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Background: Radiation-induced bone sarcoma has been associated with high doses of ionizing radiation from therapeutic or occupation-related exposures. However, the development of bone sarcoma following exposure to lower doses of ionizing radiation remains speculative.Methods: A cohort analysis based on the Life Span Study (n = 120,321) was performed to assess the development of bone sarcoma in atomic-bomb survivors of Hiroshima and Nagasaki followed from 1958 to 2001. The excess relative risk per gray of ionizing radiation absorbed by the bone marrow was estimated. Additional subject demographic, survival, and clinical factors were evaluated.Results: Nineteen cases of bone sarcoma (in eleven males and eight females) were identified among the 80,181 subjects who met the inclusion criteria, corresponding to an incidence of 0.9 per 100,000 person-years. The mean ages at the time of the bombing and at diagnosis were 32.4 and 61.6 years, respectively. The mean bone marrow dose was 0.43 Gy. Osteosarcoma was the most commonly identified bone sarcoma. The most common bone sarcoma site was the pelvis. The overall unadjusted five-year survival rate was 25%. A dose threshold was found at 0.85 Gy (95% confidence interval, 0.12 to 1.85 Gy), with a linear dose-response association above this threshold. The linear slope equaled an excess relative risk of 7.5 per Gy (95% confidence interval, 1.34 to 23.14 per Gy) in excess of 0.85 Gy.Conclusions: On the basis of what we believe is one of the longest and largest prospective studies assessing the development of bone sarcoma in individuals exposed to ionizing radiation, it appears that the development of radiation-induced bone sarcoma may be associated with exposure to much lower doses of ionizing radiation than have previously been reported. Such new insights may potentially improve bone sarcoma prevention measures and broaden our understanding of the role of ionizing radiation from various sources on the development of malignant tumors. This study stresses the need to become increasingly aware of the various health risks that may be attributable to even low levels of ionizing radiation exposure.Level Of Evidence: Prognostic Level I. See Instructions to Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

The aim of this study was to investigate the late effect on cancer mortality risk of the radiation exposure of atomic bomb survivors who comprised a study population different from that previously studied by the Radiation Effects Research Foundation (RERF). We examined survivors residing in Hiroshima Prefecture, who were followed up between 1968 and 1989 by the Research Institute for Radiation Biology and Medicine (RIRBM) at Hiroshima University. We used the doseevaluation system known as Atomic Bomb Survivors 1993 Dose (ABS93D), which was based on the Dosimetry System 1986 for the survivors registered with RERF. The dose estimation was applied in a total of 35,123 subjects. Among survivors who had been alive for 20 years after the bombing, the relative mortality risk of leukaemia at 1 Gy of organ dose was 2.37 (90% confidence interval: 1.36-3.39), which was significantly higher than the zero dose control group. Similarly, significantly higher risks were observed for all cancers except leukaemia, including cancers of the lung, colon and female breast. Comparison is made with RERF results regarding temporal changes in the relative risk. Although we observed slightly lower relative risks than RERF values for the cancer of the stomach and lung, and for all cancer except leukaemia, no marked trends for any cancer were observed in this study. Though there were some differences in population between RERF and RIRBM, no marked discrepancies were observed. [ABSTRACT FROM AUTHOR]

In Japan, cohort studies on stroke have been mainly conducted in rural areas, with few studies comparing stroke mortality between urban and rural areas. We aimed to explore urban-rural difference in stroke mortality throughout Japan using a representative sample of the general Japanese population, the NIPPON DATA80. This study included 9309 subjects (4080 men and 5229 women) aged 30 years or older who were residents of 294 areas in 211 municipalities of Japan in 1980 and followed-up until 1999. Population size of the municipality in which the aforementioned areas were located was used to distinguish between urban and rural areas, because municipalities in Japan are classified as village, town or city principally by population size. We applied a multilevel logistic regression model to take into account the hierarchical data structure of individuals (subjects) (level 1) nested within areas (level 2), and then calculated odds ratios and 95% confidence intervals (CIs) of deaths from total stroke. Statistically significant variance between areas was not observed in men but was in women. Age-adjusted odds ratios of the areas in the medium (population30,000 and <300,000) and small municipalities (<30,000) compared with the areas in the large municipalities (300,000) were 1.31 and 1.40 in men, and 1.32 and 1.62 in women, respectively. Multivariate-adjusted odds ratios (adjusted for age, body mass index, total cholesterol, diabetes, hypertension, current smoking, and daily alcohol consumption) of the areas in the medium and small municipalities compared with the areas in the large municipalities were 1.29 and 1.36 in men, and 1.34 and 1.68 in women, respectively. In conclusion, stroke mortality tended to be higher in rural areas than in urban areas in Japan, especially among women. [ABSTRACT FROM AUTHOR]

Objective: To assess whether eldecalcitol, an active vitamin D analogue 2 , can reduce the development of type 2 diabetes among adults with impaired glucose tolerance., Design: Double blinded, multicentre, randomised, placebo controlled trial., Setting: Three hospitals in Japan, between June 2013 and August 2019., Participants: People aged 30 years and older who had impaired glucose tolerance defined by using a 75 g oral glucose tolerance test and glycated haemoglobin level., Interventions: Participants were randomised to receive active vitamin D (eldecalcitol 0.75 μg per day; n=630) or matching placebo (n=626) for three years., Main Outcomes: The primary endpoint was incidence of diabetes. Prespecified secondary endpoints were regression to normoglycaemia and incidence of type 2 diabetes after adjustment for confounding factors at baseline. In addition, bone densities and bone and glucose metabolism markers were assessed., Results: Of the 1256 participants, 571 (45.5%) were women and 742 (59.1%) had a family history of type 2 diabetes. The mean age of participants was 61.3 years. The mean serum 25-hydroxyvitamin D concentration at baseline was 20.9 ng/mL (52.2 nmol/L); 548 (43.6%) participants had concentrations below 20 ng/mL (50 nmol/L). During a median follow-up of 2.9 years, 79 (12.5%) of 630 participants in the eldecalcitol group and 89 (14.2%) of 626 in the placebo group developed type 2 diabetes (hazard ratio 0.87, 95% confidence interval 0.67 to 1.17; P=0.39). Regression to normoglycaemia was achieved in 145 (23.0%) of 630 participants in the eldecalcitol group and 126 (20.1%) of 626 in the placebo group (hazard ratio 1.15, 0.93 to 1.41; P=0.21). After adjustment for confounding factors by multivariable fractional polynomial Cox regression analysis, eldecalcitol significantly lowered the development of diabetes (hazard ratio 0.69, 0.51 to 0.95; P=0.020). In addition, eldecalcitol showed its beneficial effect among the participants with the lower level of basal insulin secretion (hazard ratio 0.41, 0.23 to 0.71; P=0.001). During follow-up, bone mineral densities of the lumbar spine and femoral neck and serum osteocalcin concentrations significantly increased with eldecalcitol compared with placebo (all P<0.001). No significant difference in serious adverse events was observed., Conclusions: Although treatment with eldecalcitol did not significantly reduce the incidence of diabetes among people with pre-diabetes, the results suggested the potential for a beneficial effect of eldecalcitol on people with insufficient insulin secretion., Trial Registration: UMIN Clinical Trials Registry UMIN000010758., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support by a grant from the Kitakyushu Medical Association; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© 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.)

Objectives: To describe recent trends in the prevalence of gout and asymptomatic hyperuricemia regarding urate-lowering treatment (ULT) in Japan. Methods: A database of health insurance claims managed by the Japan Medical Data Center was used to estimate the annual prevalence of gout and asymptomatic hyperuricemia during 2010-2014. ULT was evaluated for status of the two diseases during the same period. The significance of time trends was evaluated by Cochrane-Armitage trend test. Results: The prevalence of physician-diagnosed gout in men aged 20-64 years was 1.54% (95% CI: 1.49%-1.58%) in 2010, with a slight but significant ( p  < 0.001) annual increase, up to 1.66% (95% CI: 1.62%-1.71%) in 2014. In women, gout prevalence was somewhat constant about 0.09% during 2010-2014. Among male patients with gout, 78% received ULT. The prevalence of male patients with asymptomatic hyperuricemia in the same age range, who received ULT, increased significantly from 1.77% (95% CI: 1.72%-1.81%) to 2.14% (95% CI: 2.09%-2.19%) during 2010-2014 ( p  < 0.001). Conclusion: Gout prevalence in adult men in Japan has increased significantly in recent years. The prevalence of asymptomatic hyperuricemia under ULT has also increased significantly and was higher than that of gout.

We found some trivial errors which might confuse reader. The errors can be identified as the following two types. &#13; &#13; (1) The one is that misuse of "ERR" and "ERR/Sv". We denoted "Table 4 shows ERRs/Sv and 90% CIs ..." in line 7 of page 366. While we denoted "ERR and 90% CI for all cancers, excluding leukaemia, by dose category ..." in title of Table 4. The values described in Table 4 were ERR by dose category and not ERR/Sv. In addition, the explanation about the model that derived ERR by dose category is better to be added. Therefore, the description mentioned above should be changed as follows.&#13; (Misprinted) &#13; Table 4 shows ERRs/Sv and 90% CIs for all cancers excluding leukaemia by dose category.&#13; (Corrected)&#13; Table 4 shows ERRs which were defined as follow equation and 90% CIs for all cancers excluding leukaemia by dose category. &#13; &#13; λ=λ0 (a,c,y,r,s)exp(α1z1+α2z2+α3z3) (1+βi di)&#13; &#13; where di is the dose category, and βi is the ERR by dose category. The lowest dose category was set as reference.&#13; &#13; (2) The other were errors in surface caput of several tables. We described "ERR without adjustment for smoking" and "ERR with adjustment for smoking" in Table 4. These are correct description. However, "ERR with adjustment for smoking" was described as "For smoking" in Table 2. In addition, "Without adjustment" and "With adjustment" denoted in the surface caput of Table 5, 6, 7 should be denoted as "Without adjustment for smoking" and "With adjustment for smoking".&#13; The author wishes to apologies for the errors.&#13., (Creative Commons Attribution license.)

A causal relationship between protracted exposure to low-dose rate radiation and health effects remains unclear despite extensive international studies of nuclear workers. One potential reason is that radiation epidemiological studies that adjust for tobacco smoking, which heavily influences mortality, have been limited. In the present study, we examined radiation-related cancer risk by directly assessing the possible confounding effect of smoking, using data from two questionnaire surveys performed among Japanese nuclear workers in 1997 and 2003. Mortality follow-up was carried out for 71 733 male respondents for an average of 8.2 years during the observation period of 1999-2010. The mean cumulative dose was 25.5 mSv at the end of the follow-up period. Estimates of excess relative risk per Sv (ERRs/Sv) were obtained by Poisson regression. By adjusting for smoking directly on the basis of a linear dose-response model, we quantified the confounding effects of smoking on radiation risks. Statistically significant ERRs/Sv were found for all causes, all diseases, all non-cancer diseases, and liver cancer: 0.97 (90% confidence interval: 0.23, 1.78), 1.32 (0.40, 2.34), 1.87 (0.47, 3.49), and 4.78 (0.09, 11.68), respectively, without adjustment for smoking. However, the ERRs/Sv were no longer statistically significant after adjustment for smoking: 0.45 (-0.22, 1.19), 0.77 (-0.08, 1.72), 1.28 (-0.03, 2.79), and 3.89 (-0.46, 10.34), respectively. The ERRs/Sv for all cancers excluding leukaemia and lung cancer were not significant before adjustment for smoking, but declined after adjustment for smoking. The present study demonstrates that in this cohort of workers, smoking heavily distorts radiation risk estimates of mortality. The possibility of confounding by smoking depends on how strongly smoking is correlated with radiation exposure. If a correlation between smoking and radiation dose is suggested, smoking is an important confounder when assessing the radiation and health risks.

Mortality analyses have been performed using underlying causes of death as reported on death certificates; these are uniquely determined for a deceased person according to the World Health Organization coding system. Comorbidities, the disease conditions other than the underlying cause of death from death certificates recording multiple causes of death, have rarely been explored in Life Span Study subjects. The purpose of this study was to clarify associations between atomic bomb radiation exposure and mortality from combinations of the underlying cause of death and comorbidities. The focused follow-up period was 1977-2003, prior to which death certificate accuracy was unreliable. The study cohort was comprised of 10,017 people for whom the category "all circulatory disease" was listed as the underlying cause of death, of which heart disease (rheumatic, hypertensive and ischemic heart disease) and stroke were major subtypes. Comorbidities considered were pneumonia, renal disease, diabetes mellitus, cancer and the major circulatory disease subtypes listed above. Poisson regression models were used for analyses. Excess relative risks (ERRs) for mortality at 1 Gy were significantly increased when cancer was comorbid with all circulatory disease, heart disease, ischemic heart disease or stroke, ranging from 0.61 [95% confidence interval (CI): 0.13, 1.41; N = 177] for all circulatory diseases to 1.60 (CI: 0.07, 4.86; N = 42) for ischemic heart disease. Among the other comorbidities, only diabetes comorbid with heart disease had a significant radiation dose response (ERR at 1 Gy of 0.62, CI: 0.10, 1.46; N = 128). It remains uncertain if the high ERRs with comorbid cancers were anomalous due to the small number of cases or some dissimilarity in statistical methodologies, or if this might suggest some pathogenetic basis for increased fatality. For this reason, further investigation is required.

Introduction: Recent research suggests that vitamin D deficiency may cause both bone diseases and a range of non-skeletal diseases. However, most of these data come from observational studies, and clinical trial data on the effects of vitamin D supplementation on individuals with pre-diabetes are scarce and inconsistent. The aim of the Diabetes Prevention with active Vitamin D (DPVD) study is to assess the effect of eldecalcitol, active vitamin D analogue, on the incidence of type 2 diabetes among individuals with pre-diabetes., Methods and Analysis: DPVD is an ongoing, prospective, multicentre, randomised, double-blind and placebo-controlled outcome study in individuals with impaired glucose tolerance. Participants, men and women aged ≥30 years, will be randomised to receive eldecalcitol or placebo. They will also be given a brief (5-10 min long) talk about appropriate calorie intake from diet and exercise at each 12-week visit. The primary end point is the cumulative incidence of type 2 diabetes. Secondary endpoint is the number of participants who achieve normoglycaemia at 48, 96 and 144 weeks. Follow-up is estimated to span 144 weeks., Ethics and Dissemination: All protocols and an informed consent form comply with the Ethics Guideline for Clinical Research (Japan Ministry of Health, Labour and Welfare). The study protocol has been approved by the Institutional Review Board at Kokura Medical Association and University of Occupational and Environmental Health. The study will be implemented in line with the CONSORT statement., Trial Registration Number: UMIN000010758; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

The radiation risk of skin cancer by histological types has been evaluated in the atomic bomb survivors. We examined 80,158 of the 120,321 cohort members who had their radiation dose estimated by the latest dosimetry system (DS02). Potential skin tumors diagnosed from 1958 to 1996 were reviewed by a panel of pathologists, and radiation risk of the first primary skin cancer was analyzed by histological types using a Poisson regression model. A significant excess relative risk (ERR) of basal cell carcinoma (BCC) (n = 123) was estimated at 1 Gy (0.74, 95% confidence interval (CI): 0.26, 1.6) for those age 30 at exposure and age 70 at observation based on a linear-threshold model with a threshold dose of 0.63 Gy (95% CI: 0.32, 0.89) and a slope of 2.0 (95% CI: 0.69, 4.3). The estimated risks were 15, 5.7, 1.3 and 0.9 for age at exposure of 0-9, 10-19, 20-39, over 40 years, respectively, and the risk increased 11% with each one-year decrease in age at exposure. The ERR for squamous cell carcinoma (SCC) in situ (n = 64) using a linear model was estimated as 0.71 (95% CI: 0.063, 1.9). However, there were no significant dose responses for malignant melanoma (n = 10), SCC (n = 114), Paget disease (n = 10) or other skin cancers (n = 15). The significant linear radiation risk for BCC with a threshold at 0.63 Gy suggested that the basal cells of the epidermis had a threshold sensitivity to ionizing radiation, especially for young persons at the time of exposure.

An apparent association between radiation exposure and noncancer respiratory diseases (NCRD) in the Life Span Study (LSS) of atomic bomb survivors has been reported, but the biological validity of that observation is uncertain. This study investigated the possibility of radiation causation of noncancer respiratory diseases in detail by examining subtypes of noncancer respiratory diseases, temporal associations, and the potential for misdiagnosis and other confounding factors. A total of 5,515 NCRD diagnoses listed as the underlying cause of death on the death certificate were observed among the 86,611 LSS subjects with estimated weighted absorbed lung doses. Radiation dose-response analyses were conducted using Cox proportional hazard regression for pneumonia/influenza, other acute respiratory infections, chronic obstructive pulmonary disease and asthma. The linear excess relative risks (ERR) per gray (Gy) were 0.17 (95% CI 0.08, 0.27) for all NCRD and 0.20 (CI 0.09, 0.34) for pneumonia/influenza, which accounted for 63% of noncancer respiratory disease deaths. Adjustments for lifestyle and sociodemographic variations had almost no impact on the risk estimates. However, adjustments for indications of cancer and/or cardiovascular disease decreased the risk estimates, with ERR for total noncancer respiratory diseases declined by 35% from 0.17 to 0.11. Although it was impossible to fully adjust for the misdiagnosis of other diseases as noncancer respiratory diseases deaths in this study because of limitations of available data, nevertheless, the associations were reduced or eliminated by the adjustment that could be made. This helps demonstrates that the association between noncancer respiratory diseases and radiation exposure in previous reports could be in part be attributed to coincident cancer and/or cardiovascular diseases.

Background: Very high levels of ionizing radiation exposure have been associated with the development of soft-tissue sarcoma. The effects of lower levels of ionizing radiation on sarcoma development are unknown. This study addressed the role of low to moderately high levels of ionizing radiation exposure in the development of soft-tissue sarcoma., Methods: Based on the Life Span Study cohort of Japanese atomic-bomb survivors, 80,180 individuals were prospectively assessed for the development of primary soft-tissue sarcoma. Colon dose in gray (Gy), the excess relative risk, and the excess absolute rate per Gy absorbed ionizing radiation dose were assessed. Subject demographic, age-specific, and survival parameters were evaluated., Results: One hundred and four soft-tissue sarcomas were identified (mean colon dose = 0.18 Gy), associated with a 39% five-year survival rate. Mean ages at the time of the bombings and sarcoma diagnosis were 26.8 and 63.6 years, respectively. A linear dose-response model with an excess relative risk of 1.01 per Gy (95% confidence interval [CI]: 0.13 to 2.46; p = 0.019) and an excess absolute risk per Gy of 4.3 per 100,000 persons per year (95% CI: 1.1 to 8.9; p = 0.001) were noted in the development of soft-tissue sarcoma., Conclusions: This is one of the largest and longest studies (fifty-six years from the time of exposure to the time of follow-up) to assess ionizing radiation effects on the development of soft-tissue sarcoma. This is the first study to suggest that lower levels of ionizing radiation may be associated with the development of soft-tissue sarcoma, with exposure of 1 Gy doubling the risk of soft-tissue sarcoma development (linear dose-response). The five-year survival rate of patients with soft-tissue sarcoma in this population was much lower than that reported elsewhere.

Aim: To examine whether subclinical atherosclerosis of the carotid arteries is concordant with the categories in the 2012 atherosclerosis prevention guidelines proposed by the Japan Atherosclerosis Society (JAS guidelines 2012), which adopted the estimated 10-year absolute risk of coronary artery disease (CAD) death in the NIPPON DATA80 Risk Assessment Chart., Methods: Between 2006 and 2008, 868 Japanese men 40 to 74 years of age without a history of cardiovascular disease were randomly selected from Kusatsu City, Japan. The intima media thickness (IMT) and plaque number from the common to internal carotid arteries were investigated using ultrasonography. The absolute risk of CAD death was estimated based on the individual risk factor data, and the mean IMT and plaque number in Categories Ⅰ, Ⅱ and Ⅲ of the guidelines were examined., Results: The estimated 10-year absolute risk of CAD was directly related to the IMT (mean IMT (mean ± SD) (mm) for a 10-year absolute risk of ≥ 2.0% and ≥ 5.0%: 0.88 ± 0.18 and 0.95 ± 0.19, respectively) and the plaque number. These results are compatible with the categories described by the guidelines (mean IMT (mean ± SD) (mm) for Categories Ⅰ, Ⅱ, and Ⅲ: 0.70 ± 0.11, 0.81 ± 0.16 and 0.88 ± 0.18, respectively; mean plaque number: 0.9, 2.1 and 3, respectively). These findings were similar for Category Ⅲ participants with or without DM and CKD., Conclusions: Subclinical atherosclerosis of the carotid arteries is concordant with the 10-year absolute risk of CAD and the categories in the JAS guidelines 2012.

Background: Although clockwise rotation and counterclockwise rotation are distinct findings of the ECG, their prognostic significance is rarely studied., Methods and Results: We studied prognostic values of clockwise and counterclockwise rotation on total, cardiovascular disease (CVD), and subtype mortality using the National Integrated Project for Prospective Observation of Noncommunicable Disease and Its Trends in the Aged, 1980-2004 (NIPPON DATA80) database with a 24-year follow-up. At baseline in 1980, data were collected on study participants aged ≥30 years from randomly selected areas in Japan. We followed 9067 participants (44% men; mean age, 51 years). During the 24-year follow-up, mortality was as follows: 2581 total, 887 CVD, 179 coronary heart disease, 173 heart failure, and 411 stroke. The multivariate-adjusted hazard ratio (HR) with the use of the Cox model including biochemical and other ECG variables revealed that clockwise rotation was significantly positively associated with heart failure in men and women combined (HR=1.79; 95% confidence interval [CI], 1.13-2.83; P=0.013), CVD in men and in men and women combined (HR=1.49; 95% CI, 1.12-1.98; P=0.007 in men; HR=1.28; 95% CI, 1.02-1.59; P=0.030 in combined), and total mortality in men and in men and women combined (HR=1.19; 95% CI, 1.00-1.49; P=0.0496 in men; HR=1.15; 95% CI, 1.00-1.32; P=0.045 in combined). Counterclockwise rotation was significantly inversely associated stroke in men and women combined (HR=0.77; 95% CI, 0.62-0.96; P=0.017), CVD in men and in men and women combined (HR=0.74; 95% CI, 0.59-0.94; P=0.011 in men; HR=0.81; 95% CI, 0.70-0.94; P=0.006 in combined), and total mortality in women (HR=0.87; 95% CI, 0.77-0.98; P=0.023)., Conclusions: We found a significant positive association of clockwise rotation and a significant inverse association of counterclockwise rotation with CVD mortality in men and in men and women combined, independent of confounding factors including other ECG changes.

This is the 14th report in a series of periodic general reports on mortality in the Life Span Study (LSS) cohort of atomic bomb survivors followed by the Radiation Effects Research Foundation to investigate the late health effects of the radiation from the atomic bombs. During the period 1950-2003, 58% of the 86,611 LSS cohort members with DS02 dose estimates have died. The 6 years of additional follow-up since the previous report provide substantially more information at longer periods after radiation exposure (17% more cancer deaths), especially among those under age 10 at exposure (58% more deaths). Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, and effect modification by gender, age at exposure, and attained age. The risk of all causes of death was positively associated with radiation dose. Importantly, for solid cancers the additive radiation risk (i.e., excess cancer cases per 10(4) person-years per Gy) continues to increase throughout life with a linear dose-response relationship. The sex-averaged excess relative risk per Gy was 0.42 [95% confidence interval (CI): 0.32, 0.53] for all solid cancer at age 70 years after exposure at age 30 based on a linear model. The risk increased by about 29% per decade decrease in age at exposure (95% CI: 17%, 41%). The estimated lowest dose range with a significant ERR for all solid cancer was 0 to 0.20 Gy, and a formal dose-threshold analysis indicated no threshold; i.e., zero dose was the best estimate of the threshold. The risk of cancer mortality increased significantly for most major sites, including stomach, lung, liver, colon, breast, gallbladder, esophagus, bladder and ovary, whereas rectum, pancreas, uterus, prostate and kidney parenchyma did not have significantly increased risks. An increased risk of non-neoplastic diseases including the circulatory, respiratory and digestive systems was observed, but whether these are causal relationships requires further investigation. There was no evidence of a radiation effect for infectious or external causes of death.

Whole-body and thoracic ionizing radiation exposure are associated with increased cardiovascular disease (CVD) risk. In atomic bomb survivors, radiation dose is also associated with increased hypertension incidence, suggesting that radiation dose may be associated with chronic renal failure (CRF), thus explaining part of the mechanism for increased CVD. Multivariate Poisson regression was used to evaluate the association of radiation dose with various definitions of chronic kidney disease (CKD) mortality in the Life Span Study (LSS) of atomic bomb survivors. A secondary analysis was performed using a subsample for whom self-reported information on hypertension and diabetes, the two biggest risk factors for CRF, had been collected. We found a significant association between radiation dose and only our broadest definition of CRF among the full cohort. A quadratic dose excess relative risk model [ERR/Gy(2) = 0.091 (95% CI: 0.05, 0.198)] fit minimally better than a linear model. Within the subsample, association was also observed only with the broadest CRF definition [ERR/Gy(2) = 0.15 (95% CI: 0.02, 0.32)]. Adjustment for hypertension and diabetes improved model fit but did not substantially change the ERR/Gy(2) estimate, which was 0.17 (95% CI: 0.04, 0.35). We found a significant quadratic dose relationship between radiation dose and possible chronic renal disease mortality that is similar in shape to that observed between radiation and incidence of hypertension in this population. Our results suggest that renal dysfunction could be part of the mechanism causing increased CVD risk after whole-body irradiation, a hypothesis that deserves further study.

The purpose of this study was to determine the mortality risk among Japanese men and women with height loss starting in middle age, taking into account lifestyle and physical factors. A total of 2498 subjects (755 men and 1743 women) aged 47 to 91 years old underwent physical examinations during the period 1994 to 1995. Those individuals were followed for mortality status through 2003. Mortality risk was estimated using an age-stratified Cox proportional hazards model. In addition to sex, adjustment factors such as radiation dose, lifestyle, and physical factors measured at the baseline--including smoking status, alcohol intake, total cholesterol, blood pressure, and diagnosed diseases--were used for analysis of total mortality and mortality from each cause of death. There were a total of 302 all-cause deaths, 46 coronary heart disease and stroke deaths, 58 respiratory deaths including 45 pneumonia deaths, and 132 cancer deaths during the follow-up period. Participants were followed for 20,787 person-years after baseline. Prior history of vertebral deformity and hip fracture were not associated with mortality risk. However, more than 2 cm of height loss starting in middle age showed a significant association with all-cause mortality among the study participants (HR = 1.76, 95% CI 1.31 to 2.38, p = 0.0002), after adjustment was made for sex, attained age, atomic-bomb radiation exposure, and lifestyle and physical factors. Such height loss also was significantly associated with death due to coronary heart disease or stroke (HR = 3.35, 95% CI 1.63 to 6.86, p = 0.0010), as well as respiratory-disease death (HR = 2.52, 95% CI 1.25 to 5.22, p = 0.0130), but not cancer death. Continuous HL also was associated with all-cause mortality and CHD- or stroke-caused mortality. Association between height loss and mortality was still significant, even after excluding persons with vertebral deformity. Height loss of more than 2 cm starting in middle age was an independent risk factor for cardiovascular and respiratory-disease mortality among the elderly, even after adjusting for potential risk factors., (Copyright © 2012 American Society for Bone and Mineral Research.)

This study aims to deepen the understanding of lymphocyte phenotypes related to the course of hepatitis C virus (HCV) infection and progression of liver fibrosis in a cohort of atomic bomb survivors. The study subjects comprise 3 groups: 162 HCV persistently infected, 145 spontaneously cleared, and 3,511 uninfected individuals. We observed increased percentages of peripheral blood T(H)1 and total CD8 T cells and decreased percentages of natural killer (NK) cells in the HCV persistence group compared with the other 2 groups after adjustment for age, gender, and radiation exposure dose. Subsequently, we determined that increased T(H)1 cell percentages in the HCV persistence group were significantly associated with an accelerated time-course reduction in platelet counts-accelerated progression of liver fibrosis-whereas T(C)1 and NK cell percentages were inversely associated with progression. This study suggests that T(H)1 immunity is enhanced by persistent HCV infection and that percentages of peripheral T(H)1, T(C)1, and NK cells may help predict progression of liver fibrosis., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. All rights reserved.)

In this paper we summarize the long-term effects of A-bomb radiation on the T-cell system and discuss the possible involvement of attenuated T-cell immunity in the disease development observed in A-bomb survivors. Our previous observations on such effects include impaired mitogen-dependent proliferation and IL-2 production, decreases in naive T-cell populations, and increased proportions of anergic and functionally weak memory CD4 T-cell subsets. In addition, we recently found a radiation dose-dependent increase in the percentages of CD25(+)/CD127(-) regulatory T cells in the CD4 T-cell population of the survivors. All these effects of radiation on T-cell immunity resemble effects of aging on the immune system, suggesting that ionizing radiation might direct the T-cell system toward a compromised phenotype and thereby might contribute to an enhanced immunosenescence. Furthermore, there are inverse, significant associations between plasma levels of inflammatory cytokines and the relative number of naïve CD4 T cells, also suggesting that the elevated levels of inflammatory markers found in A-bomb survivors can be ascribed in part to T-cell immunosenescence. We suggest that radiation-induced T-cell immunosenescence may result in activation of inflammatory responses and may be partly involved in the development of aging-associated and inflammation-related diseases frequently observed in A-bomb survivors.

Radiation exposure is related to risk of numerous types of cancer, but relatively little is known about its effect on risk of multiple primary cancers. Using follow-up data through 2002 from 77,752 Japanese atomic bomb survivors, we identified 14,048 participants diagnosed with a first primary cancer, of whom 1,088 were diagnosed with a second primary cancer. Relationships between radiation exposure and risks of first and second primary cancers were quantified using Poisson regression. There was a similar linear dose-response relationship between radiation exposure and risks of both first and second primary solid tumors [excess relative risk (ERR)/Gy = 0.65; 95% confidence interval (CI), 0.57-0.74 and ERR/Gy = 0.56; 95% CI, 0.33-0.80, respectively] and risk of both first and second primary leukemias (ERR/Gy = 2.65; 95% CI, 1.78-3.78 and ERR/Gy = 3.65; 95% CI, 0.96-10.70, respectively). Background incidence rates were higher for second solid cancers, compared with first solid cancers, until about age 70 years for men and 80 years for women (P < 0.0001), but radiation-related ERRs did not differ between first and second primary solid cancers (P = 0.70). Radiation dose was most strongly related to risk of solid tumors that are radiation-sensitive including second primary lung, colon, female breast, thyroid, and bladder cancers. Radiation exposure confers equally high relative risks of second primary cancers as first primary cancers. Radiation is a potent carcinogen and those with substantial exposures who are diagnosed with a first primary cancer should be carefully screened for second primary cancers, particularly for cancers that are radiation-sensitive., (©2010 AACR.)

While radiation increases the risk of lung cancer among members of the Life Span Study (LSS) cohort of atomic bomb survivors, there are still important questions about the nature of its interaction with smoking, the predominant cause of lung cancer. Among 105,404 LSS subjects, 1,803 primary lung cancer incident cases were identified for the period 1958-1999. Individual smoking history information and the latest radiation dose estimates were used to investigate the joint effects of radiation and smoking on lung cancer rates using Poisson grouped survival regression methods. Relative to never-smokers, lung cancer risks increased with the amount and duration of smoking and decreased with time since quitting smoking at any level of radiation exposure. Models assuming generalized interactions of smoking and radiation fit markedly better than simple additive or multiplicative interaction models. The joint effect appeared to be super-multiplicative for light/moderate smokers, with a rapid increase in excess risk with smoking intensity up to about 10 cigarettes per day, but additive or sub-additive for heavy smokers smoking a pack or more per day, with little indication of any radiation-associated excess risk. The gender-averaged excess relative risk per Gy of lung cancer (at age 70 after radiation exposure at 30) was estimated as 0.59 (95% confidence interval: 0.31-1.00) for nonsmokers with a female : male ratio of 3.1. About one-third of the lung cancer cases in this cohort were estimated to be attributable to smoking while about 7% were associated with radiation. The joint effect of smoking and radiation on lung cancer in the LSS is dependent on smoking intensity and is best described by the generalized interaction model rather than a simple additive or multiplicative model.

Background: The length of the interval between age at menarche and age at first birth is positively associated with breast cancer risk. We examined the risk of breast cancer in atomic bomb survivors to investigate whether women exposed to radiation between menarche and first birth had a higher risk of radiogenic breast cancer than women exposed at the same age but outside this interval., Methods: Women (n = 30,113) were classified into three reproductive status at the time of the bombings (ATB) categories (premenarche, between menarche and first birth, or after first birth). Poisson regression was used to test the primary hypothesis., Results: When the background rate of breast cancer was taken to depend on city, age ATB, and attained age only, the radiation-related excess relative risk (ERR) varied significantly among the three categories (P = 0.049). However, after controlling for significant heterogeneity in the baseline risk of breast cancer between reproductive status ATB groups (P < 0.001), no significant heterogeneity (P = 0.88) was observed in the ERR, with an ERR per Gy of 1.36 [95% confidence interval (CI), 0.54-2.75] for women exposed between menarche and first birth ATB, and 1.07 (95% CI, 0.22-3.62) and 1.53 (95% CI, 0.63-2.90) for those exposed premenarche or after first birth, respectively., Conclusions: The radiation-associated risk of breast cancer does not vary significantly by reproductive status ATB., Impact: It is possible that radiation exerts similar carcinogenic effects on the breast regardless of its stage of differentiation, or that the differences in radiosensitivity are too small to be detected in this cohort.

In two previous nation-wide surveys in the late 1980s and early 1990s, Japanese indoor radon concentrations increased in homes built after the mid 1970s. In order to ascertain whether this trend continued, a nation-wide survey was conducted from 2007 to 2010. In total 3,900 houses were allocated to 47 prefectures by the Neyman allocation method and 3,461 radon measurements were performed (88.7% success). The fraction of reinforced concrete / concrete block buildings was 32.4%, similar to the value from national statistics. Arithmetic mean (standard deviation, SD) and geometric mean (geometric SD) of radon concentration after adjusting for seasonal fluctuation were 14.3 (14.7) and 10.8 (2.1) Bq/m(3). The corresponding population-weighted values were 13.7 (12.3) and 10.4 (2.0) Bq/m(3), respectively. It was estimated that only 0.1% of dwellings exceed 100 Bq/m(3), a new WHO reference level for indoor radon. Radon concentrations were highest in houses constructed in the mid 1980s and decreased thereafter. In conclusion, arithmetic mean indoor radon in the present survey was slightly lower than in previous surveys and significant reductions in indoor radon concentrations in both wooden and concrete houses can be attributed to alterations in Japanese housing styles in recent decades.

Purpose: Our previous study showed that radiation exposure reduced the diversity of repertoires of memory thymus-derived cells (T cells) with cluster of differentiation (CD)- 4 among atomic-bomb (A-bomb) survivors. To evaluate the maintenance of T-cell memory within A-bomb survivors 60 years after radiation exposure, we examined functionally distinct memory CD4 T-cell subsets in the peripheral blood lymphocytes of the survivors., Methods: Three functionally different subsets of memory CD4 T cells were identified by differential CD43 expression levels and measured using flow cytometry. These subsets consist of functionally mature memory cells, cells weakly responsive to antigenic stimulation, and those cells functionally anergic and prone to spontaneous apoptosis., Results: The percentages of these subsets within the peripheral blood CD4 T-cell pool all significantly increased with age. Percentages of functionally weak and anergic subsets were also found to increase with radiation dose, fitting to a log linear model. Within the memory CD4 T-cell pool, however, there was an inverse association between radiation dose and the percentage of functionally mature memory cells., Conclusion: These results suggest that the steady state of T cell memory, which is regulated by cell activation and/or cell survival processes in subsets, may have been perturbed by prior radiation exposure among A-bomb survivors.

There have been few studies on cancer incidence and survival among children in Japan. Childhood cancer cases in Hiroshima City can be ascertained almost perfectly in terms of completeness and validity as both a population-based cancer registry and a tissue registry cover the whole area. We report here recent incidence and survival of childhood cancer in Hiroshima City. Subjects were cancer patients less than 15 years of age in Hiroshima City registered in the Hiroshima City Cancer Registry and/or the Hiroshima Prefecture Tumor Registry (tissue registry) between 1998 and 2000. Cancer incidence in Hiroshima City was calculated for 12 diagnostic groups according to the International Classification of Childhood Cancer, and compared with general incidence in Japan. Five-year survival was calculated by the Kaplan-Meier method. There were 63 children who had a cancer newly diagnosed during 1998-2000, with only one death-certificate-only case (1.6%). Age-standardized incidence rates (per million) were 144.3 for boys and 93.9 for girls. Leukemia was the most frequent (29%) among the 12 diagnostic groups. There were 13 cancer deaths during this period and five-year survival was 79% (95% Confidence Interval: 67%-87%). Childhood cancer incidence was slightly higher than that for all of Japan, but the relative distribution of patients by diagnostic group was compatible with the general pattern. Both of these observations might be due to the high quality of the tumor and tissue registries.

This paper provides the first comprehensive report on mortality by type of leukemia among the Japanese atomic bomb survivors in the Life Span Study (LSS). Analyses include 310 deaths due to leukemia during the period 1950-2000 among 86,611 people in the LSS. Poisson regression methods were used to evaluate associations between estimated bone marrow dose and leukemia mortality. Attention was given to variation in the radiation dose-leukemia mortality association by time since exposure, age at exposure, city and sex. The excess relative rate per gray of acute myeloid leukemia was best described by a quadratic dose-response function that peaked approximately 10 years after exposure. Acute lymphatic leukemia and chronic myeloid leukemia mortality were best described by a linear dose-response function that did not vary with time since exposure. Adult T-cell leukemia was not associated with estimated bone marrow dose. Overall, 103 of the 310 observed leukemia deaths were estimated to be excess deaths due to radiation exposure. In the most recent decade of observation (1991-2000), the estimated attributable fraction of leukemia deaths among those survivors exposed to >0.005 Gy was 0.34, suggesting that the effect of the atomic bombings on leukemia mortality has persisted in this cohort for more than five decades.

Background: Although dementia has a great impact on public health, there are few reports on dementia incidence and risk factors for Asian populations., Objectives: To determine incidence and risk factors of dementia, Alzheimer disease (AD), and vascular dementia (VaD) among Japanese women., Methods: Between 1992 and 1996, 1637 non-demented women aged > or =60 years were followed for an average of 5.9 years in RERF's Adult Health Study. Dementia diagnoses were made during biennial health examinations using a two-phase procedure. DSM IV criteria were used for diagnosing dementia, NINCDS-ADRDA for AD, and NINDS-AIREN for VaD. Potential risk factors were analyzed using Poisson regression analysis., Results: 161 cases of dementia (109 of AD and 56 of VaD, based on individual criteria) were newly diagnosed. Incidence increased dramatically with age, especially for AD. Probable AD decreased with increasing education level. Probable VaD was significantly associated with hypertension and stroke. Age at menopause did not show any effect on dementia. All dementia and probable AD were significantly associated with grip strength., Conclusions: AD is predominant in dementia incidence among Japanese women. Modification of stroke risk factors and improvement of physical fitness may help prevent dementia.

Radiotherapy has been reported to cause neuropsychological dysfunction. Here we examined whether exposure to atomic bomb radiation affected the incidence of dementia among 2286 atomic bomb survivors and controls - all members of the Adult Health Study cohort. Study subjects were non-demented and aged >or=60 years at baseline examination and had been exposed in 1945 at >or=13 years of age to a relatively low dose (or=500 mGy group. Alzheimer disease was the predominant type of dementia in each dose category. After adjustment for potential risk factors, radiation exposure did not affect the incidence rate of either all dementia or any of its subtypes. No case of dementia had a history of therapeutic cranial irradiation. Although we found no relationship between radiation exposure and the development of dementia among atomic bomb survivors exposed at >or=13 years old in this longitudinal study, effects on increased risk of early death among atomic bomb survivors will be considered.