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To conduct a long-term birth cohort study that includes genetic analysis, it is crucial to understand the attitudes of participants to genetic analysis and then take appropriate approaches for addressing their ambiguous and negative attitudes. This study aimed to explore participants’ attitudes toward genetic analysis and associated background factors among mothers who were enrolled in a large Japanese birth cohort. A questionnaire was sent to participants’ households, and the responses of 1762 mothers (34.0%) were used for the study. The majority of mothers recognized genetic analysis for themselves and their children and sharing of genetic data as beneficial. A low knowledge level of genomic terminology was associated with ambiguous attitudes toward genetic analysis and data sharing. Education level was positively associated with the recognition of the benefits of genetic analysis. Concern about handling genetic information was associated with the unacceptability of data sharing. Trust was associated with the approval of genetic analysis. Most mothers preferred that genetic analysis results be returned. These findings suggest the need for multiple efforts to maximize participants’ acceptance of genetic analysis, such as utilizing an educational approach to encourage familiarity with genetics/genomics, optimizing explanations for different educational levels, and explicitly disclosing the handling policy for genetic information.

In a meta-analysis of three GWAS for susceptibility to Kawasaki disease (KD) conducted in Japan, Korea, and Taiwan and follow-up studies with a total of 11,265 subjects (3428 cases and 7837 controls), a significantly associated SNV in the immunoglobulin heavy variable gene (IGHV) cluster in 14q33.32 was identified (rs4774175; OR = 1.20, P = 6.0 × 10−9). Investigation of nonsynonymous SNVs of the IGHV cluster in 9335 Japanese subjects identified the C allele of rs6423677, located in IGHV3-66, as the most significant reproducible association (OR = 1.25, P = 6.8 × 10−10 in 3603 cases and 5731 controls). We observed highly skewed allelic usage of IGHV3-66, wherein the rs6423677 A allele was nearly abolished in the transcripts in peripheral blood mononuclear cells of both KD patients and healthy adults. Association of the high-expression allele with KD strongly indicates some active roles of B-cells or endogenous immunoglobulins in the disease pathogenesis. Considering that significant association of SNVs in the IGHV region with disease susceptibility was previously known only for rheumatic heart disease (RHD), a complication of acute rheumatic fever (ARF), these observations suggest that common B-cell related mechanisms may mediate the symptomology of KD and ARF as well as RHD.

IntroductionRecently, the incidence of cervical cancer has increased in Japan, probably because of an interruption in human papillomavirus (HPV) vaccination and a low cervical cancer screening rate. There is a lack of evidence for self-sampling HPV testing as a cervical cancer screening tool in Japan. The Accelerating Cervical Cancer Elimination by Self-Sampling test trial aims to compare the effectiveness of screening using the self-sampling HPV test with that of routine screening concerning screening uptake and precancer detection.Methods and analysisThis trial has a single-municipality, open-label, parallel, superiority and randomised design. Approximately 20 000 women who have not undergone cervical cancer screening for at least 3 years will be assigned randomly to the self-sampling arm and the control arm using a 1:1 ratio. Participants assigned to the control arm will undergo routine cervical cancer screening (cytology test) provided by Ichihara City, while those assigned to the self-sampling arm will choose the routine screening or self-sampling HPV test. HPV tests will be performed using the cobas 8800 system (Roche Diagnostics, Rotkreuz, Switzerland). Participants who will undergo the self-sampling HPV testing will be recommended to undergo routine screening. The results of the cytology test and further tests, such as colposcopy and biopsy, will be collected and used for this trial. The risk ratio and risk difference in the proportion of participants with cervical intraepithelial neoplasia two or worse between the two arms will be calculated. The test for the null hypothesis (the detection rates are equal between the two arms) will be performed using Pearson’s χ2 test.Ethics and disseminationThis trial was approved by the Research Ethics Committees of the Chiba Foundation for Health Promotion and Disease Prevention and the collaborating research institutes. The results will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberjRCT1030200276. Pre-results.

There is no universal recommendation for managing the reactivation of HBV in patients with resolved HBV infection treated with anti-CD20 monoclonal antibodies for B-cell non-Hodgkin lymphoma. This study compared the cost-effectiveness of two commonly used strategies: prophylactic anti-HBV nucleos(t)ide analog therapy (Pro NAT), and HBV DNA monitoring followed by on-demand antiviral therapy (HBV DNA monitoring). Using a decision tree model, the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. The threshold for cost-effectiveness was set at 5,000,000 JPY, equivalent to 45,662 USD. In a base–case analysis, HBV DNA monitoring was found to be more cost-effective based on the calculation of ICER as 132,048 USD per QALY, a value that far exceeds 45,662 USD. The same results were consistently obtained by a one-way deterministic sensitivity analysis, even after changing each parameter value within the predetermined range. A probabilistic sensitivity analysis with 10,000 simulations also revealed that HBV DNA monitoring is more cost-effective than Pro NAT in 96.8% of cases. Therefore, this study suggests that HBV DNA monitoring is an appropriate managing measure in Japan from a cost-effectiveness perspective.

Biotin is a water-soluble B complex vitamin and coenzyme of five types of carboxylase and plays crucial roles in fatty acid, glucose, and amino acid metabolism. Nutritional biotin deficiency and defective enzymes essential for biotin metabolism cause inflammatory diseases such as eczema-like dermatitis and Crohn's disease; however, little is known about the pathophysiological roles of biotin. This study investigated the relationship between biotin metabolism and human allergic sensitization and diseases by measuring serum levels of biotin, total immunoglobulin E (IgE) and allergen-specific IgEs in more than 400 Japanese schoolchildren aged 6 to 12. The prevalence of allergic diseases, and environmental and life-style factors were also examined by a questionnaire. Like total IgE, serum biotin levels of children showed a log-normal distribution. Meanwhile, Spearman's rank correlation analysis showed weak but significant positive associations between serum biotin levels and total IgE (rho=0.147, p=0.0029) as well as allergen-specific IgEs against egg whites (rho=0.215, p=0.00013), cedar pollen (rho=0.176, p=0.00036), and cat dander (rho=0.130, p=0.0085). Furthermore, mean serum biotin levels in children with cedar pollinosis, but not with other allergic diseases such as asthma and allergic rhinitis, were significantly higher than in those without (p=0.0015). These results suggest a correlation between serum biotin levels and the development of cedar pollinosis. Further prospective studies are needed to evaluate the causal relationship between biotin metabolism and cedar pollen sensitization and pollinosis development.

Background and objective Improved detectability of chronic obstructive pulmonary disease (COPD) using a handheld flow meter (HFM) with symptom-based questionnaires has not been sufficiently evaluated. This study aimed to identify the benefit of using an HFM in COPD screening. Methods A total of 2008 participants, who were ≥ 40 years of age, from Isumi City, Japan, were recruited. We developed two novel point systems for detecting COPD, one incorporated score of HFM alone (sHFM) and the other incorporated the score of International Primary Care Airway Group questionnaire (IPAG) and HFM (sIPAG + HFM). Validation using random sample allocation (split-sample validation) was carried out to assess the predictive performance of these models. Results Participants were assigned to a data set for model creation (n = 1007) or a data set for model assessment (n = 1001) to perform split-sample validation. Decision curve analysis showed that the net benefits of sHFM and sIPAG + HFM were higher than that of the IPAG score (sIPAG) and specificity of the former two were also significantly higher than that of sIPAG. However, the curves of sHFM and sIPAG + HFM were crossing and practically the same with no significant difference in sensitivity and specificity. Conclusion This study confirms that HFM is significantly advantageous in detecting COPD despite the use of a conventional questionnaire.

Background Manganese (Mn) is both an essential element and a potential toxicant. Although a few studies have suggested a nonlinear relationship between the maternal whole blood Mn level at delivery and infant birth weight, little is known about the effects of Mn levels during pregnancy on fetal growth, particularly with regard to sex-specific differences. Methods In this nationwide birth cohort study, we examined the association of maternal blood Mn level during pregnancy with infant birth weight, length, and head circumference in 16,473 mother–infant pairs. Pregnant women living in 15 regions across Japan were recruited between January 2011 and March 2014. The analysis of birth size (8,484 males and 7,989 females) was conducted using a nonlinear spline, followed by the use of quadratic regression or linear regression models. The analysis of small-for-gestational-age (SGA) (6,962 males and 6,528 females born vaginally) was conducted using multivariate logistic regression. Additionally, subgroup analysis was conducted according to the timing of blood sampling. Results The median maternal blood Mn level during pregnancy (i.e., 2nd and 3rd trimesters) was 16.2 µg/L (range, 4.3–44.5 µg/L). A positive linear association between the log blood Mn level and head circumference was observed in both male and female infants. However, a nonlinear relationship between the log blood Mn level and birth weight was observed only in male infants, such that the birth weight increased up to a blood Mn level of 18.6 µg/L. In the subgroup analysis stratified by the timing of maternal blood sampling, this nonlinear relationship was obvious only when sampling was performed in the 3rd trimester. Male infants in the lowest blood Mn level quartile (≤ 13.2 µg/L) faced an increased risk of SGA (odds ratio [95% confidence interval] = 1.35 [1.04–1.74]), as did those in the highest blood Mn level quartile (≥ 21.0 µg/L) when sampling was performed during the 3rd trimester (odds ratio [95% confidence interval] = 1.62 [1.10 to 2.39]), compared to those in the third blood Mn level quartile (the category including 18.6 µg/L). No association of blood Mn level with birth weight was observed among female infants, and blood Mn level was not associated with birth length in either male or female infants. Conclusion A low blood Mn level during pregnancy or a high blood Mn level during the 3rd trimester was associated with a lower birth weight and increased risk of SGA in male infants, but not in female infants. A low blood Mn level was found to correlate slightly with a small head circumference among infants of both sexes.

Eosinophils are major effector cells of allergic disease and excellent markers of eosinophilic inflammation. Accurate and reliable biomarkers are helpful in the diagnosis, treatment, and control of allergic disease.This study aimed to investigate an alternate marker of eosinophilic inflammation, eosinophil-derived neurotoxin (EDN), in a number of allergic diseases.Three hundred ninety-six elementary school-age children with various allergic conditions were recruited for this study. Subgroups included food allergies (FAs), atopic dermatitis (AD), bronchial asthma (BA), and allergic rhinitis (AR). EDN levels in these groups were compared to those in 93 healthy controls (HC).All subjects with allergic disease had elevated levels of serum EDN (median [interquartile range]: FA, 124.2 ng/mL [59.13-160.5 ng/mL]; AD, 110.8 ng/mL [57.52-167.9 ng/mL]; BA, 131.5 ng/mL [60.60-171.0 ng/mL]; AR, 91.32 ng/mL [46.16-145.0 ng/mL]) compared to HC (38.38 ng/mL [32.40-55.62 ng/mL]) (Direct measures of eosinophilic inflammation are needed for accurate diagnosis, treatment, and monitoring of allergic diseases. EDN may be a worthy biomarker of eosinophil activity and a useful screening tool for allergic diseases including FA, AD, BA, and AR.

Background There is no worldwide standard recommendation for preventing hepatitis B virus (HBV) reactivation for patients with resolved infection treated with an anti-CD20 antibody for B-cell non-Hodgkin lymphoma. This study aims to compare the cost-effectiveness between two commonly used strategies to prevent HBV reactivation-related death. Methods The two strategies compared were prophylactic antiviral therapy (Pro NAT) and HBV DNA monitoring followed by on-demand antiviral therapy (HBV DNA monitoring) using entecavir (Entecavir, a generic drug for Baraclude). Effectiveness was defined as the prevention of death due to HBV reactivation and costs were calculated under the health insurance system of Japan as of April 2018 using Markov model. A cost-minimization analysis, one of the cost-effectiveness analyses, was applied, since the effectiveness was the same between the two strategies according to a meta-analysis. To consider the effect of uncertainty for each parameter, probabilistic sensitivity analysis (PSA) was performed. In the scenario analysis, costs were calculated using lamivudine (Zefix) or tenofovir alafenamide (Vemlidy) instead of entecavir. All analyses were done using TreeAge Pro 2019 (TreeAge Software, Inc., MA, USA). Results Estimated costs per patient during the 30 months after initiation of chemotherapy for lymphoma were 1,513 USD with Pro NAT and 1,265 USD with HBV DNA monitoring. A PSA revealed that HBV DNA monitoring was more consistently cost-effective compared with Pro NAT when some parameters were set randomly according to probability distributions. In our scenario analysis, costs of Pro NAT and HBV DNA monitoring were calculated as 2,762 and 1,401 USD using lamivudine, 4,857 and 1,629 USD using tenofovir alafenamide. Conclusions Our cost-effectiveness analysis shows that an HBV DNA monitoring strategy using entecavir should be recommended for preventing HBV reactivation-related death in Japan. Key messages Cost-effectiveness analysis demonstrated that HBV DNA monitoring was more cost-effective compared to Pro NAT; this result was consistent with PSA. HBV DNA monitoring strategy should be recommended to prevent HBV reactivation-related death for the patients with resolved HBV infection in Japan.

Smoking is a risk factor for adult-onset Crohn&rsquo, s disease (CD). Although passive smoking from family members is a major concern, especially in pediatric CD, the number of existing epidemiological studies is limited. This multicenter case&ndash, control study aimed to assess the effects of familial smoking on pediatric CD. We examined 22 pediatric CD cases and 135 controls. The subjects&rsquo, mothers were given a self-administered questionnaire about family smoking before disease onset in the CD group or the corresponding period in the control group. Univariable logistic regression model was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), whereas dose&ndash, response relationship analyses were performed for more in-depth evaluations. Univariable analyses indicated that passive smoking from the mother (OR, 2.09, 95% CI, 0.61&ndash, 7.10) was not a significant, but a candidate risk factor for developing pediatric CD. In contrast, the dose&ndash, response relationship analyses revealed that passive smoking from the mother (OR, 1.17, 95% CI, 1.04&ndash, 1.31) was significantly associated with pediatric CD. Therefore, passive smoking from the mother may be predominantly associated with the development of pediatric CD. Further follow-up studies comprising environmental measurements of passive smoking exposure doses and genetic factors interaction analysis are necessary.

ObjectivesA sufficient screening rate is indispensable to optimize the positive impact of colorectal cancer (CRC) screening. This study aimed to evaluate the effect of an additional outreach of providing an opportunity to obtain a kit for fecal immunochemical test (FIT) during the general health check-up to increase CRC screening rate.MethodsThis was a longitudinal study using pre-existing data in Kujukuri Town, Japan. The town provided CRC screening in the fiscal year (FY) 2017 using an existing procedure for all beneficiaries of the National Health Insurance, whereas in FY 2018, an additional outreach effort was made to only those with an even number of age (exposed group), who were offered an opportunity to obtain a kit for FIT at the time of general health check-ups but not to those with an odd number of age (control group). To estimate the effectiveness, generalized estimating equation (GEE) with individuals as clusters was performed.ResultsIn total, 3,530 individuals were included (1,708 in the control group and 1,822 in the exposed group). GEE showed significant interaction between the groups (control and exposed) and FYs (2017 and 2018) (pConclusionsAdditional outreach of providing an opportunity to obtain a kit for FIT at the time of the general health check-up improved the CRC screening rate. However, screening rate achieved by this strategy remained low, indicating further efforts is required.

Objective We aimed to reveal the association between body mass index (BMI) and medical costs in the current Japanese population, and to estimate the population attributable fraction (PAF) of medical costs due to overweight and obesity. Methods A generalized linear mixed model with log link function and gamma distribution was used to evaluate the association between BMI and medical costs in 34,537 beneficiaries of the National Health Insurance aged 40–69 years in Chiba City. Medical cost data were obtained from insurance claims submitted between April 2012 and March 2016. PAFs due to overweight (BMI ≥25.0 and Results Overweight and obesity were significant predictors of excessive medical costs in all age and sex groups. PAF due to overweight and obesity was estimated to be 9.62% (95% confidence interval, 8.52–10.73%). Additionally, PAFs in 40–59-year-old individuals (12.76% in men and 11.63% in women) were greater than those in 60–69-year-old subjects (6.55% in men and 7.80% in women) for both sexes. Conclusions In the Japanese population, overweight and obesity are an excessive financial burden with an estimated PAF of 9.62% of total medical costs.

Background Although adverse childhood experiences (ACEs) have been linked to negative health behaviors in adulthood, few studies have investigated if the impact continues until late adulthood. We examined the association between ACEs and fruit and vegetable intake (FVI) among older adults in Japan. Methods Data came from the Japan Gerontological Evaluation Study (JAGES), 2013 in which 24,271 individuals aged ≥65 years participated. The number of ACEs was calculated (0, 1 and ≥2) while low FVI was defined as consuming fruit and vegetables less than once a day. A sex-stratified multilevel Poisson regression analysis was used to investigate the association between ACEs and low FVI. Results Among men, 35.4% reported at least one ACE while the corresponding figure for women was 30.6%. Compared to those without ACEs, the prevalence ratios for low FVI among those who reported ≥2 ACEs were 1.51 (95% confidence interval [CI] = 1.30–1.75) for women and 1.28 (95% CI = 1.14–1.44) for men after adjusting for age and childhood economic hardship. Although these associations were attenuated after adjusting for socio-demographic and health-related variables, the link between ACEs and low FVI remained statistically significant among women. Of the seven individual forms of ACE, psychological neglect was significantly associated with low FVI (PR = 1.16, 95% CI = 1.03–1.31) among women in the final model. Conclusions ACEs are associated with low FVI among older Japanese adults. Our results suggest that the detrimental effect of ACEs on health behavior may stretch across the life course.

ORAI1 encodes a calcium channel essential in the store-operated calcium entry mechanism. A previous genetic association study identified a rare in-frame insertion variant of ORAI1 conferring Kawasaki disease (KD). To deepen our understanding of the involvement of rare variants of ORAI1 in KD pathogenesis, we investigated 3812 patients with KD and 2644 healthy individuals for variations in the protein-coding region of ORAI1. By re-sequencing the study participants’ DNA, 27 variants with minor allele frequencies (MAFs)

Summary Background Genetic studies have indicated possible involvement of the upregulated calcium-nuclear factor of activated T cells pathway in the pathogenesis of Kawasaki disease. We aimed to assess safety and efficacy of ciclosporin, an immunosuppressant targeting this pathway, for protection of patients with Kawasaki disease against coronary artery abnormalities. Methods We did a randomised, open-label, blinded endpoints trial involving 22 hospitals in Japan between May 29, 2014, and Dec 27, 2016. Eligible patients predicted to be at higher risk for intravenous immunoglobulin (IVIG) resistance were randomly assigned to IVIG plus ciclosporin (5 mg/kg per day for 5 days; study treatment) or IVIG (conventional treatment) groups, stratified by risk score, age, and sex. The primary endpoint was incidence of coronary artery abnormalities using Japanese criteria during the 12-week trial, assessed in participants who received at least one dose of study drug and who visited the study institution at least once during treatment. This trial is registered to Center for Clinical Trials, Japan Medical Association, number JMA-IIA00174. Findings We enrolled 175 participants. One patient withdrew consent after enrolment and was excluded and one patient (in the study treatment group) was excluded from analysis because of lost echocardiography data. Incidence of coronary artery abnormalities was lower in the study treatment group than in the conventional treatment group (12 [14%] of 86 patients vs 27 [31%] of 87 patients; risk ratio 0·46; 95% CI 0·25–0·86; p=0·010). No difference was found in the incidence of adverse events between the groups (9% vs 7%; p=0·78). Interpretation Combined primary therapy with IVIG and ciclosporin was safe and effective for favourable coronary artery outcomes in Kawasaki disease patients who were predicted to be unresponsive to IVIG. Funding Japan Agency for Medical Research and Development (grant CCT-B-2503).

OBJECTIVES To assess epidemiological and chronological trends of upper urinary tract stones in Japan in 2015. METHODS Patients with a first episode of upper urinary tract stones in 2015 were enrolled in this nationwide survey. The study included all hospitals approved by the Japanese Board of Urology, therefore covering most of the hospitals where urologists practice in Japan. The annual incidence and composition of urolithiasis were evaluated by age and sex. These results were compared with the previous results of the nationwide surveys from 1965 to 2005 to analyze temporal trends. RESULTS The estimated annual incidence of a first-episode upper urinary tract stone in 2015 was 137.9 (191.9 in men and 86.9 in women) per 100 000. The estimated age-standardized first-episode upper urinary tract stone incidence in 2015 was 107.8 (150.6 in men and 63.3 in women) per 100 000, which did not represent a significant increase since 2005. An equivalent incidence was observed in patients aged >50 years, whereas a reduced incidence was observed in patients aged

This study analyzes whether income inequality within a community at the neighborhood level is associated with incidence of mood disorder in Japan. A retrospective cohort study was performed using the data of 116,658 National Health Insurance beneficiaries aged between 20 and 69 in Chiba City, Japan. To evaluate income inequality within a community, the Gini coefficient within a 30-min walking distance from an individual’s residence was calculated using income distribution estimated by the National Census and the Housing and Land Survey 2013. Incidence of mood disorder was determined through insurance claims submitted from April 1, 2013, to March 31, 2016. A multilevel logistic analysis with three levels—the individual, household, and residential district—was performed to evaluate the association. Income inequality within a community at the neighborhood level was not associated with incidence of mood disorder in the models with and without equivalent household income (p for trend = 0.856 and 0.947, respectively). No difference was observed in the impact of the Gini coefficient among income levels, lower versus higher income groups (p for interaction between Gini coefficient and household income = 0.967). In contrast, lower equivalent income at the household level was significantly associated with higher incidence of mood disorder (p for trend

This study aimed to determine the incidence and risk factors for hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) undergoing immunosuppressive therapy. The National Database of Japan, in which insurance claim data have been comprehensively accumulated, was utilized. The subjects were 76 641 RA patients who were plausibly initiated on immunosuppressive therapy from April 2013 to March 2014. Laboratory tests of the hepatitis B surface antigen, anti-hepatitis B virus surface antibody, and anti-hepatitis B virus core antibody were performed in 28.23%, 12.52% and 14.63% of patients, respectively, when the therapy was initiated. We found that HBV reactivation and fulminant hepatitis occurred in both the patients with and without HBV DNA monitoring, indicating insufficient monitoring in Japan during the study. The cumulative incidence of HBV reactivation over 24 months was 1.57% (95% confidence interval [CI] = 1.28%-1.92%) in the monitoring group, which consisted of those with resolved HBV infection. Glucocorticoid administration was a potent risk factor for HBV reactivation (hazard ratio [HR] = 1.70, 95% CI = 1.26-2.29, P = .001 in all subjects, and HR = 1.82, 95% CI = 1.18-2.81, P = .007 in the nonmonitoring group), although it was not statistically significant in the monitoring group (HR = 1.49, 95% CI = 0.99-2.26 and P = .057). No significant risk difference was observed between single administration of methotrexate and biological drugs.

Background: The association between diabetes mellitus (DM) and low secretory immunoglobulin A (s-IgA)secretion rates is one mechanism suspected of influencing susceptibility to infections among DM patients. However,several studies have shown contradictory results. We examined these two factors to seek evidence of an associationamong older people.Methods: We analyzed a prospective cohort of 2306 subjects (1209 men and 1097 women) around 64 years oldfrom the New Integrated Suburban Seniority Investigation (NISSIN) Project in Nisshin, Japan. DM statuses wereascertained from levels of fasting plasma glucose and HbA 1c , and s-IgA secretion rates were obtained from 5-minsaliva samples. We used an analysis of covariance adjusted for possible confounders to compare s-IgA secretion ratesaccording to DM status.Results: s-IgA secretion rates in DM participants were lower than in those classified as normal (18.6µg/min vs15.0µg/min, P = 0.03), even after elimination of the effects of possible confounders.Conclusions: DM was associated with lower s-IgA secretion rates. This suggests that lower s-IgA levels may be amechanism of susceptibility to infection in individuals with DM.Key words: diabetes mellitus; secretory immunoglobulin A; saliva

Background: This study aimed to evaluate whether income-related inequalities in access to dental care services exist in Japan. Methods: The subjects included beneficiaries of the National Health Insurance (NHI) in Chiba City, Japan, who had been enrolled from 1 April 2014 to 31 March 2015. The presence or absence of dental visits and number of days spent on dental care services during the year were calculated using insurance claims submitted. Equivalent household income was calculated using individual income data from 1 January to 31 December 2013, declared for taxation. Results: Of the 216,211 enrolled subjects, 50.3% had dental care during the year. Among those with dental visits, the average number of days (standard deviation) spent on dental care services per year was 7.7 (7.1). Low income was associated with a decreased rate of dental care utilization regardless of age and sex. However, there was a significant inverse linear association between the number of days spent on dental care services and income levels for both sexes. Conclusions: There were income-related inequalities in access to dental care services, regardless of the age group or sex, within the Japanese universal health insurance system.

Fruit and vegetable intake (FVI) contributes to the prevention of non-communicable diseases. Although food preference is considered to be determined early in life, few studies have investigated the association between childhood socioeconomic status (SES) and FVI in older age. Because a school lunch program was initiated in Japan after World War II, we were able in this study to examine this association in an older Japanese population. We used data from a population of physically and cognitively independent adults aged 65years or older who were living independently in the community and were recruited from 27 municipalities in the Japan Gerontological Evaluation Study 2010 project (August 2010-January 2012). Three categories of childhood SES (low, middle, and high) and current FVI were evaluated via a self-reported questionnaire. Poisson regression was used to investigate the association between childhood SES and FVI in 19,920 individuals. After adjustment for age and sex, older people with low childhood SES were 1.36 times more likely (95% CI 1.23-1.52) to have poor FVI than those with high childhood SES. In the fully adjusted model, the significant association disappeared. Further age-stratified analysis revealed a positive association between childhood SES and FVI among people aged 70-76years who were partially exposed to the school lunch program, but not among people aged 65-69years old who were fully exposed to the program. In conclusion, social policy such as school lunches targeting children with low SES could help improve FVI in old age.

Although both geographic accessibility and socioeconomic status have been indicated as being important factors for the utilization of health care services, their combined effect has not been evaluated. The aim of this study was to reveal whether an income-dependent difference in the impact of geographic accessibility on the utilization of government-led annual health check-ups exists. Existing data collected and provided by Chiba City Hall were employed and analyzed as a retrospective cohort study. The subjects were 166,966 beneficiaries of National Health Insurance in Chiba City, Japan, aged 40 to 74 years. Of all subjects, 54,748 (32.8%) had an annual health check-up in fiscal year 2012. As an optimal index of geographic accessibility has not been established, five measures were calculated: travel time to the nearest health care facility, density of health care facilities (number facilities within a 30-min walking distance from the district of residence), and three indices based on the two-step floating catchment area method. Three-level logistic regression modeling with random intercepts for household and district of residence was performed. Of the five measures, density of health care facilities was the most compatible according to Akaike’s information criterion. Both low density and low income were associated with decreased utilization of the health check-ups. Furthermore, a linear relationship was observed between the density of facilities and utilization of the health check-ups in all income groups and its slope was significantly steeper among subjects with an equivalent income of 0.00 yen than among those with equivalent income of 1.01–2.00 million yen (p = 0.028) or 2.01 million yen or more (p = 0.040). This result indicated that subjects with lower incomes were more susceptible to the effects of geographic accessibility than were those with higher incomes. Thus, better geographic accessibility could increase the health check-up utilization and also decrease the income-related disparity of utilization.

Elevated risk of death from any cause and stroke associated with high body mass index (BMI) values decline with aging. However, it is not clear whether the effect of obesity on the incidence of hypertension varies by sex or age. Cox regression analyses were performed using a large historical cohort composed of 6803 men and 22,800 women. In the final model, which included the main effect (sex, age, and BMI), all two-way interactions (sex*age, sex*BMI, and age*BMI), a three-way interaction (sex*age*BMI), and adjusted variables determined by backward elimination, the three-way interaction and two of the two-way interactions (age*sex and age*BMI) were not significant; the remaining two-way interaction between sex and BMI was significant (P = .016). In the next step, the effect of BMI on the incidence of hypertension stratified by sex was evaluated. Hazard ratios (HRs) were significantly higher for BMI 27.0 to

SummaryBackground The thromboxane A2 receptor (TBXA2R) gene is associated with asthma, but no functional genetic variations are known to associate with the disease or its related phenotypes. Objective To investigate the association of TBXA2R polymorphisms with asthma susceptibility and related phenotypes and to identify functionally relevant polymorphisms. Methods We performed comprehensive sequencing of the TBXA2R gene in 48 Japanese control subjects and found a set of variants (SNP1 G>T rs2238634, SNP2 T>G rs2238633, SNP3 C>T rs2238632 and SNP4 G>A rs2238631) in intron 1 in linkage disequilibrium with c.795 T>C rs1131882, which was previously reported to be associated with asthma and related phenotypes. To investigate the effect of four common haplotypes (H1, H2, H3 and H4) on transcriptional activity, we performed a luciferase assay in primary bronchial smooth muscle cells (BSMCs) and human airway epithelial cells (BEAS-2B). We also studied the haplotype association with lung function, TBXA2R mRNA levels, and eosinophil fraction/count in peripheral blood in childhood-onset asthma patients and/or controls. Results H2 and H4, containing minor alleles of SNP2 and SNP3, had significantly higher transcriptional activities than H1 consisting of major alleles (P < 0.001 in BSMCs and BEAS-2B). Homozygotes for redefined haplotype h2 corresponding to minor alleles of SNP2 and SNP3 were associated with lower lung function in childhood-onset asthma patients compared to other zygotes (baseline Forced expiratory volume in one second (FEV1)/ Forced vital capacity (FVC) and Forced expiratory flow between 25% and 75% of the FVC (%FEF25–75%): P = 0.00201 and 0.0128, respectively, and post-bronchodilator FEV1/FVC and %FEF25–75%: P = 0.00224 and 0.0393 respectively). Haplotype h2 was also associated with higher mRNA levels in control peripheral blood cells and higher blood eosinophil fractions and counts in female controls. Conclusions and Clinical Relevance Genetic variants were identified in the TBXA2R gene that influenced transcriptional activity and were associated with asthma-related phenotypes. Thromboxane pathways may therefore play important roles in airway inflammation and remodelling in asthma patients.

雑誌掲載版, Objective: Early life events connected with the risk of later disease can occur not only in utero, but also in infancy. In study of the developmental origins of health and disease, the relationship between infantile growth patterns and adolescent body mass index and blood pressure is one of the most important issues to verify. Materials and Methods: We analyzed the correlation of current body mass index and systolic blood pressure of 168 female college students with their growth patterns in utero and in infancy. Results: Body mass index and systolic blood pressure in adolescence showed positive correlations with changes in weight-for-age z scores between 1 and 18 months but not with those between 18 and 36 months. Stepwise multiple regression analysis showed that both change in weight-for-age z scores from 1 to 18 months and body mass index at 1 month were significantly and independently associated with systolic blood pressure in adolescence. Body mass index at 36 months was positively correlated with body mass index in adolescence, while body mass index at birth was negatively correlated with body mass index in adolescence. Conclusion: Our findings shows that restricted growth in utero and accelerated weight gain in early infancy are associated with the cardiovascular risk factors of high systolic blood pressure and high body mass index in adolescence. In Japan, an increasing proportion of low birth weight infants and accelerated catch-up growth after birth have been observed in recent decades. This might be an alarming harbinger of an increase in diseases related to the developmental origins of health and disease in Japan.

Kawasaki disease (KD) is an acute systemic vasculitis occurring in medium-sized arteries, especially coronary arteries. Patients with KD who fail to respond to standard therapy with intravenous immunoglobulin (IVIG) face a higher risk of developing coronary artery lesions. Cyclosporin A (CsA) is one treatment option for IVIG-resistant KD. However, the mechanism of its suppression of inflammation in patients with KD remains unknown.We analyzed time-line profiles of multiple inflammatory cytokines in sera of 19 patients treated with CsA (4 mg/kg/day, p.o., 14 days) after additional IVIG. Trough concentration of CsA in blood was maintained between 60 and 200 ng/ml. We examined serum samples before, on day 7, and at the end (day 14) of CsA treatment. Assays were conducted using a Milliplex kit®. Fourteen patients responded to CsA and became afebrile within 5 days (Responders), although five patients were regarded as Non-responders. Serum transitional levels of IL-6 (p0.001), sIL-2R (p0.001), sTNFRII (p0.001), and G-CSF (p0.001) reflect disease severity. In Non-responders, average levels of IL-6 at day 7 (43.5 vs. 13.8 pg/ml, p0.001) and average levels of sIL-2R at day 14 (21.3 vs. 3.31 pg/ml, p=0.014) were significantly higher than those in Responders.CsA treatment effectively reduced the persisting serum inflammatory cytokines in most of the IVIG-resistant KD patients. Soluble IL-2R suppression implies a mechanism explaining the effects of CsA.

Genetic testing for breast cancer predisposing genes, BRCA1 and BRCA2, can take advantage for early identification of carriers with pathogenic germline mutations. However, conventional approaches based on Sanger sequencing are laborious and expensive. Next-generation sequencing technology has a great impact on investigation of medical genomics and now applied clinical genetics. We provide a protocol based on a pool and capture method followed by high-throughput sequencing, which realizes a rapid, high-quality, high-accuracy and low-cost testing for mutations in BRCA1 and BRCA2 by using small amounts of input DNA. Custom capture probes were designed for 195 kb regions encompassing the entire BRCA1 and BRCA2. DNA libraries of 96 samples with distinct indices were pooled before hybridizing to the capture probes, which largely reduced labor and cost. The captured library was run on the Illumina MiSeq sequencer. We applied the method to 384 Japanese individuals including 11 patients with breast cancer whose mutation statuses had been determined by standard clinical testing and 373 individuals from a general population. 99.99% of coding exons and their 20 bp flanking regions were covered with a minimum of 20 reads and the average depth was 179.5, supporting confident variant detection. The sequencing method rendered concordant results for 11 patients with breast cancer compared with the standard clinical testing including nine mutations in eight patients. Among 373 individuals from the general population, novel stop gain and frameshift deletion in BRCA2 were identified, which led to truncated protein and were most likely to be pathogenic. The result suggests the importance of a large-scale population-wide screening for carriers of mutations in these genes.