from a baseline questionnaire. We performed a Cox proportional hazards analysis to determine the association between birth month and all-cause and cause-specific mortality after adjusting for potential confounders. During the follow-up period (mean follow-up: 14.1 years), 5,303 deaths (2,881 men and 2,422 women) were identified. After controlling for multiple covariates, it was found that being born in April or June was associated with an increased risk of all-cause mortality compared to being born in January (hazard ratio [HR] 1.138; 95% confidence interval [CI], 1.006-1.288 and HR 1.169; 95% CI, 1.028-1.329, respectively). The HRs for cardiovascular mortality were significantly higher in participants born in March and May (HR 1.285; 95% CI, 1.056-1.565 and HR 1.293; 95% CI, 1.040-1.608, respectively). Our findings indicate that an individual's birth month may be an indicator of the susceptibility to mortality in later life.

Background: In Japan, there are ongoing efforts to shift the gastric cancer prevention and control policy priorities from barium-based screening to Helicobacter pylori (H. pylori)-oriented primary prevention. A comprehensive summary of the evidence regarding the effects of H. pylori eradication on the risk of gastric cancer could inform policy decisions., Methods: We conducted a systematic review and meta-analysis of published studies evaluating the effectiveness of H. pylori eradication for the prevention of gastric cancer in otherwise healthy individuals (primary prevention) and early gastric cancer patients (tertiary prevention)., Results: In total, 19 studies were included. Three moderate-quality observational cohort studies showed that H. pylori eradication may be associated with a decreased risk of gastric cancer in healthy asymptomatic Japanese people. There is moderate certainty regarding the effectiveness of H. pylori eradication in patients with gastrointestinal diseases, such as peptic ulcers. A meta-analysis of 10 observational studies with otherwise healthy individuals (mainly peptic ulcer patients) yielded an overall odds ratio of 0.34 (95% CI: 0.25-0.46). Regarding tertiary prevention, the overall odds ratio for developing metachronous gastric cancer was 0.42 (95% CI: 0.35-0.51) in the eradication group in a meta-analysis of nine studies involving early gastric cancer patients who underwent endoscopic resection., Conclusion: H. pylori eradication is effective in preventing gastric cancer in the Japanese population, regardless of symptoms. Well-designed, large cohort studies are warranted to determine the long-term efficacy and safety of H. pylori eradication in the context of reducing the gastric cancer burden through population-based screening and treatment., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: To evaluate a training program that supports community-based service staff in implementing aging-in-place and end-of-life care programs., Background: Globally, as the population ages, the need for end-of-life care has never been greater. Since Japan is facing the issues of a super-aged population sooner than most countries, there is a particularly urgent need to enhance end-of-life care for older people. Most Japan's older people wish to spend their final days at home, however, only 11-13% end their lives at home, while 73% die in hospitals. As part of care system, small-scale community-based service for aging-in-place established across Japan in 2006 managed locally. These are flexible services using home or facility care or both for the individual to live long term at their preferred place. We developed the end-of-life care educational training program to encourage behavioral changes in community-based service staff of various readiness levels., Design: Mixed methods study design., Methods: A pre-post evaluation of knowledge, confidence and attitude toward end-of-life care, combining quantitative and qualitative data from 53 community-based service staff members who participated in the training program from September 2017 to September 2019. Participants were informed of the end-of-life care process using focus group discussions about end-of-life care and completed surveys evaluating the program before, immediately following and three months after the training. We used the four-level Kirkpatrick model as the evaluation indicator., Results: Quantitative analysis results indicated that participants were satisfied with the training program. Their knowledge scores regarding end-of-life care significantly improved; they also experienced confidence gains and changes in attitudes, becoming more approving of end-of-life care. Qualitative data revealed details of participants' satisfaction and what was learned. Through the focus group discussions, they created action plans for implementing end-of-life care programs, which some had accomplished in their local centers by the three-month follow-up., Conclusions: These results suggest that the training program is effective for promoting end-of-life care through community-based services in Japan. Conducting follow-up training could effectively strengthen participants' commitment to end-of-life care at community-based services. Use of the training program is expected to promote services to support aging-in-place., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Although alcohol consumption is reported to increase the incidence of breast cancer in European studies, evidence for an association between alcohol and breast cancer in Asian populations is insufficient. We conducted a pooled analysis of eight large-scale population-based prospective cohort studies in Japan to evaluate the association between alcohol (both frequency and amount) and breast cancer risk with categorization by menopausal status at baseline and at diagnosis. Estimated hazard ratios (HR) and 95% confidence intervals were calculated in the individual cohorts and combined using random-effects models. Among 158 164 subjects with 2 369 252 person-years of follow-up, 2208 breast cancer cases were newly diagnosed. Alcohol consumption had a significant association with a higher risk of breast cancer in both women who were premenopausal at baseline (regular drinker compared to nondrinker: HR 1.37, 1.04-1.81, ≥23 g/d compared to 0 g/d: HR 1.74, 1.25-2.43, P for trend per frequency category: P = .017) and those who were premenopausal at diagnosis (≥23 g/d compared to 0 g/d: HR 1.89, 1.04-3.43, P for trend per frequency category: P = .032). In contrast, no significant association was seen in women who were postmenopausal at baseline or at diagnosis, despite a substantial number of subjects and long follow-up period. Our results revealed that frequent and high alcohol consumption are both risk factors for Asian premenopausal breast cancer, similarly to previous studies in Western countries. The lack of a clear association in postmenopausal women in our study warrants larger investigation in Asia., (© 2021 UICC.)

There has been much interest in the potential role of soy in reducing the risk of chronic diseases. Soy foods are uniquely rich in isoflavones, a fact that has triggered much research including intervention studies. However, there have been few long-term prospective observational studies that include disease itself as an outcome. High intake of soy foods is intrinsic to the Japanese diet, which can be advantageous for conducting such studies in Japan. The present report reviews the findings from Japanese prospective cohort studies on soy intake and the risk of cardiovascular diseases, cancer, type 2 diabetes, osteoporosis, menopausal symptoms, and dementia. The results suggest a beneficial role of soy in several chronic diseases, but they are not without controversy. Discrepancies have been observed in the findings of studies of Japanese or other Asians as compared to those of non Asians. This review discusses the issues to be explored in future studies.

Aims/introduction: The mechanisms underlying hypertriglyceridemia-induced impaired glucose tolerance in Japanese individuals remain unclear. We aimed to evaluate the effect of hypertriglyceridemia on glucose metabolism in comparison with that of increased low-density lipoprotein or decreased high-density lipoprotein levels and to elucidate the sex differences in hypertriglyceridemia-related dietary intake among Japanese individuals., Materials and Methods: We randomly selected 898 (384 men and 514 women) participants aged 40-78 years in the Gifu Diabetes Study; those taking medication for dyslipidemia or diabetes mellitus were excluded. Serum levels of glucose metabolism parameters and the food frequency were measured cross-sectionally. The glycated hemoglobin was measured again after 5 years., Results: Glucose metabolism parameters and the percentage of individuals with impaired glucose tolerance were significantly higher in the high triglyceride group in men and women. Similar trends were observed in the low high-density lipoprotein group, but only in men. Meanwhile, only the homeostasis model assessment of insulin resistance was higher in the high low-density lipoprotein group. In non-obese men, the percentage of energy intake from alcohol per total daily energy intake was significantly greater in the high triglyceride group. In obese women, the total energy intake was significantly greater in the high triglyceride group. At the 5-year follow up, the risk of elevated glycated hemoglobin levels with hypertriglyceridemia was increased in men., Conclusions: Hypertriglyceridemia is a stronger risk factor for impaired glucose tolerance than increased low-density lipoprotein or decreased high-density lipoprotein. For dietary habits, increased daily alcohol energy intake in non-obese men and increased total energy intake in obese women were associated with hypertriglyceridemia., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Prior studies reported the association of reproductive factors with breast cancer (BC), but the evidence is inconsistent. We conducted a pooled analysis of nine cohort studies in Japan to evaluate the impact of six reproductive factors (age at menarche/age at first birth/number of births/age at menopause/use of female hormones/breastfeeding) on BC incidence. We conducted analyses according to menopausal status at the baseline or at the diagnosis. Hazard ratio (HR) and 95% confidence interval (CI) were estimated by applying Cox proportional-hazards model in each study. These hazard ratios were integrated using a random-effects model. Among 187,999 women (premenopausal: 61,113, postmenopausal: 126,886), we observed 873 premenopausal and 1,456 postmenopausal cases. Among premenopausal women, use of female hormones significantly increased BC incidence (HR: 1.53 [1.04-2.25]). Although P value for trend was not significant for age at first birth and number of births (P for trend: 0.15 and 0.30, respectively), women giving first birth at ages ≥36 experienced significantly higher BC incidence than at ages 21-25 years, and women who had ≥2 births experienced significantly lower BC incidence than nulliparous women. Among postmenopausal women, more births significantly decreased BC incidence (P for trend: 0.03). Although P value for trend was not significant for age at first birth and age at menopause (P for trend: 0.30 and 0.37, respectively), women giving first birth at ages 26-35 years experienced significantly higher BC incidence than at ages 21-25 years, and women with age at menopause: ≥50 years experienced significantly higher BC incidence than age at menopause: ≤44 years. BC incidence was similar according to age at menarche or breastfeeding history among both premenopausal and postmenopausal women. In conclusion, among Japanese women, use of female hormones increased BC incidence in premenopausal women, and more births decreased BC incidence in postmenopausal women., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Smoking has been consistently associated with the risk of colorectal cancer (CRC) in Western populations; however, evidence is limited and inconsistent in Asian people. To assess the association of smoking status, smoking intensity and smoking cessation with colorectal risk in the Japanese population, we performed a pooled analysis of 10 population-based cohort studies. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox's proportional hazards model and then pooled using a random-effects model. Among 363 409 participants followed up for 2 666 004 person-years, 9232 incident CRCs were identified. In men, compared with never smokers, ever smokers showed higher risk of CRC. The HRs (95% CI) were 1.19 (1.10-1.29) for CRC, 1.19 (1.09-1.30) for colon cancer, 1.28 (1.13-1.46) for distal colon cancer and 1.21 (1.07-1.36) for rectal cancer. Smoking was associated with risk of CRC in a dose-response manner. In women, compared with never smokers, ever smokers showed increased risk of distal colon cancer (1.47 [1.19-1.82]). There was no evidence of a significant gender difference in the association of smoking and CRC risk. Our results confirm that smoking is associated with an increased risk of CRC, both overall and subsites, in Japanese men and distal colon cancer in Japanese women., (© 2020 Union for International Cancer Control.)

Background: Few studies have examined the association between seaweed intake and blood pressure in children. We conducted an intervention study to investigate whether seaweed intake affects blood pressure., Methods: Subjects were children aged 4 to 5 years attending a preschool in Aichi Prefecture, Japan, in 2010. Among 99 students, 89 (89.9%) were enrolled in our study. Nori (dried laver), an edible seaweed widely consumed in Japan, was used as a dietary intervention. Children in the intervention group were asked to consume 1.76 grams per day of roasted nori in addition to standard meals for 10 weeks. Children in the control group consumed their usual diet. Before the intervention and at the 10th week of the intervention, children's blood pressure was measured three times successively using an automated sphygmomanometer with subjects in a sitting position. Changes in systolic (SBP) and diastolic blood pressure (DBP) were compared between 55 children in the intervention group and 26 in the control group after adjustment for SBP and DBP before the intervention., Results: Changes in SBP were -8.29 mm Hg in the intervention group and +0.50 mm Hg in the control group (P for difference in change = 0.051). Changes in DBP were -6.77 mm Hg in the intervention group and -0.05 mm Hg in the control group (P = 0.031). In girls, no difference in blood pressure changes was found between the intervention and control groups., Conclusion: Nori intake lowered DBP level in boys. Seaweed intake might have preventive effects on elevated blood pressure in childhood.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk is needed to plan management., Objectives: To assess the performance of existing pre-eclampsia prediction models and to develop and validate models for pre-eclampsia using individual participant data meta-analysis. We also estimated the prognostic value of individual markers., Design: This was an individual participant data meta-analysis of cohort studies., Setting: Source data from secondary and tertiary care., Predictors: We identified predictors from systematic reviews, and prioritised for importance in an international survey., Primary Outcomes: Early-onset (delivery at < 34 weeks' gestation), late-onset (delivery at ≥ 34 weeks' gestation) and any-onset pre-eclampsia., Analysis: We externally validated existing prediction models in UK cohorts and reported their performance in terms of discrimination and calibration. We developed and validated 12 new models based on clinical characteristics, clinical characteristics and biochemical markers, and clinical characteristics and ultrasound markers in the first and second trimesters. We summarised the data set-specific performance of each model using a random-effects meta-analysis. Discrimination was considered promising for C -statistics of ≥ 0.7, and calibration was considered good if the slope was near 1 and calibration-in-the-large was near 0. Heterogeneity was quantified using I 2 and τ 2 . A decision curve analysis was undertaken to determine the clinical utility (net benefit) of the models. We reported the unadjusted prognostic value of individual predictors for pre-eclampsia as odds ratios with 95% confidence and prediction intervals., Results: The International Prediction of Pregnancy Complications network comprised 78 studies (3,570,993 singleton pregnancies) identified from systematic reviews of tests to predict pre-eclampsia. Twenty-four of the 131 published prediction models could be validated in 11 UK cohorts. Summary C -statistics were between 0.6 and 0.7 for most models, and calibration was generally poor owing to large between-study heterogeneity, suggesting model overfitting. The clinical utility of the models varied between showing net harm to showing minimal or no net benefit. The average discrimination for IPPIC models ranged between 0.68 and 0.83. This was highest for the second-trimester clinical characteristics and biochemical markers model to predict early-onset pre-eclampsia, and lowest for the first-trimester clinical characteristics models to predict any pre-eclampsia. Calibration performance was heterogeneous across studies. Net benefit was observed for International Prediction of Pregnancy Complications first and second-trimester clinical characteristics and clinical characteristics and biochemical markers models predicting any pre-eclampsia, when validated in singleton nulliparous women managed in the UK NHS. History of hypertension, parity, smoking, mode of conception, placental growth factor and uterine artery pulsatility index had the strongest unadjusted associations with pre-eclampsia., Limitations: Variations in study population characteristics, type of predictors reported, too few events in some validation cohorts and the type of measurements contributed to heterogeneity in performance of the International Prediction of Pregnancy Complications models. Some published models were not validated because model predictors were unavailable in the individual participant data., Conclusion: For models that could be validated, predictive performance was generally poor across data sets. Although the International Prediction of Pregnancy Complications models show good predictive performance on average, and in the singleton nulliparous population, heterogeneity in calibration performance is likely across settings., Future Work: Recalibration of model parameters within populations may improve calibration performance. Additional strong predictors need to be identified to improve model performance and consistency. Validation, including examination of calibration heterogeneity, is required for the models we could not validate., Study Registration: This study is registered as PROSPERO CRD42015029349., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 72. See the NIHR Journals Library website for further project information.

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality and morbidity. Early identification of women at risk during pregnancy is required to plan management. Although there are many published prediction models for pre-eclampsia, few have been validated in external data. Our objective was to externally validate published prediction models for pre-eclampsia using individual participant data (IPD) from UK studies, to evaluate whether any of the models can accurately predict the condition when used within the UK healthcare setting., Methods: IPD from 11 UK cohort studies (217,415 pregnant women) within the International Prediction of Pregnancy Complications (IPPIC) pre-eclampsia network contributed to external validation of published prediction models, identified by systematic review. Cohorts that measured all predictor variables in at least one of the identified models and reported pre-eclampsia as an outcome were included for validation. We reported the model predictive performance as discrimination (C-statistic), calibration (calibration plots, calibration slope, calibration-in-the-large), and net benefit. Performance measures were estimated separately in each available study and then, where possible, combined across studies in a random-effects meta-analysis., Results: Of 131 published models, 67 provided the full model equation and 24 could be validated in 11 UK cohorts. Most of the models showed modest discrimination with summary C-statistics between 0.6 and 0.7. The calibration of the predicted compared to observed risk was generally poor for most models with observed calibration slopes less than 1, indicating that predictions were generally too extreme, although confidence intervals were wide. There was large between-study heterogeneity in each model's calibration-in-the-large, suggesting poor calibration of the predicted overall risk across populations. In a subset of models, the net benefit of using the models to inform clinical decisions appeared small and limited to probability thresholds between 5 and 7%., Conclusions: The evaluated models had modest predictive performance, with key limitations such as poor calibration (likely due to overfitting in the original development datasets), substantial heterogeneity, and small net benefit across settings. The evidence to support the use of these prediction models for pre-eclampsia in clinical decision-making is limited. Any models that we could not validate should be examined in terms of their predictive performance, net benefit, and heterogeneity across multiple UK settings before consideration for use in practice., Trial Registration: PROSPERO ID: CRD42015029349 .

Purpose: To investigate impact of the one-carbon metabolism (OCM) on oocyte maturity and embryo development., Methods: This prospective study analyzed 18 women who agreed to participate. We measured the OCM biomarkers' concentrations including Vitamin B12 (VB12), folic acid (FA), and homocysteine (Hcy) in serum and follicular fluid (FF), and assessed their correlation. We also evaluated the influence of such OCM biomarker concentrations in mono-FF on oocyte maturation, fertilization, embryo quality, and consequent pregnancy after embryo transfers., Results: All biomarkers showed a high concentration variability in different follicles of each woman, but their mean levels correlated with the serum levels. Among the 106 collected oocytes, 92 were mature, 59 were fertilized, and 16 yielded good-quality embryos. We performed 26 single embryo transfers, and 7 patients achieved clinical pregnancies. VB12 concentration (FF) was significantly lower in fertilized than unfertilized oocytes by univariate analysis. In multivariate logistic analysis, a significant correlation was found between FA concentration (FF) <14.25 ng/mL and good-quality embryos and between Hcy concentration (FF) <4.9 nmol/mL and clinical pregnancy., Conclusion: OCM in FF may affect fertilization, embryo quality, and clinical pregnancy., Competing Interests: Conflicts of Interest: Kozue Akamine, Keiko Mekaru, Keiya Gibo, Chinatsu Nagata, Rie Nakamura, Sugiko Oishi, Maho Miyagi, Chiaki Heshiki, and Yoichi Aoki declare that they have no conflict of interest. Human rights statements and informed consent: All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and its later amendments. Informed consent was obtained from all patients for being included in the study. This article does not contain any studies with animal subjects performed by the any of the authors. Approval by Ethics Committee: This retrospective study was approved by the Institutional Review Board of the University of the Ryukyus Hospital (February 21, 2013; No. 498)., (© 2020 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Background: Although endogenous advanced glycation end products (AGEs) have been implicated in the development of various chronic diseases, whether AGEs in foods represent a risk to human health remains unknown., Objectives: We aimed to estimate the intake of Nε-carboxymethyl-lysine (CML), a major AGE product, using a database of CML contents on LC-MS methods, and to examine CML's association with total and cause-specific mortality in Japanese adults., Methods: The analysis included 13,355 men and 15,724 women, aged 35 years and older, from the Takayama study. They responded to a self-administered questionnaire in 1992. Their diet, including the CML intake, was assessed using a food-frequency questionnaire at baseline. Mortality was ascertained during 16 years of follow-up. HRs and 95% CIs for mortality were estimated separately for men and women according to CMI quartiles., Results: We noted 2901 deaths in men and 2438 deaths in women during the follow-up. In men, as compared with the lowest quartile of intake, the highest quartile of CML was inversely associated with the risks of both total and non-cancer, non-cardiovascular disease mortality after controlling for covariates [HR = 0.89 (95% CI, 0.79-1.00; P-trend = 0.047) and HR = 0.74 (95% CI, 0.58-0.94; P-trend = 0.03), respectively]. However, stratified analyses showed both inverse and positive associations between CML intake and cause-specific mortality in women, depending on their characteristics. For example, years of education had a modifying effect on both the CML intake and non-cancer, non-cardiovascular disease mortality in women. In men, the associations of CML intake with mortality depended on food sources., Conclusions: Overall, the present study does not support a positive association between CML intake and mortality in Japanese adults. The potential relevance of the food source of CML to the link between dietary CML and mortality warrants further attention., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Aims/introduction: Although moderate alcohol consumption lowers the risk of type 2 diabetes in European populations, the same cannot be assumed for Japanese patients with diabetes related to low insulin secretion rather than resistance. We aimed to evaluate the effects of daily alcohol consumption on glucose tolerance and diabetes development risk in Japanese populations., Materials and Methods: This retrospective study randomly enrolled 452 men and 659 women aged 40-78 years in 2005 (Gifu, Japan). The participants completed a 75-g oral glucose tolerance test and medical questionnaire. The homeostasis model assessment of insulin resistance, homeostasis model assessment of β-cell function and insulinogenic index were used to estimate insulin sensitivity and secretion. The relationships between alcohol consumption and these parameters were analyzed using logistic regression after adjusting for potential confounders. The 5-year changes in hemoglobin A1c levels were also evaluated., Results: The adjusted odds ratios for elevated homeostasis model assessment of β-cell function values (<40%) in the 0-19.9 g/day, 20.0-39.9 g/day and ≥ 40 g/day alcohol consumption groups were 0.98, 1.46 and 2.68, respectively. Alcohol consumption induced a significant decrease in the insulin secretion level among the ≥40 g/day drinkers, especially in men. However, there was no risk of increased insulin resistance based on the homeostasis model assessment of insulin resistance (<2.5) results. The 5-year risk of elevated hemoglobin A1c levels (≥6.5%) was increased according to increase in alcohol consumption in both men and women., Conclusions: Daily alcohol consumption was associated with reduced insulin secretion and an increased diabetes development risk in Japanese populations., (© 2020 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: The association of alcohol drinking with bladder cancer risk remains unclear in East Asian populations. Aldehyde dehydrogenase 2 (ALDH2) enzyme oxidizes alcohol-metabolized carcinogenic acetaldehyde into acetate. It is well known that the inactive ALDH2 carriers, specific to East Asian populations, have an increased risk of several cancer types because of increased exposure to acetaldehyde after alcohol consumption. The aim of this study was to examine the association between alcohol drinking and bladder cancer risk using data from ten population-based prospective cohort studies in Japan, where approximately 40% of the population has inactive ALDH2 enzyme., Methods: We analyzed 340,497 Japanese participants with average follow-up of 13.4 years. The association between alcohol drinking and bladder cancer risk was evaluated using Cox regression models within each study, and random-effects models were used to estimate pooled hazard ratios (HRs) with corresponding 95% confidence intervals (CIs)., Results: During 4,729,071 person-years, 936 men and 325 women were newly diagnosed with bladder cancer. Our results showed no evidence of significant association between alcohol drinking and bladder cancer risk even among men who consumed alcohol of ≥69 g/week, with HR of 1.02 (95% CI, 0.79-1.33). The null result was observed consistently among women., Conclusions: Our findings do not support an association between alcohol drinking and bladder cancer risk in the Japanese, at least without consideration of the polymorphisms of alcohol-metabolizing enzymes.

Background: A few studies related to pediatric behavior have measured secondhand smoke exposure in children using valid objective biochemical markers. We aimed at investigating the associations between current and cumulative exposure to tobacco smoke, measured both subjectively and objectively, and behavioral problems in children., Methods: Subjects were 437 Japanese children, aged 3-6 years in 2006. Exposure to tobacco smoke was evaluated from a parent-administered questionnaire and urinary cotinine concentrations. The cotinine concentrations were measured using first-void morning urine by liquid chromatography-tandem mass spectrometry. Children's behaviors were assessed by the parent-completed Strengths and Difficulties Questionnaire., Results: After multiple adjustments for covariates, higher total difficulty scores of children were significantly associated with the larger number of cigarettes parents smoke, more smokers among cohabiters, and more pack-years of exposure to tobacco smoke from parents and cohabiters. The total difficulty scores were 8.72, 9.09, and 10.52, respectively, for children in the low, middle, and high tertiles of creatinine-corrected cotinine concentrations in urine ( p =0.002, trend p =0.005). There was no substantial sex difference in the positive associations between passive smoking and the SDQ scores., Conclusions: Exposure to tobacco smoke in early childhood may be involved in the development of pediatric behavioral problems. The importance of reducing the exposure of children to tobacco smoke, particularly in the home, was further emphasized for the prevention of psychological and behavioral problems in childhood., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this article., (Copyright © 2020 Keiko Wada et al.)

Background: The association between the number of teeth and mortality among community-dwelling people has been examined in many epidemiological studies. However, few Japanese studies have included cancer mortality as an endpoint. We prospectively investigated the association between number of remaining teeth and all-cause and cancer mortality in a Japanese community., Methods: This study included participants in the Takayama Study who were aged 35-70 years old at baseline in 1992. Information on the number of remaining teeth was obtained from 11,273 participants via questionnaire at the second survey in 2002. The response rate was 66.9%. Deaths and their causes were ascertained during 11.8 years of follow-up., Results: A total of 1,098 deaths (435 cancer-related and 235 cardiovascular-related) were identified during the follow-up period. After adjusting for covariates, participants with 0 to 9 teeth were at moderate but significantly increased risk of all-cause mortality (hazard ratio [HR] 1.19; 95% confidence interval [CI], 1.03-1.39) and cancer mortality (HR 1.31; 95% CI, 1.03-1.67) compared to those with 20 or more teeth. With regard to cancer site, a significant association was observed for lung cancer (HR for 0-9 teeth vs. 20 or more teeth, 1.75; 95% CI, 1.08-2.83). This association was somewhat strengthened among never-smokers (HR 3.56; 95% CI, 1.02-12.45)., Conclusions: We observed that a lower number of remaining teeth was significantly associated with increased risk from all-cause and lung cancer mortality. Further studies on the number of teeth and lung and other types of cancer are needed.

Introduction: Infrastructure and the capacity to conduct clinical research in pediatrics have not been fully established in Japan. To elucidate the physicians' perspectives on clinical research, level of experience, existing barriers, and requests for support, we conducted a survey at 34 children's hospitals in Japan., Methods: In January 2016, an online survey with 13 questions was sent to approximately 2000 physicians working in 34 pediatric hospitals belonging to the Japanese Association of Children's Hospitals and Related Institutions., Results: Of the 360 respondents, 318 (88.3%) had presentations at academic conferences, and 261 (72.5%) had publications in academic journals, in the previous year. The most common study designs of clinical research conducted were case reports and case series. The most requested supports were for statistical analysis, followed by study design, grant application, and English-language editing. Younger physicians were more likely to prefer educational lectures ( p < 0.001), whereas experienced physicians were more likely to request support for conducting statistical analysis ( p = 0.002). Whereas physicians who had ever led a clinical trial requested support for the development of study protocol ( p = .013), those without this experience preferred support for literature review ( p = .002) and consultation services for study design ( p = .027)., Conclusions: The requests for supports were different, depending on the physicians' years after graduation and experience level in clinical research. In order to enhance clinical research in pediatrics, it is essential to provide appropriate types and levels of educational and support programs., Competing Interests: None, (Copyright © Japan Medical Association.)

Purpose: Several epidemiological studies have demonstrated the health benefits of polyphenols, but the associations between polyphenol intake and mortality including total and major causes of death remain unclear. We investigated the associations between subjects' total polyphenol intake and their mortality from all causes, cardiovascular disease (CVD), cancer, and other causes of death in a population-based cohort study in Japan., Methods: A total of 29,079 residents of Takayama City, Japan were analyzed. Their dietary intake was assessed using a validated semi-quantitative food-frequency questionnaire (FFQ) in 1992. Mortality was ascertained over the subsequent 16 years. The dietary polyphenol intake was calculated by matching the subjects' food consumption data with our original polyphenol content database., Results: A total of 5339 deaths occurred during the follow-up. After multivariable adjustment, the highest quartile of total polyphenol intake compared with the lowest quartile was significantly associated with a lower risk of all-cause mortality (HR: 0.93, 95% CI: 0.82-0.99, p trend = 0.003). The subjects in the highest quartile showed significantly lower CVD mortality compared to those in the lowest quartile, and among the types of CVD mortality, a strong inverse association was observed for stroke mortality. Inverse associations were also observed for mortality from other causes, specifically digestive disease. The total polyphenol intake was not significantly associated with the risk of cancer mortality., Conclusions: The results of this prospective study indicate that dietary total polyphenol intake in Japanese is inversely associated with all-cause mortality and mortality from cardiovascular and digestive diseases.

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Background and Aim: Metofluthrin, profluthrin, tefluthrin, and transfluthrin are pyrethroid (PYR) insecticides increasingly used to control mosquitoes, flies, and moths in households and public places (hygiene-PYRs). Currently, there is limited data available concerning exposure to these novel hygiene-PYRs. The goal of this study was to monitor exposure to these hygiene-PYRs by analysing their urinary metabolites and to investigate the temporal and seasonal trends in the concentrations of these metabolites., Methods: First morning urine samples were obtained from 50 Japanese children (four-six years old) in October of 2006, 2011, and 2015 (total = 150 children) in order to investigate temporal trends. Additionally, first-morning urine samples were collected from 44 three-year-old children in August-September of 2012 (summer) and in February of 2013 (winter) to investigate seasonal differences. The urinary concentrations of 2,3,5,6-tetrafluorobenzyl alcohol (FB-Al; a specific metabolite of transfluthrin), 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol (CH 3 -FB-Al; a common metabolite of tefluthrin and profluthrin), 4-methoxymethyl-2,3,5,6-tetrafluorobenzyl alcohol (CH 3 OCH 2 -FB-Al; a specific metabolite of metofluthrin), and 2,3,5,6-tetrafluoro-1,4-benzenedimethanol (HOCH 2 -FB-Al; a common metabolite of metofluthrin, tefluthrin, and profluthrin) were measured using GC-MS/MS., Results: For the investigated years, rapid increases in the detection rates of the hygiene-PYR metabolites were observed. In 2015, FB-Al was identified in 64% of the samples, CH 3 -FB-Al in 46%, CH 3 OCH 2 -FB-Al in 50%, and HOCH 2 -FB-Al in 83%. Significant increasing trends were found for the concentrations of all hygiene-PYR metabolites from 2006 to 2015 (Jonckheere-Terpstra test, p < 0.001). The concentrations of FB-Al and CH 3 OCH 2 -FB-Al were higher in summer than in winter (Mann Whitney-U test, p < 0.05)., Conclusions: These findings suggest that, in Japanese children, exposure to hygiene-PYRs has increased over the past decade, and that children are exposed to higher levels of hygiene-PYRs in summer than in winter., Competing Interests: Declarations of competing interest None., (Copyright © 2019. Published by Elsevier GmbH.)

Aim: We aimed to assess the outcomes of combined spinal-epidural (CSE) analgesia compared with no analgesia in spontaneous labor., Methods: We performed a retrospective cohort study of deliveries between 2008 and 2014 comparing two groups based on the use of CSE analgesia in both nulliparous and multiparous women. Adjusted odds ratios (aOR) were calculated using logistic regression analysis., Results: Among 5247 (3334 nulliparous, 1913 multiparous) singleton deliveries, 3041 (2045, 996, respectively) patients received CSE analgesia and 2206 (1289, 917, respectively) had no analgesia. CSE analgesia was associated with increased risk of oxytocin augmentation (P < 0.01), prolonged duration of labor (P < 0.01), instrumental delivery (aOR, 3.35; 95% confidence interval (CI), 2.69-4.19 for nulliparous and aOR, 2.13; 95% CI, 1.32-3.53 for multiparous women), blood loss volume during vaginal delivery (P < 0.01), meconium-stained amniotic fluid (aOR, 1.23; 95% CI, 1.02-1.51 and aOR, 1.39; 95% CI, 1.01-1.93) and Apgar score less than 7 at 1 min (aOR, 1.85; 95% CI, 1.28-2.74 and aOR, 2.65; 95% CI, 1.35-5.61) in both nulliparous and multiparous women, respectively, and umbilical arterial blood gas pH less than 7.15 (aOR, 2.69; 95% CI, 1.35-5.75) and umbilical arterial blood gas pH less than 7.10 (aOR, 3.69; 95% CI, 1.11-16.69) in multiparous women. There was no significant difference in incidence of cesarean delivery or Apgar score less than 7 at 5 min., Conclusion: We observed several increased risks in obstetric and neonatal outcomes among pregnant women who received CSE analgesia during labor. Preparations for these risks are needed when administering CSE analgesia during labor., (© 2020 Japan Society of Obstetrics and Gynecology.)

Background: Available evidence for associations between sugar intake and body weight is largely from short-term controlled trials and studies focusing on sugar-sweetened beverages. Studies on long-term weight change related to the intake of types of sugar are thus needed., Objective: We examined the associations between weight change and the intake of various types of carbohydrates, including starch, total sugars, and free or naturally occurring sugars and saccharides (i.e., glucose, fructose, sucrose, and lactose), among Japanese men and women., Methods: This prospective cohort study included 14,971 residents of Takayama City in Japan who were aged 35-69 y at the first survey in 1992 and responded to a self-administrated questionnaire at the second survey in 2002. We excluded those with cancer, coronary artery disease, stroke, or diabetes on the first survey and those with missing information about body weight on both surveys, leaving 13,229 participants for analysis (5879 men and 7350 women). Mean (95% CI) values of 10-y weight change according to types of carbohydrates were estimated using linear regression models with adjustment for total energy intake and other dietary and lifestyle factors. Dietary intake was assessed at the first survey using a validated FFQ., Results: Among men, free sugar intake was associated with weight gain and the estimated means (95% CIs) of weight change were -0.60 (-0.67, -0.54), -0.31 (-0.38, -0.24), -0.12 (-0.19, -0.05), and 0.20 (0.13, 0.27) kg from the first to fourth quartiles (P-trend = 0.002). Moreover, high intakes of sucrose and fructose were associated with weight gain (P-trend: 0.018 for sucrose and 0.001 for fructose). Among women, the intake of any type of carbohydrate was not significantly associated with weight change., Conclusions: These results suggested that high intakes of free sugars, sucrose, and fructose were associated with long-term weight gain among Japanese men., (Copyright © American Society for Nutrition 2019.)

Aim: In recent years in Japan, forest therapies have been implemented in various places. While the effects of such therapies have been reported in previous research papers, those of artificial gardens have not been clarified. At the 2018 Yamaguchi Yume Flower Expo, the Yamaguchi University Faculty of Medicine had the opportunity to provide a "Well-being Garden" in collaboration with the Japan Landscape Contractors Association Yamaguchi Prefecture Branch. We examined the physical and mental responses of older people who strolled in the Well-being Garden., Methods: Participants were 158 people ≥ 65 years old. Pre-and post-stroll interviews were conducted, and the heart rate, blood pressure, and autonomic nervous activities were measured., Results: After strolling in the garden, the heart rate significantly decreased from 76.1±12.9 to 73.9±11.8/min (p<0.01), and both the systolic and diastolic blood pressure significantly decreased from 142.5±24.4 to 139.4±24.1 mmHg and from 83.7±12.0 to 81.5±11.9 mmHg, respectively (p<0.01). The ralue of low frequency/high frequency (LF/HF) after strolling in the garden came closer to the standard one than before, both in the participants with much tension and with less tension. In the post-stroll interview, 74 reported feeling very good, and 84 felt good., Conclusions: These results suggested that strolling in the Well-being Garden positively influenced the physical and mental condition of the participants.

Background: Ischaemic heart disease including heart failure is the most common cause of death in the world, and the incidence of the condition is rapidly increasing. Heart failure is characterised by symptoms such as fatigue and breathlessness during light activity, as well as disordered breathing during sleep. In particular, sleep disordered breathing (SDB), including central sleep apnoea (CSA) and obstructive sleep apnoea (OSA), is highly prevalent in people with chronic heart failure. A previous meta-analysis demonstrated that positive airway pressure (PAP) therapy dramatically increased the survival rate of people with heart failure who had CSA, and thus could contribute to improving the prognosis of these individuals. However, recent trials found that adaptive servo-ventilation (ASV) including PAP therapy had a higher risk of all-cause mortality and cardiovascular mortality. A meta-analysis that included recent trials was therefore needed., Objectives: To assess the effects of positive airway pressure therapy for people with heart failure who experience central sleep apnoea., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, and Web of Science Core Collection on 7 February 2019 with no limitations on date, language, or publication status. We also searched two clinical trials registers in July 2019 and checked the reference lists of primary studies., Selection Criteria: We excluded cross-over trials and included individually randomised controlled trials, reported as full-texts, those published as abstract only, and unpublished data., Data Collection and Analysis: Two review authors independently extracted outcome data from the included studies. We double-checked that data had been entered correctly by comparing the data presented in the systematic review with study reports. We analysed dichotomous data as risk ratios (RRs) with 95% confidence intervals (CIs) and continuous data as mean difference (MD) or standardised mean difference (SMD) with 95% CIs. Furthermore, we performed subgroup analysis in the ASV group or continuous PAP group separately. We used GRADEpro GDT software to assess the quality of evidence as it relates to those studies that contribute data to the meta-analyses for the prespecified outcomes., Main Results: We included 16 randomised controlled trials involving a total of 2125 participants. The trials evaluated PAP therapy consisting of ASV or continuous PAP therapy for 1 to 31 months. Many trials included participants with heart failure with reduced ejection fraction. Only one trial included participants with heart failure with preserved ejection fraction. We are uncertain about the effects of PAP therapy on all-cause mortality (RR 0.81, 95% CI 0.54 to 1.21; participants = 1804; studies = 6; I 2 = 47%; very low-quality evidence). We found moderate-quality evidence of no difference between PAP therapy and usual care on cardiac-related mortality (RR 0.97, 95% CI 0.77 to 1.24; participants = 1775; studies = 5; I 2 = 11%). We found low-quality evidence of no difference between PAP therapy and usual care on all-cause rehospitalisation (RR 0.95, 95% CI 0.70 to 1.30; participants = 1533; studies = 5; I 2 = 40%) and cardiac-related rehospitalisation (RR 0.97, 95% CI 0.70 to 1.35; participants = 1533; studies = 5; I 2 = 40%). In contrast, PAP therapy showed some indication of an improvement in quality of life scores assessed by all measurements (SMD -0.32, 95% CI -0.67 to 0.04; participants = 1617; studies = 6; I 2 = 76%; low-quality evidence) and by the Minnesota Living with Heart Failure Questionnaire (MD -0.51, 95% CI -0.78 to -0.24; participants = 1458; studies = 4; I 2 = 0%; low-quality evidence) compared with usual care. Death due to pneumonia (N = 1, 3% of PAP group); cardiac arrest (N = 18, 3% of PAP group); heart transplantation (N = 8, 1% of PAP group); cardiac worsening (N = 3, 9% of PAP group); deep vein thrombosis/pulmonary embolism (N = 1, 3% of PAP group); and foot ulcer (N = 1, 3% of PAP group) occurred in the PAP therapy group, whereas cardiac arrest (N = 16, 2% of usual care group); heart transplantation (N = 12, 2% of usual care group); cardiac worsening (N = 5, 14% of usual care group); and duodenal ulcer (N = 1, 3% of usual care group) occurred in the usual care group across three trials., Authors' Conclusions: The effect of PAP therapy on all-cause mortality was uncertain. In addition, although we found evidence that PAP therapy did not reduce the risk of cardiac-related mortality and rehospitalisation, there was some indication of an improvement in quality of life for heart failure patients with CSA. Furthermore, the evidence was insufficient to determine whether adverse events were more common with PAP than with usual care. These findings were limited by low- or very low-quality evidence. PAP therapy may be worth considering for individuals with heart failure to improve quality of life., (Copyright © 2019 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Red meat and processed meat have been suggested to increase risk of colorectal cancer (CRC), especially colon cancer. However, it remains unclear whether these associations differ according to meat subtypes or colon subsites. The present study addressed this issue by undertaking a pooled analysis of large population-based cohort studies in Japan: 5 studies comprising 232 403 participants (5694 CRC cases) for analysis based on frequency of meat intake, and 2 studies comprising 123 635 participants (3550 CRC cases) for analysis based on intake quantity. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model and then pooled using the random effect model. Comparing the highest vs lowest quartile, beef intake was associated with an increased risk of colon cancer in women (pooled HR 1.20; 95% CI, 1.01-1.44) and distal colon cancer (DCC) risk in men (pooled HR 1.30; 95% CI, 1.05-1.61). Frequent intake of pork was associated with an increased risk of distal colon cancer in women (pooled HR 1.44; 95% CI, 1.10-1.87) for "3 times/wk or more" vs "less than 1 time/wk". Frequent intake of processed red meat was associated with an increased risk of colon cancer in women (pooled HR 1.39; 95% CI, 0.97-2.00; P trend = .04) for "almost every day" vs "less than 1 time/wk". No association was observed for chicken consumption. The present findings support that intake of beef, pork (women only), and processed red meat (women only) might be associated with a higher risk of colon (distal colon) cancer in Japanese., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: To date, few epidemiologic studies have been conducted to elucidate lifestyle-related risk factors for multiple myeloma in Asia. We investigated the association of body mass index (BMI), smoking, and alcohol intake with the risk of multiple myeloma mortality through a pooled analysis of more than 800,000 participants in the Asia Cohort Consortium., Methods: The analysis included 805,309 participants contributing 10,221,623 person-years of accumulated follow-up across Asia Cohort Consortium cohorts. HRs and 95% confidence intervals (95% CI) for the association between BMI, smoking, and alcohol at baseline and the risk of multiple myeloma mortality were assessed using a Cox proportional hazards model with shared frailty., Results: We observed a statistically significant dose-dependent association between BMI categories and the risk of multiple myeloma mortality (<18.5 kg/m 2 : HR = 0.80, 95% CI: 0.52-1.24; 18.5-24.9 kg/m 2 : reference; 25.0-29.9 kg/m 2 : HR = 1.17, 95% CI: 0.94-1.47; ≥30 kg/m 2 : HR = 1.61, 95% CI: 0.99-2.64, P trend = 0.014). By sex, this association was more apparent in women than in men (P for heterogeneity between sexes = 0.150). We observed no significant associations between smoking or alcohol consumption and risk of multiple myeloma mortality., Conclusions: This study showed that excess body mass is associated with an increased risk of multiple myeloma mortality among Asian populations. In contrast, our results do not support an association between smoking or alcohol consumption and the risk of multiple myeloma mortality in Asian populations., Impact: This study provides important evidence on the association of BMI, smoking, and alcohol with the risk of multiple myeloma mortality in Asian populations., (©2019 American Association for Cancer Research.)

Studies on the intake of different types of carbohydrates and long-term mortality are sparse. We examined the association of starch, total and each type of sugar and free sugars with the risk of total and cause-specific mortality in a cohort of the general population in Japan. Study subjects were 29 079 residents from the Takayama Study, Japan, who responded to a self-administered questionnaire in 1992. Diet was assessed by a validated FFQ at the baseline. Mortality was ascertained during 16 years of follow-up. We noted 2901 deaths (974 cancer related and 775 cardiovascular related) in men and 2438 death (646 cancer related and 903 cardiovascular related) in women. In men, intake of starch was inversely associated with total mortality after controlling for covariates (hazard ratio (HR) for the highest quartile v. lowest quartile: 0·71; 95 % CI 0·60, 0·84; Ptrend < 0·001). Intakes of total sugars, glucose, fructose, sucrose, maltose and free and naturally occurring sugars were significantly positively associated with total mortality in men (HR for the highest v. lowest quartile of total sugar: 1·27; 95 % CI 1·12, 1·45; Ptrend < 0·0001). Similar relations were observed for cardiovascular mortality and non-cancer, non-cardiovascular mortality in men. In women, there was no significant association between any type of carbohydrates and mortality except that intake of free sugars was significantly positively associated with total and non-cancer, non-cardiovascular mortality. Data suggest that the high intake of starch reduces mortality, whereas the high intake of sugars, including glucose, fructose and sucrose, increases mortality in Japanese men.

Background: Coffee and green tea, two popular drinks in the Japanese, have recently drawn much attention as potential protective factors against the occurrence of liver cancer., Methods: We systematically reviewed epidemiologic studies on coffee, green tea and liver cancer among Japanese populations. Original data were obtained by searching the MEDLINE (PubMed) and Ichushi databases, complemented with manual searches. The evaluation was performed in terms of the magnitude of association in each study and the strength of evidence ('convincing', 'probable', 'possible', or 'insufficient'), together with biological plausibility., Results: We identified four cohort and four case-control studies on coffee and liver cancer and six cohort and one case-control studies on green tea and liver cancer. All cohort and case-control studies on coffee reported a weak to strong inverse association, with a summary relative risk (RR) for one cup increase being 0.72 (95% confidence interval [CI] 0.66-0.79). Conversely, all studies but two cohort studies on green tea reported no association, with a corresponding summary RR of 0.99 (95% CI 0.97-1.01, P = 0.37)., Conclusion: Coffee drinking 'probably' decreases the risk of primary liver cancer among the Japanese population whereas the evidence on an association between green tea and liver cancer is 'insufficient' in this population., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The aim of our study was to assess the association between green tea consumption and all-cause and cause-specific mortality in a pooled analysis of eight Japanese population-based cohort studies. Pooled hazard ratios (HR) and 95% confidence intervals (CI), derived from random effects models, were used to evaluate the associations between green tea consumption, based on self-report at baseline, and risk of all-cause and cause-specific mortality. During a mean follow-up of 17.3 years, among 313,381 persons, 52,943 deaths occurred. Compared with individuals who consumed < 1 cup/day, those in the highest consumption category (≥ 5 cups/day) had a decreased risk of all-cause mortality [the multivariate-adjusted HR was 0.90 (95% CI 0.87-0.94) for men and 0.82 (0.74-0.90) for women]. A similar inverse association was observed for heart disease mortality [HR 0.82 (0.75-0.90) for men, and 0.75 (0.68-0.84) for women], and cerebrovascular disease mortality [HR 0.76 (0.68-0.85) for men, and 0.78 (0.68-0.89) for women]. Among women, green tea consumption was associated with decreased risk of total cancer mortality: 0.89 (0.83-0.96) for the 1-2 cups/day category and 0.91 (0.85-0.98) for the 3-4 cups/day category. Results for respiratory disease mortality were [HR 0.75 (0.61-0.94)] among 3-4 cup daily consumers and [HR 0.66 (0.55-0.79)] for ≥ 5 cups/day. Higher consumption of green tea is associated with lower risk for all-cause mortality in Japanese, especially for heart and cerebrovascular disease. Moderate consumption decreased the risk of total cancer and respiratory disease mortality in women.

Objective: Epidemiological studies suggest that coffee consumption is inversely associated with all-cause and cause-specific mortality. Evidence from studies targeting non-white, non-Western populations is still sparse, although coffee is popular and widely consumed in Asian countries., Design: Population-based, prospective cohort study. We used Cox proportional hazards models with adjustment for dietary and lifestyle factors to estimate associations between coffee consumption and all-cause and cause-specific mortality. Dietary intake including coffee consumption was assessed only at baseline using a validated FFQ., Setting: A Japanese city., Participants: Individuals aged 35 years or older without cancer, CHD and stroke at baseline (n 29 079) and followed from 1992 to 2008., Results: From 410 352 person-years, 5339 deaths were identified (mean follow-up = 14·1 years). Coffee consumption was inversely associated with mortality from all causes and CVD among all participants, but not from cancer. Compared with the category of 'none', the multivariate hazard ratio (95 % CI) for all-cause mortality was 0·93 (0·86, 1·00) for <1 cup/d, 0·84 (0·76, 0·93) for 1 cup/d and 0·81 (0·71, 0·92) for 2-3 cups/d. The multivariate hazard ratio (95 % CI) for cardiovascular mortality were 0·87 (0·77, 0·99) for <1 cup/d, 0·76 (0·63, 0·92) for 1 cup/d and 0·67 (0·50, 0·89) for 2-3 cups/d. Inverse associations were also observed for mortality from other causes, specifically infectious and digestive diseases., Conclusion: Drinking coffee, even 1 cup/d, was inversely associated with all-cause mortality and mortality from cardiovascular, infectious and digestive diseases.

Cigarette smoking and alcohol drinking are two major risk factors for esophageal cancer. Not all, but several of case-control studies have indicated interaction between the two factors; however, no prospective study has validated this phenomenon to date. Therefore, the interaction between smoking and alcohol drinking is still open-ended question. To answer this, we conducted a pooled analysis using large-scale population-based cohort studies in Japan. Male subjects from eight cohort studies were included. Cigarette smoking and alcohol drinking were both categorized categorically (never/ever), and in the three consumption levels of pack years and ethanol consumption/day. Effects of smoking and drinking in each study were estimated by Cox regression models. The study-specific results were combined through meta-analysis to obtain summary effects of hazard ratios (HRs) and measures of interactions at both additive and multiplicative scales. Population attributable fractions (PAFs) from smoking and drinking were obtained using distributions of exposures and fully adjusted HRs. In 162 826 male subjects, 954 esophageal cancer incidences were identified. HRs of ever smoking, ever drinking, and their combination were 2.92 (1.59-5.36), 2.73 (1.78-4.18), and 8.86 (4.82-16.30), respectively. Interaction between cigarette smoking and alcohol drinking was significantly positive on the additive scale, but not significant on the multiplicative scale. The joint effect of smoking and drinking in three levels of evaluation showed a similar significant super-additive interaction. PAFs from smoking, drinking, and their combination were 55.4%, 61.2%, and 81.4%, respectively. Cigarette smoking and alcohol drinking had a significant positive additive interaction for esophageal cancer risk., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Effects of using mobile devices on childhood obesity have not been well studied. We aimed to ascertain whether cell phone use and screen viewing are associated with excess body weight in a cross-sectional study of Japanese school children. Methods: Subjects were 3141 students, ages 6 to 7 years, who participated in the Hekinan Children's Study conducted during 2011-2015. Participants were asked to submit a parent-administered questionnaire on child and parent demographics, health status, and lifestyles, including cell phone use and screen time. Heights and weights were measured at the schools. Being overweight was defined according to the cutoff point for children specified by the Extended International Obesity Task Force. Among 2596 analytic children, the odds ratios (ORs) for being overweight were estimated according to cell phone use, time spent watching television, and time spent on games and computers using the logistic regression models. Analyses were conducted after adjustments for potential confounders, including dietary intake, physical activities, sleep duration, and quality of sleep. Results: After multivariate adjustments, cell phone users were found to have an OR of 1.74 for being overweight compared with nonusers. Cell phone use of longer duration was associated with higher risk of being overweight (trend p  = 0.018). Time spent watching television was positively associated with the risk of being overweight (trend p  = 0.003). Conclusions: Just as earlier studies have shown for television viewing, cell phone use might be a risk factor related to being overweight among children.

Objective: To study the association of educational level and risk of death from all causes, cardiovascular disease (CVD) and cancer among Asian populations., Design: A pooled analysis of 15 population-based cohort studies., Setting and Participants: 694 434 Asian individuals from 15 prospective cohorts within the Asia Cohort Consortium., Interventions: None., Main Outcome Measures: HRs and 95% CIs for all-cause mortality, as well as for CVD-specific mortality and cancer-specific mortality., Results: A total of 694 434 participants (mean age at baseline=53.2 years) were included in the analysis. During a mean follow-up period of 12.5 years, 103 023 deaths were observed, among which 33 939 were due to cancer and 34 645 were due to CVD. Higher educational levels were significantly associated with lower risk of death from all causes compared with a low educational level (≤primary education); HRs and 95% CIs for secondary education, trade/technical education and ≥university education were 0.88 (0.85 to 0.92), 0.81 (0.73 to 0.90) and 0.71 (0.63 to 0.80), respectively (p trend =0.002). Similarly, HRs (95% CIs) were 0.93 (0.89 to 0.97), 0.86 (0.78 to 0.94) and 0.81 (0.73 to 0.89) for cancer death, and 0.88 (0.83 to 0.93), 0.77 (0.66 to 0.91) and 0.67 (0.58 to 0.77) for CVD death with increasing levels of education (both p trend <0.01). The pattern of the association among East Asians and South Asians was similar compared with ≤primary education; HR (95% CI) for all-cause mortality associated with ≥university education was 0.72 (0.63 to 0.81) among 539 724 East Asians (Chinese, Japanese and Korean) and 0.61 (0.54 to 0.69) among 154 710 South Asians (Indians and Bangladeshis)., Conclusion: Higher educational level was associated with substantially lower risk of death among Asian populations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Detailed prospective evaluation of cigarette smoking associated with pancreatic cancer risk in large Asian populations is limited. The aim of this study was to examine this association in a Japanese population, with a particular focus on evaluating sex differences., Methods: We performed a pooled analysis of 10 population-based cohort studies. We calculated study-specific HRs and 95% confidence intervals (CI) using Cox proportional hazards regression, and then estimated summary HRs by pooling these estimates with a random effects model., Results: During 4,695,593 person-years of follow-up in 354,154 participants, 1,779 incident pancreatic cancer cases were identified. We observed an increased pancreatic cancer risk for current smoking compared with never smoking in both males [HR (95% CI), 1.59 (1.32-1.91)] and females [HR (95% CI), 1.81 (1.43-2.30)]. Significant risk elevations for former smoking and small cumulative dose of ≤20 pack-years (PY) were observed only among females, regardless of environmental tobacco smoke exposure. Trend analysis indicated significant 6% and nonsignificant 6% increases in pancreatic cancer risk for every 10 PYs in males and females, respectively. Risk became comparable with never smokers after 5 years of smoking cessation in males. In females, however, we observed no risk attenuation by smoking cessation., Conclusions: This study supports the well-known association between smoking and pancreatic cancer and indicates potential sex differences in a Japanese population. Quitting smoking would be beneficial for pancreatic cancer prevention, especially in males., Impact: Pancreatic cancer risk is increased with cumulative smoking exposure and decreased with smoking cessation, with potential sex differences., (©2019 American Association for Cancer Research.)

Background & Aims: Many studies have suggested that fish intake is associated with protection from risk of atherosclerotic diseases; however, this association with aortic diseases has not been elucidated worldwide. We hypothesized that fish intake is inversely associated with mortality from aortic diseases (aortic dissection and aneurysm)., Methods: The study was conducted as a pooled analysis of original data from a maximum of 8 cohort studies, comprising a total of 366,048 community-based men and women who had no history of cardiovascular disease or cancer. In each cohort, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality from aortic dissection, aneurysm and total aortic disease according to the frequency of fish intake and estimated summary HRs derived from each study., Results: Nonlinear inverse associations were found between fish intake and total aortic disease. Compared with persons who ate fish 1-2 times/week, persons who seldom ate fish had higher mortality from total aortic disease (multivariable-adjusted pooled HR = 1.93; 95% CI, 1.13-3.31). Higher mortality was not seen in those who ate fish 1-2 times/month. A similar pattern was observed for aortic dissection. Regarding aortic aneurysm, both persons who seldom ate fish and those who ate fish 1-2 times/month had higher mortality (HR = 1.99; 95% CI, 0.90-4.40 and HR = 1.86; 95% CI, 0.87-3.98, respectively)., Conclusions: Persons who seldom ate fish had higher mortality from aortic dissection, aneurysm, and total aortic diseases., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: The early life environment is now recognized as a key factor contributing to susceptibility to certain diseases in later life., Methods: We initiated a cohort study among school children in 2011 to primarily investigate the associations between lifestyle and environmental factors and some surrogate markers of chronic diseases, such as cardiometabolic risk factors (ie, obesity, high blood pressure, high blood glucose, insulin, or lipids) and cancer risk factors (ie, height and age at menarche). A baseline questionnaire asked for information, including demographic variables, medical history and use of medication, dietary habits, physical activity, sleep habits, and behavioral and emotional problems of children. Follow-up surveys are planned for the fourth grade of elementary school and the first grade of junior high school. At these follow-up surveys, fasting blood samples will be obtained to measure cardiometabolic markers. We also checked the validity of a food frequency questionnaire, which was originally created for 6-year-olds but was modified for use in older children., Results: A total of 3,141 first-year students at elementary schools in Hekinan City, Aichi Prefecture, participated in the study. The response rate was 87.4%. The means of age and body mass index were 6.99 (standard deviation, 0.28) years and 15.3 (standard deviation, 1.7) kg/m 2 , respectively, in the 3,067 Japanese children (1,639 boys and 1,428 girls)., Conclusions: This cohort will reveal determinants of cardiometabolic risk factors and cancer risk factors during childhood.

Background: Whole soy foods, as well as their components, including protein and isoflavones, have garnered attention because they may have beneficial effects against diabetes., Objectives: We examined associations between the intake of soy foods, soy protein, and soy isoflavones and the risk of diabetes in the Japanese population., Methods: This prospective cohort study included 13,521 residents (5883 men and 7638 women; 35-69 y old) of Takayama City, Japan. The subjects responded to a self-administered baseline questionnaire in 1992 and to a follow-up questionnaire seeking information about diabetes in 2002. Their mean ± SD body mass index was 22.6 ± 2.6 kg/m2 (men) and 22.1 ± 2.7 (women). The intakes of total soy foods, fried soy foods, nonfried soy foods, soy protein, and soy isoflavones were estimated through the use of a validated food-frequency questionnaire administered in 1992. Associations between soy intake and the risk of diabetes were evaluated through the use of Cox proportional hazards models incorporating age, education level, physical activity, smoking status, alcohol consumption, history of hypertension, use of vitamin supplements, menopausal status, and dietary factors including glycemic load, total energy, total fat, meat, fruit, vegetables, and coffee., Results: During a 10-y follow-up, 438 participants reported physician-diagnosed diabetes. Women in the highest tertile of intakes of total soy foods, fried soy foods, nonfried soy foods, soy protein, and soy isoflavone had significantly lower HRs, after controlling for covariates, than those with the lowest intakes. For example, HRs were 0.45 (95% CI: 0.30, 0.68; P-trend <0.001) for total soy food intake. In men, there were no significant associations between soy intake and the risk of diabetes., Conclusions: These results suggest that a high soy intake may be associated with a lower risk of diabetes in Japanese women., (Copyright © American Society for Nutrition 2019.)

Coffee consumption is increasing globally. We aimed to assess the effect of coffee consumption on the risk of all-cause and cause-specific mortality in a pooled analysis of eight population-based cohort studies in Japan (Japan Cohort Consortium). Data came from eight Japanese cohort studies (144,750 men and 168,631 women). During a mean follow-up time of 17 years, 52,943 deaths occurred. More specifically, 19,495 cancer deaths, 7321 deaths due to heart disease, 6387 cerebrovascular, 3490 respiratory disease and 3382 injuries and accidents. A random effects model was applied to obtain pooled hazard ratios (HRs) and 95% confidence intervals (95%CIs). In both sexes, coffee consumption up to 5 cups/day was overall protective in relation to all-cause mortality, with the association attenuating in the highest category of coffee consumption (≥5 cups/day). In men, a similar inverse association was observed for major causes of mortality except cancer. In women, coffee consumption decreased the risk for mortality due to heart disease in the 1-2 cups/day category, but increased the risk in the ≥5 cups/day category. Coffee consumption was not associated with cancer in both sexes. Results were similar among male current smokers and female never-smokers. Based on available data, this pooled analysis suggests that coffee consumption under five cups per day may be beneficial for reducing the risk of mortality due to major causes., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Reportedly, green tea has a preventive effect against colorectal cancer in animal models. Nevertheless, results from epidemiological studies of the association between green tea consumption and colorectal cancer have been inconsistent. We aimed to evaluate colorectal cancer risk in relation to green tea consumption in a population-based prospective cohort study., Methods: Subjects were 13 957 men and 16 374 women aged ≥35 years in September 1992. The participants' green tea consumption was elicited by administering a food frequency questionnaire. The colorectal cancer incidence was confirmed through regional population-based cancer registries and histological identification from colonoscopy in two main hospitals in the study area. Colorectal cancer was defined as the sum of code C18 (colon cancer) and codes C19 and C20 (rectal cancer) according to ICD-10., Results: Up to March 2008, 429 men and 343 women were diagnosed with colorectal cancer. No significant association was found between green tea consumption and colorectal cancer in men and women, respectively. However, for men, compared with the group of 'none or less than once per day' of green tea consumption, the multiple-adjusted relative risks (95% CIs) for colon cancer were 1.32 (0.90, 1.94), 0.76 (0.57, 1.02), and 0.78 (0.49, 1.22), respectively, in the group of 'once per day,' '2-3 times per day', and 'four times per day or more' (trend P = 0.045)., Conclusions: This study observed no overall significant associations between green tea consumption and colorectal cancer risk, except that there was a weak trend for greater consumption of green tea with decreased risk of male colon cancer., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To assess general knowledge of diabetes and its determinants among adult men and women in a Japanese community., Setting: A cross-sectional study with the residential registry in Gifu City. Blood tests were conducted to measure fasting blood glucose levels and the levels after 2 hours of a 75-gram oral glucose load. Participants' previous diagnosis of diabetes and demographic status were identified from a questionnaire. A validated food frequency questionnaire was also administered. To assess the association between good knowledge of diabetes and the level of each factor, a logistic regression was utilised with adjustments for age, education and parental history of diabetes., Participants: A total of 1019 men and women aged 40-78 years., Primary Outcome Measure: The Diabetes Knowledge Questionnaire was administered. Participants with ≥75% of answers correct were defined as having a good knowledge of diabetes., Results: Previous diagnosis of diabetes was significantly associated with good knowledge of diabetes (OR=2.36; 95% CI 1.19 to 4.68). Among individuals with no previous diagnosis of diabetes, age ≥60 years (OR=0.55; 95% CI 0.36 to 0.86, p value for trend=0.02) and education <12 years (OR=0.54; 95% CI 0.30 to 0.97) were significantly associated with low knowledge of diabetes. The highest tertile intakes of green-yellow vegetables (OR=1.77; 95% CI 1.07 to 2.91, p value for trend=0.03) and seafood (OR=1.76; 95% CI 1.04 to 2.95, p value for trend=0.03) were associated with high knowledge of diabetes., Conclusions: Some diabetes risk factors were implied to determine the general knowledge of diabetes. Conducting further studies of knowledge in various populations is warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations., Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status., Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018., Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status., Main Outcomes and Measures: All-cause and cause-specific mortality., Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction < .001) and more evident among adults aged 30 to 49 years (HR, 2.43; 95% CI, 2.08-2.84) than among adults aged 70 years and older (HR, 1.51; 95% CI, 1.40-1.62) (P for interaction < .001). A similar pattern of association was found between diabetes and cause-specific mortality, with significant variations noted by sex and age., Conclusions and Relevance: This study found that diabetes was associated with increased risk of death from several diseases among Asian populations. Development and implementation of diabetes management programs are urgently needed to reduce the burden of diabetes in Asia.

Importance: Understanding birth cohort-specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations., Objectives: To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations., Design, Setting, and Participants: This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India., Exposures: Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking., Main Outcomes and Measures: Country or region and birth cohort-specific mortality and the population attributable risk for deaths from all causes and from lung cancer., Results: Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions., Conclusions and Relevance: In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.

Background: Although pregnancies conceived by assisted reproductive technology (ART) have a higher risk of maternal/perinatal complications, the overall risk of adverse outcomes necessitating advanced obstetric care has not been closely examined. The present study aimed to assess and compare the risk of maternal/perinatal complications and adverse outcomes in pregnancy and childbirth conceived by ART with those conceived naturally., Methods: This study was conducted as a part of the Japan environment and children's study (JECS), an ongoing nationwide birth cohort study in Japan. The risk of maternal/perinatal complications and adverse outcomes was assessed by mode of conception (natural conception, ovulation induction [OI] without ART, conventional in vitro fertilization and embryo transfer [IVF-ET], or intracytoplasmic sperm injection [ICSI]) using logistic regression and generalized estimating equations controlling for potential confounders., Results: The final dataset included women who conceived naturally (N = 90,506), by OI without ART (N = 3939), by conventional IVF-ET (N = 1476), and by ICSI (N = 1671). Compared with women who conceived naturally, those who conceived by conventional IVF-ET were at higher risk of placenta previa (adjusted OR 2.90 [95% CI 1.94, 4.34]), morbidly adherent placenta (6.85 [3.88, 12.13]), and pregnancy-induced hypertension (1.40 [1.10, 1.78]) whereas those who conceived by ICSI had a higher risk of placental abruption (2.16 [1.20, 3.88]) as well as placenta previa (2.01 [1.29, 3.13]) and morbidly adherent placenta (7.81 [4.56, 13.38]). Women who conceived by ART had a higher risk of blood transfusion (conventional IVF-ET: 3.85 [2.52, 5.88]; ICSI: 3.76 [2.49, 5.66]) and ICU admission (conventional IVF-ET: 2.58 [1.11, 6.01]; ICSI: 3.45 [1.68, 7.06]) even after controlling for potential confounders. Neonates conceived by ART had a higher risk of preterm birth (conventional IVF-ET: 1.42 [1.13, 1.78]; ICSI: 1.31 [1.05, 1.64])., Conclusions: Women who conceived by ART had a higher risk of maternal/perinatal complications necessitating advanced obstetric care. Obstetricians should be aware of the increased risk of adverse outcomes among this population.

Background: Cedar pollinosis is one of the most prevalent forms of seasonal allergic reaction in Japan. Only one prospective study has examined the association between cedar pollinosis and mortality. Using a symptom-based questionnaire on cedar pollinosis, we investigated the association of cedar pollinosis with all-cause and cause-specific mortality., Methods: Data came from the Takayama Study, which recruited residents aged ≥35 years in 1992 from Takayama city in Gifu Prefecture, Japan. The current study used information on cedar pollinosis that was obtained from the second survey in 2002. A total of 12,471 persons who were 45-80 years old and had no history of cancer, coronary heart disease, or stroke responded to a questionnaire asking about four symptoms related to cedar pollinosis. Mortality and migration data were obtained throughout the follow-up period up to March 2013. Cox proportional hazard models were used to examine the relation between cedar pollinosis and mortality., Results: A total of 1,276 persons died during follow-up period. Among these, there were 504 neoplasm, 278 cardiovascular, and 181 respiratory deaths. After adjusting for potential confounders, cedar pollinosis was associated with significantly lower all-cause mortality (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.65-0.95) and respiratory mortality (HR 0.38; 95% CI, 0.18-0.82). There was no significant association between cedar pollinosis and mortality due to neoplasm or cardiovascular disease., Conclusions: We found an inverse association between cedar pollinosis and the risk of all-cause and respiratory mortality. Further research is needed to elucidate the association between cedar pollinosis and mortality.

Background: We aimed to examine the association of exposure to environmental tobacco smoke with dental caries among preschool children. Exposure to environmental tobacco smoke was assessed in terms of urinary cotinine concentrations and pack-years of exposure to smoking by parents and other family members at home., Methods: This cross-sectional study included 405 preschool children aged 3-6 years from two preschools in Japan in 2006. Information on the smoking habits of family members living with the child was obtained from parent-administered questionnaires. Dental examination was conducted to assess dental caries, that is, decayed and/or filled teeth. Urinary cotinine levels were measured using first-void morning urine samples., Results: Overall, 31.1% of the children had dental caries, and 29.5% had decayed teeth. Exposure to current maternal and paternal smoking was positively associated with the presence of dental caries after controlling for covariates. More than three pack-years of exposure to maternal smoking and more than five pack-years of exposure to smoking by all family members were significantly associated with the presence of dental caries as compared with no exposure (odds ratio [OR] = 5.55, 95% confidence interval [CI] = 2.17-14.22, P for trend < 0.001 and OR = 2.00, 95% CI = 1.12-3.58, P for trend = 0.004, respectively). These exposure variables were similarly associated with the presence of decayed teeth (OR = 2.92, 95% CI = 1.23-6.96, P for trend = 0.01 and OR = 1.75, 95% CI = 0.96-3.20, P for trend = 0.03, respectively). As compared with lowest tertile of the urinary cotinine level, the highest tertile of the urinary cotinine level was significantly associated with the presence of dental caries as well as decayed teeth; the ORs for the highest vs. lowest tertile of urinary cotinine levels were 3.10 (95% CI = 1.71-5.63, P for trend = 0.012) and 2.02 (95% CI = 1.10-3.70, P for trend = 0.10), respectively., Conclusions: These data suggest that exposure to tobacco smoke may have a dose-dependent influence on the development of caries.

Exposure to acrylamide during pregnancy may disturb pregnancy hormones and the growth of the fetus. The present study aimed to examine the association of maternal acrylamide intake with maternal and cord sex hormone levels during pregnancy and at birth and birth size of offspring. The study subjects were 204 pregnant Japanese women and their newborn girls. Intake of acrylamide was assessed based on 5-day diet records at approximately the 29th week of pregnancy. The concentrations of estradiol, estriol, and testosterone were measured in maternal serum at the 29th weeks of pregnancy and at delivery and umbilical cord blood at delivery. Birth weight, length, and head circumference were measured at the delivery. After controlling for covariates, higher intake of acrylamide was significantly positively associated with higher level of umbilical cord estradiol at the delivery (p for trend = .01), but not with any hormone levels measured in maternal blood. A positive association between acrylamide intake and head circumference was of borderline significance (p for trend = .06). Overall, there were no consistent associations between maternal acrylamide intake and sex hormone levels during pregnancy. However, as this is the first study to examine these associations, additional studies are needed.

Clinical trials show that protein supplement increases infant size in malnourished populations; however, epidemiological studies in high-income countries have reported mixed results. Although these findings suggest a non-linear relationship between maternal macronutrient intake and fetal growth, this relationship has not been closely examined. We assessed the association between maternal protein intake and fetal growth among 91 637 Japanese women with singletons in a nation-wide cohort study using validated FFQ. The respondents answered the FFQ twice, once during early pregnancy (FFQ1; 16·3 (sd 6·0) weeks), and second during mid-pregnancy (FFQ2, 28·1 (sd 4·1) weeks). Daily energy intake and percentage energy from protein, fats and carbohydrates were 7477 (sd 2577) kJ and 13·5 (sd 2·0), 29·5 (sd 6·5) and 55·3 (sd 7·8) %, respectively, for FFQ1, and 7184 (sd 2506) kJ and 13·6 (sd 2·1), 29·8 (sd 6·6) and 55·3 (sd 7·9) %, respectively, for FFQ2. The average birth weight was 3028 (sd 406) g, and 6350 infants (6·9 %) were small for gestational age (SGA). In both phases of the survey, birth weight was highest and the risk of SGA was lowest when the percentage energy from protein was 12 %, regardless of whether isoenergetic replacement was with fat or carbohydrates. Furthermore, when protein density in the maternal diet was held constant, birth weight was highest when 25 % of energy intake came from fat and 61 % came from carbohydrates during early pregnancy. We found maternal protein intake to have an inverse U-curve relationship with fetal growth. Our results strongly suggest that the effect of protein on birth weight is non-linear, and that a balanced diet fulfilling the minimum requirement for all macronutrients was ideal for avoiding fetal growth restriction.