Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria.

Familial episodic pain syndrome (FEPS) is an early childhood onset disorder of severe episodic limb pain caused mainly by pathogenic variants of SCN11A, SCN10A, and SCN9A, which encode three voltage-gated sodium channels (VGSCs) expressed as key determinants of nociceptor excitability in primary sensory neurons. There may still be many undiagnosed patients with FEPS. A better understanding of the associated pathogenesis, epidemiology, and clinical characteristics is needed to provide appropriate diagnosis and care. For this study, nationwide recruitment of Japanese patients was conducted using provisional clinical diagnostic criteria, followed by genetic testing for SCN11A, SCN10A, and SCN9A. In the cohort of 212 recruited patients, genetic testing revealed that 64 patients (30.2%) harbored pathogenic or likely pathogenic variants of these genes, consisting of 42 (19.8%), 14 (6.60%), and 8 (3.77%) patients with variants of SCN11A, SCN10A, and SCN9A, respectively. Meanwhile, the proportions of patients meeting the tentative clinical criteria were 89.1%, 52.0%, and 54.5% among patients with pathogenic or likely pathogenic variants of each of the three genes, suggesting the validity of these clinical criteria, especially for patients with SCN11A variants. These clinical diagnostic criteria of FEPS will accelerate the recruitment of patients with underlying pathogenic variants who are unexpectedly prevalent in Japan.

Diabetes and gastric cancer incidence and mortality in the Asia Cohort Consortium: A pooled analysis of more than a half million participants.

BACKGROUND: Evidence suggests a possible link between diabetes and gastric cancer risk, but the findings remain inconclusive, with limited studies in the Asian population. We aimed to assess the impact of diabetes and diabetes duration on the development of gastric cancer overall, by anatomical and histological subtypes. METHODS: A pooled analysis was conducted using 12 prospective studies included in the Asia Cohort Consortium. Among 558 981 participants (median age 52), after a median follow-up of 14.9 years and 10.5 years, 8556 incident primary gastric cancers and 8058 gastric cancer deaths occurred, respectively. Cox proportional hazard regression models were used to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) and pooled using random-effects meta-analyses. RESULTS: Diabetes was associated with an increased incidence of overall gastric cancer (HR 1.15, 95% CI 1.06-1.25). The risk association did not differ significantly by sex (women vs men: HR 1.31, 95% CI 1.07-1.60 vs 1.12, 1.01-1.23), anatomical subsites (noncardia vs cardia: 1.14, 1.02-1.28 vs 1.17, 0.77-1.78) and histological subtypes (intestinal vs diffuse: 1.22, 1.02-1.46 vs 1.00, 0.62-1.61). Gastric cancer risk increased significantly during the first decade following diabetes diagnosis (HR 4.70, 95% CI 3.77-5.86), and decreased with time (nonlinear p < .01). Positive associations between diabetes and gastric cancer mortality were observed (HR 1.15, 95% CI 1.03-1.28) but attenuated after a 2-year time lag. CONCLUSION: Diabetes was associated with an increased gastric cancer incidence regardless of sex, anatomical subsite, or subtypes of gastric cancer. The risk of gastric cancer was particularly high during the first decade following diabetes diagnosis.

The Association of Retinal Disease with Vision Impairment and Functional Status in Medicare Patients.

Background: The association of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO) with functional status in the general Medicare population are not well established. Objectives: This study examined patient-reported survey data linked with Medicare claims to describe the burden of these vision-threatening retinal diseases (VTRDs) among Medicare beneficiaries. Methods: Medicare Current Beneficiary Survey data linked with Medicare Fee-for-Service claims data from 2006 to 2018 were used in a nationally representative retrospective pooled cross-sectional population-based comparison study. Outcomes between community-dwelling beneficiaries with nAMD (n = 1228), DME (n = 101), or RVO (n = 251) were compared with community-dwelling beneficiaries without any VTRDs (n = 104 088), controlling for baseline demographic and clinical differences. Beneficiaries with a diagnosis of nAMD, DME, or RVO during the data year were included; those with other VTRDs were excluded. Outcomes included vision function and loss, overall functioning as assessed by difficulties with activities of daily living (ADLs) and instrumental ADLs (iADLs), anxiety/depression, falls, and fractures. Results: In patient cohorts with nAMD, DME, and RVO, approximately one-third (34.2%-38.3%) reported "a little trouble seeing" (vs 28.3% for controls), and 26%, 17%, and 9%, respectively, reported "a lot of trouble seeing/blindness" (vs 5% of controls). Difficulty walking and doing heavy housework were the most reported ADLs and iADLs, respectively. Compared with those without VTRDs, beneficiaries with nAMD had higher odds of diagnosed vision loss (odds ratio [OR], 5.39; 95% confidence interval, 4.06-7.16; P < .001) and difficulties with iADLs (odds ratio, 1.41; 95% confidence interval, 1.11-1.80; P = .005); no differences were observed for DME or RVO vs control. After adjusting for age, sex, race/ethnicity, poverty status, comorbidities, and other relevant covariates, nAMD, DME, and RVO were not significantly associated with anxiety/depression, falls, or fractures. Discussion: Patients with nAMD or DME were more likely to report severe visual impairment than those without VTRDs, although only those with nAMD were more likely to be diagnosed with vision loss. Conclusions: Patients with nAMD continue to experience more vision impairment and worse functional status compared with a similar population of Medicare beneficiaries despite availability of therapies like antivascular endothelial growth factor to treat retinal disease.

Active and passive smoking and breast cancer in Japan: a pooled analysis of nine population-based cohort studies.

BACKGROUND: Epidemiological studies have shown inconsistent results regarding the link between smoking and breast cancer risk, despite the biological plausibility of a positive association. METHODS: Participants were 166 611 women from nine prospective cohort studies in Japan which launched in 1984-1994 and followed for 8-22 years. Information on smoking and secondhand smoke was obtained through self-administered baseline questionnaires. Breast cancer was defined as code C50 according to the International Classification of Diseases for Oncology, 3rd Edition or the International Classification of Diseases, 10th Revision. After adjusting for several potential confounders, relative risks for breast cancer were calculated in the individual studies according to the current or previous status of active and passive smoking using Cox regression, followed by a summary estimate of hazard ratios using random-effects meta-analyses. RESULTS: Of the 60 441 participants who reported being premenopausal and 106 170 who reported being postmenopausal at baseline, 897 and 1168 developed breast cancer during follow-up, respectively. Compared with never smokers, current smokers had a higher risk of developing breast cancer before the age of 50 years. In addition, ever smokers who started smoking at 30 years of age or younger, or who started smoking before first childbirth, had a higher risk of developing breast cancer before the age of 50 years. No association between adulthood or childhood exposure to secondhand smoke and breast cancer was observed. CONCLUSION: Smoking may increase the risk of premenopausal breast cancer, and smoking earlier in life might be especially harmful. The impact of secondhand smoke needs further investigation.

Diabetes is associated with increased liver cancer incidence and mortality in adults: A report from Asia Cohort Consortium.

There has been growing evidence suggesting that diabetes may be associated with increased liver cancer risk. However, studies conducted in Asian countries are limited. This project considered data of 968,738 adults pooled from 20 cohort studies of Asia Cohort Consortium to examine the association between baseline diabetes and liver cancer incidence and mortality. Cox proportional hazard model and competing risk approach was used for pooled data. Two-stage meta-analysis across studies was also done. There were 839,194 subjects with valid data regarding liver cancer incidence (5654 liver cancer cases [48.29/100,000 person-years]), follow-up time and baseline diabetes (44,781 with diabetes [5.3%]). There were 747,198 subjects with valid data regarding liver cancer mortality (5020 liver cancer deaths [44.03/100,000 person-years]), follow-up time and baseline diabetes (43,243 with diabetes [5.8%]). Hazard ratio (HR) (95% confidence interval [95%CI]) of liver cancer diagnosis in those with vs. without baseline diabetes was 1.97 (1.79, 2.16) (p < .0001) after adjusting for baseline age, gender, body mass index, tobacco smoking, alcohol use, and heterogeneity across studies (n = 586,072; events = 4620). Baseline diabetes was associated with increased cumulative incidence of death due to liver cancer (adjusted HR (95%CI) = 1.97 (1.79, 2.18); p < .0001) (n = 595,193; events = 4110). A two-stage meta-analytic approach showed similar results. This paper adds important population-based evidence to current literature regarding the increased incidence and mortality of liver cancer in adults with diabetes. The analysis of data pooled from 20 studies of different Asian countries and the meta-analysis across studies with large number of subjects makes the results robust.

Body mass index and lung cancer risk: Pooled analysis of 10 prospective cohort studies in Japan.

Mounting evidence suggests that body mass index (BMI) is inversely associated with the risk of lung cancer. However, relatively few studies have explored this association in Asian people, who have a much lower prevalence of obesity than Caucasians. We pooled data from 10 prospective cohort studies involving 444,143 Japanese men and women to address the association between BMI and the risk of lung cancer. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated in each cohort using the Cox proportional hazards model. A meta-analysis was undertaken by combining the results from each cohort. Heterogeneity across studies was evaluated using Cochran's Q and I2statistics. During 5,730,013 person-years of follow-up, 6454 incident lung cancer cases (4727 men and 1727 women) were identified. Baseline BMI was inversely associated with lung cancer risk in men and women combined. While leanness (BMI <18.5) was associated with a higher risk of lung cancer (HR 1.35; 95% CI, 1.16-1.57), overweight and obesity were associated with a lower risk, with HRs of 0.77 (95% CI, 0.71-0.84) and 0.69 (95% CI, 0.45-1.07), respectively. Every 5 kg/m2 increase in BMI was associated with a 21% lower risk of lung cancer (HR 0.79; 95% CI, 0.75-0.83; p < 0.0001). Our pooled analysis indicated that BMI is inversely associated with the risk of lung cancer in the Japanese population. This inverse association could be partly attributed to residual confounding by smoking, as it was more pronounced among male smokers.

Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time.

Dietary melatonin and liver cancer incidence in Japan: From the Takayama study.

There is some biological plausibility that exogenous melatonin plays a role in preventing liver carcinogenesis. There has been little research on the association between melatonin intake in a normal diet and health outcomes. We evaluated the association between dietary melatonin intake and the incidence of liver cancer in a population-based prospective study in Japan. This study included 30,824 residents of Takayama city who were 35 years of age or older in 1992 and had participated in the Takayama study, Japan. Dietary intake was assessed using a validated food frequency questionnaire at the baseline. Melatonin content in foods was measured by liquid chromatography-tandem mass spectrometry. Cancer incidence was confirmed through regional population-based cancer registries in Gifu. Liver cancer was defined as code C22 according to the International Classification of Diseases and Related Health Problems, 10th Revision. Hazard ratios for liver cancer were estimated for the tertile groups of melatonin intake using a Cox proportional hazards model. During the mean follow-up period of 13.6 years, 189 individuals developed liver cancer. Compared with subjects in the lowest tertile of melatonin intake, those in the middle and highest tertiles had decreased risks of liver cancer, with a significant linear trend after multivariate adjustments (hazard ratios: 0.64 and 0.65, respectively, trend p = 0.023). There was no significant interaction by sex (interaction p = 0.54). This initial finding, which needs to be confirmed by further studies, suggests that consuming melatonin-containing foods might play a role in the prevention of liver cancer.

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea.

BACKGROUND: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. METHODS: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. RESULTS: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26]). CONCLUSION: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts.

Adult Height and Risk of Colorectal Cancer: A Pooled Analysis of 10 Population-based Cohort Studies in Japan.

BACKGROUND: While tall stature has been linked to an increase in the risk of colorectal cancer (CRC), its association with cancer in the colorectum and its subsites remains unclear among Asians. METHODS: We conducted a pooled analysis of 10 population-based cohort studies among adults in Japan. Each study estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC incidence associated with adult height were estimated using Cox proportional hazards regression with adjustment of the same set of covariates were then pooled to estimate summary HRs incidence using random-effect models. RESULTS: We identified 9,470 CRC incidences among 390,063 participants during 5,672,930 person-years of follow-up. Men and women with tall stature had a higher risk of CRC and colon cancer. HRs for CRC, colon cancer, and distal colon cancer for the highest versus lowest height categories were 1.23 (95% CI, 1.07-1.40), 1.22 (95% CI, 1.09-1.36), and 1.27 (95% CI, 1.08-1.49), respectively, in men and 1.21 (95% CI, 1.09-1.35), 1.23 (95% CI, 1.08-1.40), and 1.35 (95% CI, 1.003-1.81), respectively, in women. The association with proximal colon cancer and rectal cancer was less evident in both sexes. CONCLUSION: This pooled analysis confirms the link between tall stature and a higher risk of CRC and colon cancer (especially distal colon) among the Japanese and adds evidence to support the use of adult height to identify those at a higher risk of CRC.

Real-world utilization of lenvatinib and pembrolizumab combination therapy for the treatment of endometrial cancer in the USA.

Aim: Describe treatment and dosing patterns of lenvatinib and pembrolizumab combination therapy (lenva+pembro) among endometrial cancer (EC) patients in US clinical practice. Materials & methods: Retrospective cohort study among adults with EC initiating lenva+pembro in second line (2L) or third line and later (≥3L) between 17 September 2019 and 30 June 2021. Results: 110 patients initiated lenva+pembro in 2L and 135 patients in ≥3L. Majority of patients initiated lenva+pembro at label-recommended starting doses/interval. Less than half changed lenvatinib dose over time. At median follow-up of 7.3 and 8.7 months, median (95% CI) duration of therapy was 5.1 (4.7-6.1) and 5.8 (4.2-7.3) months for patients in 2L and ≥3L, respectively. Conclusion: Lenva+pembro was mostly initiated at label-recommended dose.

This study looked at details of lenvatinib and pembrolizumab combination treatment among patients with endometrial cancer (EC) in the USA. Specifically, these patients had received prior chemotherapy or hormone therapy before starting lenvatinib and pembrolizumab. Most patients started lenvatinib and pembrolizumab at the dose recommended by the product label and received the next pembrolizumab injection within the recommended timeframe. Over time, more than half of the patients did not change the dose of lenvatinib, and most patients had the same dose of pembrolizumab. On average, patients were treated with lenvatinib and pembrolizumab for 5­6 months. This study showed that in general, patients were taking lenvatinib and pembrolizumab for treatment of EC as recommended by product labels.

Dietary polyamine intake and all-cause and cause-specific mortality in Japanese adults in the Takayama study.

Epidemiological studies on the potential health effects of dietary polyamines are scarce. The present study aimed to estimate habitual intake of polyamines (putrescine, spermidine and spermine) and examine whether spermidine intake is inversely associated with all-cause and cause-specific mortality in a population-based cohort study in Japan. The study included 13 355 men and 15 724 women aged 35 years and older. Diet was assessed via a validated FFQ at the baseline in 1992. The intake of polyamines was estimated mainly using databases of polyamine content in foods consumed among Japanese population. Sex-specific hazard ratios (HR) and 95 % CI for all-cause and cause-specific mortality were estimated according to polyamine quartiles. During 16 years of follow-up, 2901 deaths in men and 2438 in women occurred. The intake of any polyamine was not significantly associated with all-cause or cause-specific mortality after controlling for covariates in men and women. There was a suggestive positive association between spermidine intake and cancer mortality in women: HR for the highest v. lowest quartile were 1·38 (95 % CI (0·99, 1·93); Ptrend = 0·02). Our results did not provide support for the notion that dietary spermidine has beneficial effects on mortality. Further studies on dietary polyamines and longevity, as well as the morbidity of specific diseases, including cancer, are needed across populations with different dietary habits.

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Lung Cancer Risk Prediction Models for Asian Ever-Smokers.

INTRODUCTION: Although lung cancer prediction models are widely used to support risk-based screening, their performance outside Western populations remains uncertain. This study aims to evaluate the performance of 11 existing risk prediction models in multiple Asian populations and to refit prediction models for Asians. METHODS: In a pooled analysis of 186,458 Asian ever-smokers from 19 prospective cohorts, we assessed calibration (expected-to-observed ratio) and discrimination (area under the receiver operating characteristic curve [AUC]) for each model. In addition, we developed the "Shanghai models" to better refine risk models for Asians on the basis of two well-characterized population-based prospective cohorts and externally validated them in other Asian cohorts. RESULTS: Among the 11 models, the Lung Cancer Death Risk Assessment Tool yielded the highest AUC (AUC [95% confidence interval (CI)] = 0.71 [0.67-0.74] for lung cancer death and 0.69 [0.67-0.72] for lung cancer incidence) and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model had good calibration overall (expected-to-observed ratio [95% CI] = 1.06 [0.90-1.25]). Nevertheless, these models substantially underestimated lung cancer risk among Asians who reported less than 10 smoking pack-years or stopped smoking more than or equal to 20 years ago. The Shanghai models were found to have marginal improvement overall in discrimination (AUC [95% CI] = 0.72 [0.69-0.74] for lung cancer death and 0.70 [0.67-0.72] for lung cancer incidence) but consistently outperformed the selected Western models among low-intensity smokers and long-term quitters. CONCLUSIONS: The Shanghai models had comparable performance overall to the best existing models, but they improved much in predicting the lung cancer risk of low-intensity smokers and long-term quitters in Asia.

Reproductive Factors and Endometrial Cancer Risk Among Women.

Importance: Despite evidence of an association between reproductive factors and endometrial cancer risk, prospective studies have been conducted mainly in non-Asian countries. Objective: To assess the association between reproductive factors, such as number of deliveries, age at menarche, or menopause, and endometrial cancer risk. Design, Setting, and Participants: This cohort study used pooled individual data from 13 prospective cohort studies conducted between 1963 and 2014 in the Asia Cohort Consortium. Participants were Asian women. Data analysis was conducted from September 2019 to April 2023. Exposures: Reproductive factors were assessed using a questionnaire in each cohort. Main Outcomes and Measures: The main outcome was time to incidence of endometrial cancer. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% CIs. Results: A total of 1005 endometrial cancer cases were detected among 332 625 women (mean [SD] age, 54.3 [10.4] years) during a mean (SD) of 16.5 (6.4) years of follow-up. Increasing number of deliveries was associated with a decreased endometrial cancer risk in a dose-response manner (≥5 deliveries vs nulliparous [reference]: HR, 0.37; 95% CI, 0.26-0.53; P for trend < .001). Compared with menarche at younger than 13 years, menarche at 17 years or older had an HR of 0.64 (95% CI, 0.48-0.86; P for trend < .001). Late menopause (age ≥55 years) showed an HR of 2.84 (95% CI, 1.78-4.55; P for trend < .001) compared with the youngest age category for menopause (<45 years). Age at first delivery, hormone therapy, and breastfeeding were not associated with endometrial cancer risk. Conclusions and Relevance: This large pooled study of individual participant data found that late menarche, early menopause, and a higher number of deliveries were significantly associated with a lower risk of endometrial cancer. These convincing results from Asian prospective studies add to the growing body of evidence for the association between reproductive factors and endometrial cancer.

Associations of the timing of sleep and meals with the presence of gastroesophageal reflux disease in community-dwelling women in Japan.

BACKGROUND: It has been suspected that circadian rhythms may play a part in the pathogenesis of gastrointestinal diseases including gastroesophageal reflux disease (GERD). The present study aimed to examine the cross-sectional association of the timing of sleep and meals with the presence of GERD in community-dwelling women in Japan. METHODS: In total, 605 women responded to a self-administered questionnaire asking for information on GERD symptoms, sleep habits, sleep disturbances and the timing of meals. GERD symptoms were evaluated using the Frequency Scale for the Symptoms of GERD, and participants with a score of more than seven points were classified as having GERD. RESULTS: In total, 104 (17.2%) women were found to have GERD. Later bedtime on both weekdays and weekends and later midpoint of sleep were significantly associated with the odds ratios (OR) of GERD after controlling for covariates: ORs for each 1 h delay were 1.31 (95% confidence interval [CI] = 1.03-1.68), 1.38 (95% CI = 1.08-1.75) and 1.43 (95% CI = 1.06-1.95). Having lunch at irregular times was significantly associated with the increased OR of GERD (1.99; 95% CI = 1.02-3.91). Longer overnight fasting duration and longer time intervals from the midpoint of sleep to breakfast and lunch were significantly associated with decreased OR of GERD (ORs for each 1 h increase were 0.73 [95% CI = 0.56-0.95], 0.64 [95% CI = 0.46-0.88] and 0.70 [95% CI = 0.51-0.96]). CONCLUSIONS: These data suggest that the timing of sleep and timing of meals relative to the sleep/wake cycle are associated with the presence of GERD.

Milk and dairy product intakes, intestinal bacteria, and respiratory infections in children of elementary school age and older in Japan.

OBJECTIVES: The aim of this study was to examine the associations between milk and dairy product intakes, intestinal bacteria, and respiratory infections in children of elementary school age and older in Japan. METHODS: We conducted cross-sectional surveys each year from 2013 to 2015 for grades 2, 5, and 8 students of an elementary and junior high school (n = 1020). Exclusion owing to ineligibility regarding data on dietary intake, respiratory infections, and intestinal bacteria led to 922 participants for the analyses. Dietary intake was assessed with a self-administered food frequency questionnaire. Respiratory infections occurring ≥ 4 episodes over the past year were determined based on the caregivers' reports. Intestinal bacteria (species and counts) were analyzed with real-time polymerase chain reaction. Logistic regression models were used to estimate the odds ratios (ORs) and 95% CIs. RESULTS: The odds of ≥ 4 respiratory infection episodes decreased with higher milk intake after adjusting for potential confounders, and the ORs (95% CIs) for the second and third tertile categories, compared with the first tertile category, were 0.91 (0.58-1.42) and 0.48 (0.29-0.77), respectively (P for trend = 0.001). A decreasing trend in the ORs for lactic acid drink intake was observed only in those with a low count of intestinal Faecalibacterium prausnitzii. CONCLUSIONS: We found that higher milk intake was inversely associated with respiratory infections in children older than preschool age. Higher lactic acid drink intake could be inversely associated only in children with a low F. prausnitzii count in the intestine.

Association of dietary fibre intake with subsequent fasting glucose levels and indicators of adiposity in school-age Japanese children.

OBJECTIVE: To evaluate the relationships of fibre intake with subsequent BMI sd-score, waist-to-height ratio and serum fasting glucose levels among school-age Japanese children. DESIGN: This is a prospective study of school-age Japanese children. Participants were followed from 6-7 to 9-10 years of age (follow-up rate: 92·0 %). Fibre intake was assessed using a validated FFQ. Serum fasting glucose was measured by a hexokinase enzymatic method. Using a general linear model, the associations between dietary fibre intake at baseline and BMI sd-score, waist-to-height ratio, and serum levels of fasting glucose at follow-up were evaluated after considering potential confounding factors. SETTING: Public elementary schools in a city in Japan. PARTICIPANTS: A total of 2784 students. RESULTS: The estimated means for fasting glucose at 9-10 years of age were 86·45, 85·68, 85·88 and 85·58 mg/dl in the lowest, second, third and highest quartile of fibre intake at 6-7 years of age, respectively (P = 0·033, trend P = 0·018). Higher fibre intake at 6-7 years of age was associated with lower waist-to-height ratio at 9-10 years of age (trend P = 0·023). The change in fibre intake was inversely associated with concurrent change of BMI sd-score (trend P = 0·044). CONCLUSION: These results suggest that dietary fibre intake may be potentially effective to limit excess weight gain and lower glucose levels during childhood.

Body mass index and esophageal and gastric cancer: A pooled analysis of 10 population-based cohort studies in Japan.

The effect of body mass index (BMI) on esophageal and gastric carcinogenesis might be heterogeneous, depending on subtype or subsite. However, findings from prospective evaluations of BMI associated with these cancers among Asian populations have been inconsistent and limited, especially for esophageal adenocarcinoma and gastric cardia cancer. We performed a pooled analysis of 10 population-based cohort studies to examine this association in 394,247 Japanese individuals. We used Cox proportional hazards regression to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs), then pooled these estimates to calculate summary HRs with a random effects model. During 5,750,107 person-years of follow-up, 1569 esophageal cancer (1038 squamous cell carcinoma and 86 adenocarcinoma) and 11,095 gastric (728 cardia and 5620 noncardia) cancer incident cases were identified. An inverse association was observed between BMI and esophageal squamous cell carcinoma (HR per 5-kg/m2 increase 0.57, 95% CI 0.50-0.65), whereas a positive association was seen in gastric cardia cancer (HR 1.15, 95% CI 1.00-1.32). A nonsignificant and significant positive association for overweight or obese (BMI ≥25 kg/m2 ) relative to BMI <25 kg/m2 was observed with esophageal adenocarcinoma (HR 1.32, 95% CI 0.80-2.17) and gastric cardia cancer (HR 1.24, 95% CI 1.05-1.46), respectively. No clear association with BMI was found for gastric noncardia cancer. This prospective study-the largest in an Asian country-provides a comprehensive quantitative estimate of the association of BMI with upper gastrointestinal cancer and confirms the subtype- or subsite-specific carcinogenic impact of BMI in a Japanese population.

Response to antiviral therapy for chronic hepatitis C and risk of hepatocellular carcinoma occurrence in Japan: a systematic review and meta-analysis of observational studies.

In Japan, hepatocellular carcinoma (HCC) is a leading cause of cancer mortality and hepatitis C virus infection is a major cause of HCC. We conducted a systematic review and meta-analysis of published studies evaluating patient response to antiviral therapy for chronic hepatitis C on the risk of HCC occurrence in Japan. Articles were searched using terms determined a priori through PubMed, screened by title and abstract, and selected by full-text assessment according to criteria determined a priori, including HCC occurrence in response to interferon (IFN)-based or IFN-free therapy, Japanese study, and 2 or more years of follow-up. We excluded studies on HCC recurrence. We calculated the pooled estimate of the crude incidence rate ratio with data from the selected studies using the person-years method with Poisson regression model and pooled estimate of the hazard ratio adjusted for potential confounders reported by the studies using a random effects model. A total of 26 studies were identified, all of which examined only IFN-based therapy as a result of the selection process. The pooled estimate (95% confidence interval [CI]) of 25 studies was 0.37 (0.33-0.43) for sustained virologic response (SVR) and 1.70 (1.61-1.80) for non-SVR for the HCC incidence rate per 100 person-years, and 0.22 (0.19-0.26) for the incidence rate ratio (SVR vs. non-SVR). The pooled estimate of the hazard ratio (95% CI) of HCC incidence adjusted for potential confounders of 8 studies was 0.25 (0.19-0.34). SVR to interferon therapy for chronic hepatitis C reduces the risk of HCC occurrence.