The Association of Radiation Exposure with Stable Chromosome Aberrations in Atomic Bomb Survivors Based on DS02R1 Dosimetry and FISH Methods.

The frequency of stable chromosome aberrations (sCA) in lymphocytes is a recognized radiation biological dosimeter. Its analysis can provide insights into factors that affect individual susceptibility as well as into the adequacy of radiation dose estimates used in studies of atomic bomb survivors. We analyzed the relationship between atomic bomb radiation exposure using the most recent DS02R1 dose estimates and the frequency of sCA as determined by FISH in 1,868 atomic bomb survivors. We investigated factors that may affect the background sCA rate and the shape and magnitude of the dose response. As in previous analyses of sCA in atomic bomb survivors that were based on Giemsa staining methods and used older DS86 dose estimates, the relationship between radiation dose and sCA rate was significant (P < 0.0001) with a linear-quadratic relationship at lower doses that did not persist at higher doses. As before, age at the time of the bombing and type of radiation shielding were significant dose-effect modifiers (P < 0.0001), but in contrast the difference in dose response by city was not so pronounced (P = 0.026) with a city effect not evident at doses below 1.25Gy. Background sCA rate increased with age at the time of examination (P < 0.0001), but neither sex, city, nor smoking was significantly associated with background rate. Based on FISH methods and recent dosimetry, the relationship between radiation dose and sCA frequency is largely consistent with previous findings, although the lesser importance of city as an effect modifier may reflect better dosimetry as well as more reproducible scoring of sCA. The persisting difference in sCA dose response by shielding category points to remaining problems with the accuracy or precision of radiation dose estimates in some A-bomb survivors.

Incidence of Diabetes in the Atomic Bomb Survivors: 1969-2015.

CONTEXT: Recent epidemiological studies have shown increased risk of diabetes among childhood cancer survivors who received high therapeutic doses of radiation, particularly to the total body or to the abdomen. However, the effect of low-to-moderate dose radiation (<4 Gy) on the risk of diabetes is still unknown. OBJECTIVES: To investigate the radiation effect on diabetes incidence among atomic bomb (A-bomb) survivors, and whether the dose response is modified by other factors including city, sex, and age at time of bombing (ATB). METHODS: 9131 participants without diabetes at baseline were observed through biennial clinical exams from 1969 to 2015. A Cox proportional hazards model was used to estimate hazard ratios (HR) to evaluate the dose response for diabetes incidence. RESULTS: During the study period, 1417 incident diabetes cases were identified. The overall crude incidence rate was 7.01/103 person-years. Radiation dose was significantly associated with diabetes incidence, with effect modification by city and age ATB. In Hiroshima, at ages 10 and 30 ATB, the HRs at 1 Gy of pancreatic radiation dose were 1.47 (95% CI, 1.31-1.66) and 1.13 (95% CI, 0.97-1.31), respectively. However, no significant radiation dose response was observed at these ages in Nagasaki. The HR for radiation dose was higher among those who were younger ATB and decreased 1% for each additional year of age. CONCLUSIONS: Among A-bomb survivors, a radiation association was suggested for incidence of diabetes. Results were inconsistent by city and age ATB, which could indicate potential confounding of the radiation association with diabetes.

Complementarity in daily marijuana and alcohol among emerging adults.

Objective: The relationship between marijuana and alcohol use among late adolescents was examined as whether marijuana use was related to quantity of alcohol consumed that day, and whether changes in marijuana and alcohol use frequency over 3 years were related. Method: College students (n = 375) reported marijuana and alcohol use for 28 days over 3 years. Results: Within-day analyses showed that more alcohol was consumed on days on which marijuana was used. Co-use varied by alcohol use problems, day of week, and year in study; the relation between marijuana and alcohol use was stronger among those who reported less problematic alcohol use, on weekdays, and as time increased. Daily level co-use relations also differed marginally by gender. At the annual level, there was a marginal relation between changes in use such that increasing use of one substance over time was weakly associated with increased use of the other substance over the same time period. Conclusions: Results add to the emerging conclusion of complementary marijuana and alcohol co-use within a single day, showing it occurs for both women and men, across a full range of marijuana use, and increases with time while being affected by alcohol use problems and day of week. The overall strong co-use relationship highlights risky behavior among late adolescents and supports an emphasis on common underlying substance use causes. However, the different pattern when assessed yearly demonstrates the importance of tailoring the timescale of analysis to the specific substance use question. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Radiation effects on atherosclerosis in atomic bomb survivors: a cross-sectional study using structural equation modeling.

Past reports indicated that total-body irradiation at low to moderate doses could be responsible for cardiovascular disease risks, but the mechanism remains unclear. The purpose of this study was to investigate the association between radiation exposure and atherosclerosis, an underlying pathology of cardiovascular diseases, in the Japanese atomic bomb survivors. We performed a cross-sectional study measuring 14 clinical-physiological atherosclerosis indicators during clinical exams from 2010 to 2014 in 3274 participants of the Adult Health Study cohort. Multivariable analyses were performed by using a structural equation model with latent factors representing underlying atherosclerotic pathologies: (1) arterial stiffness, (2) calcification, and (3) plaque　as measured with indicators chosen a priori on the basis of clinical-physiological knowledge. Radiation was linearly associated with calcification (standardized coefficient per Gy 0.15, 95 % confidence interval: CI [0.070, 0.23]) and plaque (0.11, 95 % CI [0.029, 0.20]), small associations that were comparable to about 2 years of aging per Gy of radiation exposure, but not with arterial stiffness (0.036, 95 % CI [- 0.025, 0.095]). The model fitted better and had narrower confidence intervals than separate ordinary regression models explaining individual indicators independently. The associations were less evident when the dose range was restricted to a maximum of 2 or 1 Gy. By combining individual clinical-physiological indicators that are correlated because of common, underlying atherosclerotic pathologies, we found a small, but significant association of radiation with atherosclerosis.

Assessing the Relative Biological Effectiveness of Neutrons across Organs of Varying Depth among the Atomic Bomb Survivors.

When assessing radiation-related risk among the atomic bomb survivors, choices in modeling approach can have an important impact on the results, which are then used to inform radiation protection standards throughout the world. The atomic bombings of Hiroshima and Nagasaki produced a mixed-field radiation exposure from two sources: neutrons and gamma rays. Neutrons are more densely ionizing and cause greater biological damage per unit absorbed dose, resulting in greater relative biological effectiveness (RBE) than gamma rays. To account for this, a combined weighted dose is typically calculated as the sum of the gamma-ray dose and 10 times the neutron dose in the Radiation Effects Research Foundation's reports of mortality, solid cancer incidence and other outcomes. In addition, the colon, which is often chosen as the whole-body representative organ in these analyses, is relatively deep in the body and therefore its dose calculation involves heavy body shielding of neutrons and a low neutron/gamma-ray ratio. With added follow-up and recently updated doses, we used a data-driven approach to determine the best-fitting neutron RBE for a range of organs of varying depth. Aggregated person-year tables of solid cancer incidence (1958-2009) from the Life Span Study were created with separate neutron and gamma-ray DS02R1 doses for several organs including breast, brain, thyroid, bone marrow, lung, liver and colon. Typical excess relative risk models estimating the linear effect of radiation dose were fitted using a range of neutron weights (1-250) to calculate combined dose for each organ, and model deviances were compared to assess fit. Furthermore, models using separate terms for gamma-ray and neutron dose were also examined, wherein the ratio of the neutron/gamma-ray linear terms indicated the best estimate of the RBE. The best-fitting RBE value for the traditional weighted colon dose was 80 [95% confidence interval (CI): 20-190], while the RBEs for other organs using weighted doses ranged from 25 to 60, with the best-fitting weights and confidence interval widths both incrementally increasing with greater depth of organ. Models using separate neutron- and gamma-ray-dose terms gave similar results to weighted linear combinations, with a neutron/gamma-ray term ratio of 79.9 (95% CI: 18.8-192.3) for colon. These results indicated that the traditionally modeled RBE of 10 may underestimate the effect of neutrons across the full dose range, although these updated estimates still have fairly wide confidence bounds. Furthermore, the colon is among the deepest of organs and may not be the best choice as a single surrogate organ dose, as it may minimize the role of the neutrons. Future work with more refined organ doses could shed more light on RBE-related information available in the Life Span Study data.

Tooth enamel ESR doses and cytogenetic doses of Nagasaki atomic-bomb survivors in comparison with DS02R1 doses.

PURPOSE: Cancer risks for Nagasaki survivors once appeared to be lower than for Hiroshima survivors. The possibility that this was due to overestimation of the doses for the Nagasaki survivors was tested by measuring biological doses of Nagasaki survivors and comparing them with DS02R1 individual doses as previously done for Hiroshima survivors. MATERIALS AND METHODS: The electron spin resonance (ESR) method and cytogenetic method were used to estimate radiation doses for 24 Nagasaki survivors, and the results were compared to calculated DS02R1 doses. RESULTS: Six factory workers and 10 other survivors showed ESR or cytogenetically estimated doses that were in reasonably good agreement with their DS02R1 doses, while one factory worker was found to have an ESR dose estimate of nearly one half of the DS02R1 dose to the eye lens (a proxy organ for teeth). A few outliers were also observed. CONCLUSIONS: Although apparently lower cancer risks were observed in the past for Nagasaki survivors when compared to Hiroshima survivors, the present results do not indicate the existence of a trend that DS02R1 doses are overestimated when compared with biologically estimated tooth or cytogenetic doses. This observation is in line with the recent disappearance of the city difference in cancer risks.

Increased risk of skin cancer in Japanese heterozygotes of xeroderma pigmentosum group A.

This study was designed to learn if asymptomatic heterozygotes with mutations in a DNA repair gene are at an increased risk for cancer. To examine this, we focused on carriers of an XPA founder mutation because the frequency of xeroderma pigmentosum (XP) patients is much greater among Japanese than Caucasians, more than half of Japanese XP patients are affected at the XPA gene, and the majority of XP-A patients carry the same founder mutation in the XPA gene. Here we show that the frequency of XPA heterozygote was 14/1698 (0.8%) in cancer-free controls, and the corresponding frequency in patients with nonmelanocytic skin cancer that developed in sun-exposed areas was 11/440 (2.5%, OR = 3.08, p = 0.0097) for basal cell carcinoma, and 3/272 (1.1%, OR = 1.34, p = 0.72) for squamous cell carcinoma. These results suggest a moderately elevated risk for skin cancer among XPA heterozygotes.

Cytogenetic Reconstruction of Gamma-Ray Doses Delivered to Atomic Bomb Survivors: Dealing with Wide Distributions of Photon Energies and Contributions from Hematopoietic Stem/Progenitor Cells.

Retrospective estimation of the doses received by atomic bomb (A-bomb) survivors by cytogenetic methods has been hindered by two factors: One is that the photon energies released from the bomb were widely distributed, and since the aberration yield varies depending on the energy, the use of monoenergetic 60Co gamma radiation to construct a calibration curve may bias the estimate. The second problem is the increasing proportion of newly formed lymphocytes entering into the lymphocyte pool with increasing time intervals since the exposures. These new cells are derived from irradiated precursor/stem cells whose radiosensitivity may differ from that of blood lymphocytes. To overcome these problems, radiation doses to tooth enamel were estimated using the electron spin resonance (ESR; or EPR, electron paramagnetic resonance) method and compared with the cytogenetically estimated doses from the same survivors. The ESR method is only weakly dependent on the photon energy and independent of the years elapsed since an exposure. Both ESR and cytogenetic doses were estimated from 107 survivors. The latter estimates were made by assuming that although a part of the cells examined could be lymphoid stem or precursor cells at the time of exposure, all the cells had the same radiosensitivity as blood lymphocytes, and that the A-bomb gamma-ray spectrum was the same as that of the 60Co gamma rays. Subsequently, ESR and cytogenetic endpoints were used to estimate the kerma doses using individual DS02R1 information on shielding conditions. The results showed that the two sets of kerma doses were in close agreement, indicating that perhaps no correction is needed in estimating atomic bomb gamma-ray doses from the cytogenetically estimated 60Co gamma-ray equivalent doses. The present results will make it possible to directly compare cytogenetic doses with the physically estimated doses of the survivors, which would pave the way for testing whether or not there are any systematic trends or factors affecting physically estimated doses.

Aging-related changes in human T-cell repertoire over 20years delineated by deep sequencing of peripheral T-cell receptors.

Recent deep sequencing studies on T-cell receptor (TCR) repertoire have provided robust data to characterize diversity of T-cell immune responsiveness to a wide variety of peptide antigens, including viral and tumor antigens. The human TCR repertoire declines with age, but this decline has not been fully investigated longitudinally in individuals. Using a deep sequencing approach, we analyzed TCRß repertoires longitudinally over approximately 20years, with ages ranging from 23 to 50years at the start (23 to 65years overall), in peripheral-blood CD4 and CD8 T-cell populations that were collected and cryopreserved 3 times at intervals of approximately 10years from each of 6 healthy adults (3 men and 3 women). Sequence data at the hypervariable complementarity determining region 3 (CDR3) in the TCRB gene locus were evaluated by applying a random-coefficient statistical regression model. Two outcomes were analyzed: total number of distinct TCRB CDR3 sequences as a TCR diversity metric, and clonality of the T-cell populations. TCR repertoire diversity decreased (p<0.001) and frequencies of clonal populations increased (p=0.003) with age in CD8 T cells, whereas CD4 T cells retained fairly diverse TCR repertoires along with relatively low clonality. We also found that approximately 10-30% and 30-80% of read sequences in CD4 and CD8 T cells, respectively, overlapped at different ages within each individual, indicating long-term stable maintenance of T-cell clonal composition. Moreover, many of the most frequent TCRB CDR3 sequences (i.e., top T-cell clones) persisted over 20years, and some of them expanded and exerted a dominating influence on clonality of peripheral T-cell populations. It is thus possible that persistence or expansion of top T-cell clones is a driver of T-cell immunity aging, and therefore represents a potential interventional target.

Can marijuana make it better? Prospective effects of marijuana and temperament on risk for anxiety and depression.

Increases in marijuana use in recent years highlight the importance of understanding how marijuana affects mental health. Of particular relevance is the effect of marijuana use on anxiety and depression given that marijuana use is highest among late adolescents/early adults, the same age range in which risk for anxiety and depression is the highest. Here we examine how marijuana use moderates the effects of temperament on level of anxiety and depression in a prospective design in which baseline marijuana use and temperament predict anxiety and depression 1 year later. We found that harm avoidance (HA) is associated with higher anxiety and depression a year later, but only among those low in marijuana use. Those higher in marijuana use show no relation between HA and symptoms of anxiety and depression. Marijuana use also moderated the effect of novelty seeking (NS), with symptoms of anxiety and depression increasing with NS only among those with high marijuana use. NS was unrelated to symptoms of anxiety and depression among those low in marijuana use. The temperament dimension of reward dependence was unrelated to anxiety and depression symptoms. Our results suggest that marijuana use does not have an invariant relationship with anxiety and depression, and that the effects of relatively stable temperament dimensions can be moderated by other contextual factors.

Testing an expanded theory of planned behavior model to explain marijuana use among emerging adults in a promarijuana community.

Opinions about marijuana use in the United States are becoming increasingly favorable, making it important to understand how psychosocial influences impact individuals' use in this context. Here, we used the theory of planned behavior to examine the influence of initial attitudes, norms, and efficacy to resist use on initial intentions and then to examine the effect of initial intentions on actual marijuana use measured 1 year later using data drawn from a community with relatively high use. We expanded the traditional theory of planned behavior model by investigating 2 types of normative influence (descriptive and injunctive) and 2 types of intentions (use intentions and proximity intentions), reasoning that exposure to high use in the population may produce high descriptive norms and proximity intentions overall, but not necessarily increase actual use. By contrast, we expected greater variability in injunctive norms and use intentions and that only use intentions would predict actual use. Consistent with hypotheses, intentions to use marijuana were predicted by injunctive norms (and attitudes) and in turn predicted marijuana use 1 year later. By contrast, descriptive norms were relatively high among all participants and did not predict intentions. Moreover, proximity intentions were not predictive of actual use. We also found that increasing intentions to use over a 1-year period predicted greater use. Given the greater efficacy of theory-based as compared with non-theory-based interventions, these findings provide critical information for the design of successful interventions to decrease marijuana-associated harms.