With the increasing use of radiation in medical and other settings, the potential effects of low-dose radiation on coronary heart disease including myocardial infarction (MI) are of great public health concern. The impact of low-dose radiation on myocardial infarction incidence remains controversial. The purpose of this study was to examine whether atomic bomb radiation exposure (dose < 4 Gy) is associated with the incidence of myocardial infarction. This prospective cohort study included 11,838 Japanese atomic bomb survivors with individually estimated radiation doses from the Adult Health Study cohort who had no history of myocardial infarction or radiotherapy at the first visit. Participants were followed until the earliest of first occurrence of an myocardial infarction, death, or the end of 2015 (57 years maximum). The incidence of myocardial infarctions (non-fatal and fatal), categorized by graded diagnostic accuracy, and the dose-response relationship of atomic bomb radiation were analyzed using Cox proportional hazards models. A total of 515 incident myocardial infarctions were documented, consisting of 188 definite, 30 probable, and 15 possible non-fatal myocardial infarctions, along with 282 fatal myocardial infarctions. For definite and probable non-fatal myocardial infarctions with high diagnostic accuracy, no significant association with radiation was found for both sexes combined [hazard ratio (HR) at 1 Gy = 1.17; 95% confidence interval (CI): 0.91-1.51], but sex-stratified analyses indicated a higher HR for females than for males [at 1 Gy, HRfemale = 1.42 (95% CI:1.02-1.98), HRmale = 1.02, 95% CI: 0.74-1.41], although the difference was not statistically significant (P = 0.13). No statistically significant modification of radiation effect was identified by city, age at exposure, attained age, time since exposure, smoking, or alcohol use. For all myocardial infarctions, including possible non-fatal myocardial infarction and fatal myocardial infarction with low diagnostic accuracy, the HRs at 1 Gy were 1.04 (95% CI: 0.86-1.25) for both sexes combined, 1.14 (95% CI: 0.88-1.47) for females, and 0.96 (95% CI: 0.75-1.22) for males. Findings from this long-term cohort study of atomic bomb survivors suggest an association between exposure to atomic bomb radiation and the incidence of myocardial infarction in females, but not in males. Further studies are necessary to clarify the reasons underlying the sex difference in dose-response relationship for myocardial infarction.

Supplementary Table 1: Study population and exclusion criteria by cohorts as established by the ACC reproductive factor working group

Supplementary Table 3: Pooled relative risks for recategorized age at menarche and age at menopause & incident thyroid cancer risk, Overall and papillary type

Supplementary Table 2: Distribution of total cases according to histology according to participating cohorts

Supplementary Figure 3: Forest plots of the pooled hazard ratios (HRs) and 95% confidence intervals (CIs) generated by combining cohort-specific HRs for the association between reproductive factors and the overall risk of thyroid cancer in the Asia Cohort Consortium. A - Forest plot for the pooled HRs and CIs for breastfeeding status and thyroid cancer risk, overall B - Forest plot for the pooled HRs and CIs for postmenopausal status and thyroid cancer risk, overall C - Forest plot for the pooled HRs and CIs for age at menopause and thyroid cancer risk, overall

BACKGROUND:Tobacco smoking and alcohol drinking are major risk factors for head and neck cancer (HNC), but their interaction effects have not been investigated in the Japanese population. METHODS:We conducted a pooled analysis using data from 11 prospective cohorts in Japan, covering a total of 434 431 participants with 5 969 082 person-years of follow-up. Cox proportional hazards model analyses were performed separately in each cohort. Interactions and population-attributable fractions (PAFs) were estimated through meta-analyses. RESULTS:During follow-up, 1835 incidents of HNC were newly identified. Both smoking and drinking habits significantly increased HNC risk. Subsite analysis showed that smoking increased risk in several subsites, while drinking was associated with hypopharyngeal cancer only. The multiplicative interaction was 1.55 [95% confidence interval (CI): 1.12-2.14] and the additive interaction (relative excess risk due to interaction) was 0.87 (95% CI: 0.42-1.36). Among men, PAFs were 0.414 for smoking and 0.336 for drinking, while the combined PAF was 0.469. Subsite-specific analysis showed larger PAFs of smoking in the nasopharynx and larynx, and larger PAFs of drinking in the oral cavity and hypopharynx. CONCLUSION:Tobacco smoking and alcohol drinking interact to increase the risk of HNC in the Japanese population. The attributable fraction of each factor differs by subsite. These findings may aid the development of future preventive strategies for HNC.

Supplementary Methods 1: Details on the development of the Asia Cohort Consortium reproductive factor working group protocol

Supplementary Figure 4: Forest plots of the pooled hazard ratios (HRs) and 95% confidence intervals (CIs) generated by combining cohort-specific HRs for the association between reproductive factors and the overall risk of thyroid cancer in the Asia Cohort Consortium. A - Forest plot for the pooled HRs and CIs for oral contraceptive use and thyroid cancer risk, overall B - Forest plot for the pooled HRs and CIs for hormone replace therapy use and thyroid cancer risk, overall

Supplementary Figure 5: Forest plot of stratified analysis between number of children/deliveries and thyroid cancer risk by birth years in the Asia Cohort Consortium. The Pooled Hazard Ratios (HRs) with 95% Confidence intervals (CIs) were generated by combining cohort-specific HRs. Models were adjusted for smoking status, alcohol drinking status and Body mass index. a Significant (p-value <0.05) trend across categories of the reproductive factor. b Significant (p-value <0.05) for interaction indicating a modifying effect on the association between the reproductive factor and thyroid cancer risk.

Supplementary Figure 6: Forest plot of pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between reproductive factors and thyroid cancer risk, by age of diagnosis in the Asia Cohort Consortium. The Pooled Hazard Ratios (HRs) with 95% Confidence intervals (CIs) were generated by combining cohort-specific HRs. Models were adjusted for smoking status, alcohol drinking status and Body mass index. a Significant (p-value <0.05). b The model included all 9 cohorts. c The model for Breastfeeding included 6 cohorts, that for Oral contraceptive use included 5 cohorts and that for hormone replacement therapy included 6 cohorts.

Supplementary Figure 1: Forest plots of the pooled hazard ratios (HRs) and 95% confidence intervals (CIs) generated by combining cohort-specific HRs for the association between reproductive factors and the overall risk of thyroid cancer in the Asia Cohort Consortium. A - Forest plot for the pooled HRs and CIs for age at menarche and thyroid cancer risk, overall B - Forest plot for the pooled HRs and CIs for age at first delivery and thyroid cancer risk, overall

Supplementary Figure 2: Forest plots of the pooled hazard ratios (HRs) and 95% confidence intervals (CIs) generated by combining cohort-specific HRs for the association between reproductive factors and the overall risk of thyroid cancer in the Asia Cohort Consortium. A - Forest plot for the pooled HRs and CIs for parity status and thyroid cancer risk, overall B - Forest plot for the pooled HRs and CIs for number of children/deliveries and thyroid cancer risk, overall C - Forest plot for the pooled HRs and CIs for recategorized number of children/deliveries and thyroid cancer risk, overall

Supplementary Figure 7: Forest plot of stratified analyses between reproductive factors and thyroid cancer risk by body mass index (BMI) and smoking status in the Asia Cohort Consortium. The Pooled Hazard Ratios (HRs) with 95% Confidence intervals (CIs) were generated by combining cohort-specific HRs. Models for stratified analyses by smoking status were adjusted for alcohol drinking status and BMI and those for BMI were adjusted for smoking status and alcohol drinking status. a Significant (p-value <0.05). b Significant (p-value <0.05) for interaction indicating a modifying effect on the association between the reproductive factor and thyroid cancer risk. c The model included all 9 cohorts. d The model for Breastfeeding included 6 cohorts, that for Oral contraceptive use included 5 cohorts, and that for hormone replacement therapy included 6 cohorts

Supplementary Table 4: Stratified analyses of the Association between reproductive factors and the risk of thyroid cancer by country and birth years

This paper concludes the third comprehensive report on radiation effects on solid cancer incidence within the Life Span Study (LSS) cohort of Japanese atomic bomb survivors, adding 11 years of follow-up. Over 1958-2009, 22 538 solid cancer cases and 3.1 million person-years were identified among 105 444 individuals. The study utilized improved radiation doses (DS02R1), updated migration probabilities, and adjustments for smoking and lifestyle factors. Poisson regression was used to model excess relative risk (ERR) and excess absolute rate (EAR) per 1 Gy for all-solid cancers combined and specific sites. Among females, a linear dose-response model best described all-solid cancer risk [ERR = 0.64 Gy-1, 95% confidence interval (CI): 0.52-0.77], whereas among males, a linear-quadratic model with upward curvature provided the best fit (ERR = 0.20 at 1 Gy, 95% CI: 0.12-0.28). Radiation-associated ERR declined with attained age, more rapidly in males than in females, while EAR increased with age. Independently, radiation-associated ERR and EAR decreased with age at exposure. A significant dose-response was identified for prostate cancer for the first time; for brain and central nervous system tumors, female pancreatic, and uterine corpus cancers dose-response reached statistical significance. A new age-at-exposure pattern emerged for female breast and uterine corpus cancers, suggesting that radiation-associated risk increased as exposure age approached menarche (∼age 15), decreasing at older exposure ages. Most cancers exhibited linear dose-response, except non-melanoma skin, bone and joint, esophageal, and kidney parenchyma cancers in males. Sixty-four years post-exposure, solid cancer risks remain elevated, reinforcing the LSS's critical role in unraveling lifetime cancer effects of a-bomb radiation after exposure at various ages.

This year marks the 80th anniversary of the atomic bombings of Hiroshima and Nagasaki. Over the past eight decades, large-scale cohort studies of atomic bomb survivors and their offspring conducted by the Radiation Effects Research Foundation and its predecessor, the Atomic Bomb Casualty Commission, have provided critical insights into the long-term health effects of radiation exposure. Key findings include early identification of radiation-associated leukemia, as well as excess risks of all solid cancers combined, and most individual cancer sites. Observed radiation dose-response relationships have generally followed a linear-quadratic model for leukemia and a linear model for all solid cancers. Recent findings indicating possible upward curvature in the dose-response for all solid cancers may reflect underlying heterogeneity in factors related to individual cancer sites and should be explored further. Generally, younger age at exposure, lower attained age, and female sex appear to show greater radiation sensitivity for all solid cancers combined but results differ by individual cancer site. Recent studies have also identified potential radiation-related excesses for non-cancer diseases such as cataracts, various circulatory diseases, and others. Studies of heritable effects on the offspring of exposed atomic bomb survivors, in contrast, have shown no elevated risk to date in offspring from parental radiation exposure, either at the molecular or disease level. With the cooperation of the atomic bomb survivors and their families, Radiation Effects Research Foundation's research will continue to play a crucial role in informing the health of survivors, their families, and global radiation protection in the decades to come.

This is a brief review of studies conducted at the Atomic Bomb Casualty Commission and Radiation Effects Research Foundation regarding the possible transgenerational effects of atomic bomb radiation. These include clinical, epidemiological, and biological studies on birth defect, sex ratio, chromosome aberration, molecular changes, disease prevalence and incidence, and whole genome analysis. Also, future plans are addressed.

Human T-cell leukemia virus type 1 (HTLV-1) has been identified as a cause of adult T-cell leukemia-lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Despite several HTLV-1 endemic areas being identified, comprehensive investigations have yet to be conducted in all the regions of the world. This review aims to summarize the current reports on HTLV-1. As vertical transmission is known to be a risk factor for ATL development, prevention strategies have been initiated in Japan, and these efforts may be related to the decrease in the estimated number of HTLV-1 carriers in Japan. In numerous HTLV-1 endemic regions, the prevalence of HTLV-1 increases with age, which may be attributed to horizontal infection. However, the incidence of HTLV-1 infection appears to be high among adolescents and young adults in Japan, especially in non-endemic areas. The clinical significance of HTLV-1 infections, other than ATL and HAM/TSP, has recently been documented. Consequently, it is imperative to develop treatment strategies for HTLV-1 infections, including measures to prevent horizontal infections.

BACKGROUND:Menarche timing may affect female health. While previous studies evaluated self-reported age at menarche reproducibility, they did not assess types of respondents. This study compared the reproducibility of age at menarche among self-responders and proxy respondents and assessed proxy-respondent reproducibility by relationship and survey age. METHODS:Data on age at menarche reported in both the 1969 and 1978 mail questionnaires among 9,043 females from the Life Span Study cohort of atomic bomb survivors were analyzed. The reproducibility of menarcheal age was assessed by the type of respondents, by proxy's relationship to participant, and by age at the 1969 survey using Bland-Altman's method and the intraclass correlation coefficient (ICC). RESULTS:Reproducibility was moderate (95% limits of agreement, -2.3 to 2.4 years; ICC 0.72; 95% confidence interval, 0.71-0.73). Both self-respondents (N = 6,664) and the total study population (N = 9,043) maintained moderate reproducibility even at older ages. Groups with proxy reports showed lower reproducibility than self-respondents, with spouse proxy reports showing highest reproducibility and parent proxy reports showing lowest reproducibility among proxy reports, although the comparisons are based on different survey ages in 1969. CONCLUSION:This is the first study to evaluate menarcheal-age reproducibility between self- and proxy-reports using appropriate measures. Mail questionnaires at 9-year interval showed moderate reproducibility across all ages, including elderly self-respondents. Reproducibility varied by the respondent-target relationship, with spouse proxies showing highest and parent proxies showing lowest reproducibility among proxy reports. Additional data are required to establish appropriate methods for handling specific proxy responses.

Background There are scarce data on risk factors for epithelial ovarian cancer (EOC) in Asian populations. Our goal was to advance knowledge on reproductive -related risk factors for EOC in a large population of Asian women. Methods This study used pooled individual data from baseline questionnaires in 11 prospective cohorts (baseline years, 1958-2015) in the Asia Cohort Consortium. A Cox proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) adjusting for age, parity and cohort. Results After a mean = 17.0 years (SD = 6.3) of follow-up, 674 incident invasive EOC cases were identified among 325,626 women. In multivariable adjusted models we observed an inverse association with parity (5+ children vs. 0, HR = 0.44, 95% CI = 0.28-0.68, Ptrend < 0.001), and a positive association with increasing menopausal age (55+ years vs. <45, HR = 1.77, 95% CI = 1.05-3.01, Ptrend = 0.02) for risk of all EOC. Conclusions In this large study of Asian women we identified an inverse association with parity and a positive association with higher menopausal age in relation to EOC risk. Further work is needed to understand EOC risk factors for rare histologic subtypes that occur more frequently in Asian populations.