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This article summarizes a Symposium on 'Radiation risks of the central nervous system' held virtually at the 67th Annual Meeting of the Radiation Research Society, 3-6 October 2021. Repeated low-dose radiation exposure over a certain period could lead to reduced neuronal proliferation, altered neurogenesis, neuroinflammation and various neurological complications, including psychological consequences, necessitating further research in these areas. Four speakers from radiation biology, genetics and epidemiology presented the latest data from their studies seeking insights into this important topic. This symposium highlighted new and important directions for further research on mental health disorders, neurodegenerative conditions and cognitive impairment. Future studies will examine risks of mental and behavioral disorders and neurodegenerative diseases following protracted radiation exposures to better understand risks of occupational exposures as well as provide insights into risks from exposures to galactic cosmic rays.

Objective To systematically review and perform a meta-analysis of radiation associated risks of cardiovascular disease in all groups exposed to radiation with individual radiation dose estimates. Design Systematic review and meta-analysis. Main outcome measures Excess relative risk per unit dose (Gy), estimated by restricted maximum likelihood methods. Data sources PubMed and Medline, Embase, Scopus, Web of Science Core collection databases. Eligibility criteria for selecting studies Databases were searched on 6 October 2022, with no limits on date of publication or language. Animal studies and studies without an abstract were excluded. Results The meta-analysis yielded 93 relevant studies. Relative risk per Gy increased for all cardiovascular disease (excess relative risk per Gy of 0.11 (95% confidence interval 0.08 to 0.14)) and for the four major subtypes of cardiovascular disease (ischaemic heart disease, other heart disease, cerebrovascular disease, all other cardiovascular disease). However, interstudy heterogeneity was noted (P Conclusions Results provide evidence supporting a causal association between radiation exposure and cardiovascular disease at high dose, and to a lesser extent at low dose, with some indications of differences in risk between acute and chronic exposures, which require further investigation. The observed heterogeneity complicates a causal interpretation of these findings, although this heterogeneity is much reduced if only higher quality studies or those at moderate doses or low dose rates are considered. Studies are needed to assess in more detail modifications of radiation effect by lifestyle and medical risk factors. Systematic review registration PROSPERO CRD42020202036

Context Assisted reproductive technologies (ART) and non–in vitro fertilization fertility treatments (NIFT) are treatments for infertility. These technologies may have long-term health effects in children such as increased hypertension, glucose intolerance, and hypertriglyceridemia. Few studies have compared children born following ART and NIFT to those conceived spontaneously by subfertile couples. Objective This work aimed to describe metabolic differences in children conceived by ART and NIFT compared to children conceived spontaneously by infertile couples. Methods Children conceived by parent(s) receiving infertility care at the University of California, San Francisco, between 2000 and 2017 were invited to participate in the Developmental Epidemiological Study of Children born through Reproductive Technology (DESCRT). Serum metabolomic analyses were conducted using samples from 143 enrolled children (age range 4-12 years, 43% female) conceived using NIFT or ART (with fresh or frozen embryos with and without intracytoplasmic sperm injection [ICSI]) and children conceived spontaneously by subfertile couples. Principal component analysis and multivariable regression were used to compare the distribution of metabolites between groups. Results There was no separation in metabolites based on treatment or sex. NIFT-conceived children showed no differences compared to spontaneously conceived controls. Only spontaneously conceived children had different metabolomics profiles from children conceived from fresh ART, frozen ART, and all ICSI. Pantoate and propionylglycine levels were elevated in fresh ART compared to the spontaneous group (P < .001). Propionylglycine levels were elevated in the ICSI (both fresh and frozen) vs the spontaneous group (P < .001). Finally, 5-oxoproline levels were decreased in frozen ART compared to the spontaneous group (P < .001). Conclusion NIFT-conceived children did not show any metabolic differences compared with spontaneously conceived children. The metabolic differences between ART-conceived children and children conceived spontaneously were small but unlikely to be clinically significant but should be examined in future studies.

ObjectivesRadon is a ubiquitous occupational and environmental lung carcinogen. We aim to quantify the association between radon progeny and lung cancer mortality in the largest and most up-to-date pooled study of uranium miners.MethodsThe pooled uranium miners analysis combines 7 cohorts of male uranium miners with 7754 lung cancer deaths and 4.3 million person-years of follow-up. Vital status and lung cancer deaths were ascertained between 1946 and 2014. The association between cumulative radon exposure in working level months (WLM) and lung cancer was modelled as the excess relative rate (ERR) per 100 WLM using Poisson regression; variation in the association by temporal and exposure factors was examined. We also examined analyses restricted to miners first hired before 1960 and with ResultsIn a model that allows for variation by attained age, time since exposure and annual exposure rate, the ERR/100 WLM was 4.68 (95% CI 2.88 to 6.96) among miners who were less than 55 years of age and were exposed in the prior 5 to ConclusionsThis new large, pooled study confirms and supports a linear exposure–response relationship between cumulative radon exposure and lung cancer mortality which is jointly modified by temporal and exposure factors.

BackgroundDespite reductions in exposure for workers and the general public, radon remains a leading cause of lung cancer. Prior studies of underground miners depended heavily upon information on deaths among miners employed in the early years of mine operations when exposures were high and tended to be poorly estimated.ObjectivesTo strengthen the basis for radiation protection, we report on the follow-up of workers employed in the later periods of mine operations for whom we have more accurate exposure information and for whom exposures tended to be accrued at intensities that are more comparable to contemporary settings.MethodsWe conducted a pooled analysis of cohort studies of lung cancer mortality among 57,873 male uranium miners in Canada, Czech Republic, France, Germany, and the United States, who were first employed in 1960 or later (thereby excluding miners employed during the periods of highest exposure and focusing on miners who tend to have higher quality assessments of radon progeny exposures). We derived estimates of excess relative rate per 100 working level months (ERR/100 WLM) for mortality from lung cancer.ResultsThe analysis included 1.9 million person-years of observation and 1,217 deaths due to lung cancer. The relative rate of lung cancer increased in a linear fashion with cumulative exposure to radon progeny (ERR/100 WLM=1.33; 95% CI: 0.89, 1.88). The association was modified by attained age, age at exposure, and annual exposure rate; for attained ages

Large-scale genome-wide analyses scans provide massive volumes of genetic variants on large number of cases and controls that can be used to estimate the genetic effects. Yet, the sets of non-genetic variables available in publicly available databases are often brief. It is known that omitting a continuous variable from a logistic regression model can result in biased estimates of odds ratios (OR) (e.g., Gail et al (1984), Neuhaus et al (1993), Hauck et al (1991), Zeger et al (1988)). We are interested to assess what information is needed to recover the bias in the OR estimate of genotype due to omitting a continuous variable in settings when the actual values of the omitted variable are not available. We derive two estimating procedures that can recover the degree of bias based on a conditional density of the omitted variable or knowing the distribution of the omitted variable. Importantly, our derivations show that omitting a continuous variable can result in either under- or over-estimation of the genetic effects. We performed extensive simulation studies to examine bias, variability, false positive rate, and power in the model that omits a continuous variable. We show the application to two genome-wide studies of Alzheimer’s disease.Data Availability StatementThe data that support the findings of this study are openly available in the Database of Genotypes and Phenotypes at [https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000372.v1.p1], reference number [phs000372.v1.p1] and at the Alzheimer’s Disease Neuroimaging Initiative http://adni.loni.usc.edu/.

BackgroundThe study of Japanese atomic bomb survivors, exposed briefly to radiation, finds the risk of radiation-induced lung cancer to be nearly three times greater for women than for men. Because protection standards for astronauts are based on individual lifetime risk projections, this sex-specific difference limits the time women can spend in space. Populations exposed to chronic or fractionated radiation were evaluated to learn whether similar differences exist when exposures occur gradually over years.Methods and materialsFive occupational cohorts within the Million Person Study of Low-Dose Health Effects (MPS) and a Canadian Fluoroscopy Cohort Study (CFCS) of tuberculosis patients who underwent frequent chest fluoroscopic examinations are evaluated. Included are male and female workers at the Mound nuclear facility, nuclear power plants (NPP), and industrial radiographers (IR). Workers at the Mallinckrodt Chemical Works and military participants at aboveground nuclear weapons tests provide information on the risk among males. Cox proportional hazards and Poisson regression models were used to estimate sex-specific radiation risks for lung cancer and to compare any differences.ResultsOverall, 15,065 lung cancers occurred among the 443,684 subjects studied: 50,111 women and 395,573 men. The mean cumulative dose to the lung was 166.3 mGy (range 6 to 1,055 mGy) with the highest among the TB-fluoroscopy patients (mean 1,055 mGy). Mean lung dose for women in the worker cohorts was generally 4 times lower than for men. Of the 12 estimates of radiation-related risk, only one, for male IRs, showed a significant elevation (ERR 0.09; 95% CI 0.02-0.16, at 100 mGy). In contrast, the dose response for male NPP workers was negative (ERR -0.05; 95% CI -0.10, 0.01, at 100 mGy). Combined, these two cohorts provided little evidence for a radiation effect among males (ERR 0.01; 95% CI -0.04, 0.06, at 100 mGy). There was no significant dose-response among females within any cohort. There was no difference in the sex-specific estimates of lung cancer risk.ConclusionsThere was little evidence that chronic or fractionated exposures increased the risk of lung cancer. There were no differences in the risks of lung cancer between men and women. However, the sex-specific analyses are limited because of small numbers of women and relatively low doses. A more definitive study is ongoing of medical radiation workers which include 85,000 women and 85,000 men (overall mean dose 82 mGy, max 1,140 mGy). Additional understanding will come from the ongoing follow-up of the CFCS.

PurposeTo date, only a few studies have examined long-term health risks of exposures in the uranium processing industry and reported contradictory results, necessitating further research in this area. This is the first description of a cohort of ∼65,000 uranium processing workers (20.6% women) of the Siberian Group of Chemical Enterprises (SGCE) in Seversk, Russia, first employed during 1950-2010.MethodsSGCE is one of the largest and oldest uranium processing complexes in the world. SGCE workers at the Radiochemical, Plutonium, Sublimate and Enrichment plants were exposed to a combination of internal and external radiation, while workers at the Support Facility were primarily exposed to non-radiation factors.ResultsMean cumulative gamma-ray dose based on individual external dosimetry was 28.3 millisievert. About 4,000 workers have individual biophysical survey data that could be used for estimation of organ doses from uranium. SGCE workers were followed up for mortality and cancer incidence during 1950-2013 (vital status known for 80.8% of workers). The SGCE computerized database contains information on the results of regular medical examinations, and on smoking, alcohol and other individual characteristics.ConclusionsThe SGCE cohort is uniquely suited to examine long-term health risks of exposures to gamma-radiation and long-lived radionuclides in uranium processing workers.

Background The Pooled Uranium Miners Analysis (PUMA) study draws together information from cohorts of uranium miners from Canada, the Czech Republic, France, Germany and the USA. Methods Vital status and cause of death were ascertained and compared with expectations based upon national mortality rates by computing standardized mortality ratios (SMRs) overall and by categories of time since first hire, calendar period of first employment and duration of employment as a miner. Results There were 51 787 deaths observed among 118 329 male miners [SMR = 1.05; 95% confidence interval (CI): 1.04, 1.06]. The SMR was elevated for all cancers (n = 16 633, SMR = 1.23; 95% CI: 1.21, 1.25), due primarily to excess mortality from cancers of the lung (n = 7756, SMR = 1.90; 95% CI: 1.86, 1.94), liver and gallbladder (n = 549, SMR = 1.15; 95% CI: 1.06, 1.25), larynx (n = 229, SMR = 1.10; 95% CI: 0.97, 1.26), stomach (n = 1058, SMR = 1.08; 95% CI: 1.02, 1.15) and pleura (n = 39, SMR = 1.06; 95% CI: 0.75, 1.44). Lung-cancer SMRs increased with duration of employment, decreased with calendar period and persisted with time since first hire. Among non-malignant causes, the SMR was elevated for external causes (n = 3362, SMR = 1.41; 95% CI: 1.36, 1.46) and respiratory diseases (n = 4508, SMR = 1.32; 95% CI: 1.28, 1.36), most notably silicosis (n = 814, SMR = 13.56; 95% CI: 12.64, 14.52), but not chronic obstructive pulmonary disease (n = 1729, SMR = 0.98; 95% CI: 0.93, 1.02). Conclusions Whereas there are important obstacles to the ability to detect adverse effects of occupational exposures via SMR analyses, PUMA provides evidence of excess mortality among uranium miners due to a range of categories of cause of death. The persistent elevation of SMRs with time since first hire as a uranium miner underscores the importance of long-term follow-up of these workers.

Dr. William Francis Morgan, known as Bill by many of his friends and colleagues, was a leading figure in the field of radiation research. He passed away on 13 November 2015, at the age of 62 years ...

As part of ongoing efforts to assess lifespan disease mortality and incidence in 63,715 patients from the Canadian Fluoroscopy Cohort Study (CFCS) who were treated for tuberculosis between 1930 and 1969, we developed a new FLUoroscopy X-ray ORgan-specific dosimetry system (FLUXOR) to estimate radiation doses to various organs and tissues. Approximately 45% of patients received medical procedures accompanied by fluoroscopy, including artificial pneumothorax (air in pleural cavity to collapse of lungs), pneumoperitoneum (air in peritoneal cavity), aspiration of fluid from pleural cavity and gastrointestinal series. In addition, patients received chest radiographs for purposes of diagnosis and monitoring of disease status. FLUXOR utilizes age-, sex- and body size-dependent dose coefficients for fluoroscopy and radiography exams, estimated using radiation transport simulations in up-to-date computational hybrid anthropomorphic phantoms. The phantoms include an updated heart model, and were adjusted to match the estimated mean height and body mass of tuberculosis patients in Canada during the relevant time period. Patient-specific data (machine settings, exposure duration, patient orientation) used during individual fluoroscopy or radiography exams were not recorded. Doses to patients were based on parameter values inferred from interviews with 91 physicians practicing at the time, historical literature, and estimated number of procedures from patient records. FLUXOR uses probability distributions to represent the uncertainty in the unknown true, average value of each dosimetry parameter. Uncertainties were shared across all patients within specific subgroups of the cohort, defined by age at treatment, sex, type of procedure, time period of exams and region (Nova Scotia or other provinces). Monte Carlo techniques were used to propagate uncertainties, by sampling alternative average values for each parameter. Alternative average doses per exam were estimated for patients in each subgroup, with the total average dose per individual determined by the number of exams received. This process was repeated to produce alternative cohort vectors of average organ doses per patient. This article presents estimates of doses to lungs, female breast, active bone marrow and heart wall. Means and 95% confidence intervals (CI) of average organ doses across all 63,715 patients were 320 (160, 560) mGy to lungs, 250 (120, 450) mGy to female breast, 190 (100, 340) mGy to heart wall and 92 (47, 160) mGy to active bone marrow. Approximately 60% of all patients had average doses to the four studied organs of less than 10 mGy, 10% received between 10 and 100 mGy, 25% between 100 and 1,000 mGy, and 5% above 1,000 mGy. Pneumothorax was the medical procedure that accounted for the largest contribution to cohort average doses. The major contributors to uncertainty in estimated doses per procedure for the four organs of interest are the uncertainties in exposure duration, tube voltage, tube output, and patient orientation relative to the X-ray tube, with the uncertainty in exposure duration being most often the dominant source. Uncertainty in patient orientation was important for doses to female breast, and, to a lesser degree, for doses to heart wall. The uncertainty in number of exams was an important contributor to uncertainty for ∼30% of patients. The estimated organ doses and their uncertainties will be used for analyses of incidence and mortality of cancer and non-cancer diseases. The CFCS cohort is an important addition to existing radio-epidemiological cohorts, given the moderate-to-high doses received fractionated over several years, the type of irradiation (external irradiation only), radiation type (X rays only), a balanced combination of both genders and inclusion of people of all ages.

There is limited evidence that non-leukaemic lymphoid malignancies are radiogenic. As radiation-related cancer risks are generally higher after childhood exposure, we analysed pooled lymphoid neoplasm data in nine cohorts first exposed to external radiation aged 0.4). In six cohorts with estimates of lymphatic tissue dose, borderline significant increased risks (p-trend = 0.02-0.07) were observed for NHL + CLL, NHL, andCLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.

PURPOSE: Risks of occupational radiation exposures of workers involved in uranium refining and processing (“uranium processing workers”) may be different from risks of other workers from the nuclear fuel cycle. Pooling of individual-level data from published studies and analysis using similar dosimetry and statistical methods might provide valuable insights into risks from occupational uranium and external ionizing radiation exposures. METHODS: We pooled the data for workers from four uranium processing facilities (Fernald Feed Materials Production Center, Ohio; Mallinckrodt Chemical Works Uranium Division, Missouri; Middlesex Sampling Plant, New Jersey; and the Port Hope Radium and Uranium Refining and Processing Plant, Canada). Employment began as early as the 1930s in Canada and follow-up for vital status was as late as 2017. These facilities used similar methods to process Belgian Congo pitchblende ore which contained high concentrations of uranium, radium, and their decay products. In addition, workers were exposed to elevated levels of gamma radiation, fission product contaminants in recycled uranium and ambient radon decay products. Non-radiation exposures of industrial hygiene concern were silica dust inhalation, heavy metal toxicity from uranium, solvents, acid mists and chemicals associated with uranium processing. Exposure and outcome data were harmonized using similar definitions and dose reconstruction methods. Standardized mortality ratios (SMR) were estimated by comparing mortality in the pooled cohort with age-, sex- and calendar time-specific general population mortality rates for the U.S. and Canada. RESULTS: Over 12,400 workers will be evaluated for cancer and non-cancer mortality in relation to exposures to uranium byproducts and gamma radiation (including ~1,300 females). In total, death from 560 lung cancers, 503 non-malignant respiratory diseases, 67 renal diseases, 1,596 ischemic heart diseases, and 101 dementia and Alzheimer’s diseases (AD) were detected among male workers during follow-up. Mean cumulative doses were 45 millisievert for whole-body external exposures and 172 milligray for lung dose from radon decay products. Of the 16 pooled SMRs, seven were above 1.00, none were significantly low, and only one was significantly high, i.e., dementia and AD among males (SMR=1.29; 95% confidence interval: 1.04,1.54). CONCLUSIONS: This is the largest study to date to examine health risks in uranium processing workers (excluding uranium enrichment workers). The pooling of uranium processing worker data will address issues of importance today, specifically the concerns for cleanup workers and environmental contamination from the operation of past and present nuclear reactor and radiation facilities, reactor accidents, and possible terrorist events.

Author(s): Thiessen, Kathleen M; Apostoaei, A Iulian; Zablotska, Lydia B | Abstract: AbstractThis paper documents the estimation of mean heights and body masses, by age and sex, used in development of organ-specific dose conversion coefficients for external radiation for a historical cohort of about 64,000 patients from the Canadian Fluoroscopy Cohort Study. Patients were exposed to repeated fluoroscopy and chest radiography examinations in the course of treatment for tuberculosis in residential medical facilities throughout Canada between 1930 and 1969. Using Canadian national survey data and extensive literature review, mean heights and masses were obtained for the White population of Canada during the time period of interest, and the differences in mean body mass between tuberculosis patients and the general population were estimated. Results in terms of mean height and body mass of Canadian tuberculosis patients, with uncertainties, are reported for selected age groups (children of ages 1, 5, 10, and 15 y and adults age 20+) and for both sexes. Use of estimated average heights and body masses by age and sex permits the adjustment of computerized phantoms for body mass for a given age, thereby increasing the relevance of the organ-specific dose conversion coefficients for the cohort and improving the accuracy of the resulting estimated organ doses.

ObjectivesWe investigated the association between low-dose external occupational radiation exposure and circulatory disease morbidity among diagnostic medical radiation workers.MethodsA cohort of 11 500 diagnostic medical radiation workers was linked with the National Dosimetry Registry data and the National Health Insurance Service data. Relative risks (RRs) were calculated to explore the association between occupational factors and circulatory disease morbidity, and excess relative risks per 100 milligray (ERR/100 mGy) were estimated to quantify the radiation dose-response relationship.ResultsOverall, there were 2270 cases of circulatory diseases during 93 696 person-years of observation (average follow-up=8.1 years). RRs for hypertension were significantly increased for individuals who started working before 2000 compared with those who started in 2005 and later. ERR/100 mGy for all circulatory diseases was 0.14 (95% CI −0.57 to 0.99). Radiation risks of cerebrovascular diseases and ischaemic heart disease were non-significantly increased with estimates of individual cumulative doses to the heart (ERR/100 mGy=3.10 (−0.75 to 11.59) and 1.22 (−0.71 to 4.73), respectively). However, ERR estimates were generally more strongly positive for female versus male workers and for younger workers versus more than 50-year-old workers.ConclusionsThis study provides little evidence in support of a positive association between occupational radiation exposure and the overall risk of circulatory disease over a short follow-up period among medical radiation workers in South Korea. However, significantly increased RR with earlier year first worked, elevated ERR in female workers and young workers should be further followed up.

Background Primary CNS tumors constitute a heterogeneous group of neoplasms that share a considerable morbidity and mortality rate. To help control tumor growth and clinical outcomes (overall survival, progression-free survival, quality of life) symptoms, patients often resort to alternative therapies, including the use of cannabis. Despite rapidly growing popularity, cannabis and its impact on patients with primary malignant CNS tumors is understudied. Methods To shed light on the lack of scientific evidence in this field, in November 2018 we conducted a search and examination of cannabis in neuro-oncology in major journal databases and bibliographies of selected articles, and through abstracts of annual meetings using prespecified criteria in line with the Cochrane Collaboration guidelines. Results We identified 45 publications, of which 9 were selected. Five studies were included. Publication dates ranged from 2004 to 2018 and included varying histologies of primary brain tumors. The average survival at 1 year was 56.09% (95% CI: 48.28-63.9). There was no difference in risk ratio (RR) for death at 1 year between groups (RR: 1.069 [95% CI: 0.139-8.25]). We found strong evidence of heterogeneity (Q = 74.0%; P = .021). We found no statistical evidence of publication bias (P = .117; SD = 1.91). Conclusions There was limited moderate-quality evidence that supports the use of cannabinoids as adjuvant to the standard of care in the treatment of brain and CNS tumors. There was very low-quality evidence suggesting that cannabinoids were associated with adult-onset gliomas. Further prospective clinical trials are necessary to adequately evaluate the impact of cannabinoids on CNS tumors, specifically on survival and quality of life.

Author(s): Burtt, Julie Jane; Rickard, Melanie; McAllister, Andrew; Bergman, Lauren; Zablotska, Lydia B | Abstract: IntroductionA robust emergency management framework can limit radiation exposures and effectively minimize the potentially devastating consequences of a nuclear emergency. We projected thyroid cancer risk resulting from two hypothetical severe nuclear accidents occurring at the Darlington nuclear power plant (NPP) located in Ontario, Canada.MethodsSingle- and multi-unit accidents were considered. A dose assessment was previously performed using the MELCOR Accident Consequences Code System. The generic criteria used to select the appropriate protective actions are described in the Ontario Provincial Nuclear Emergency Response Plan (PNERP). We hypothesized protection actions only within the 10 kilometre (km) radius of the NPP given the time sensitivity of iodine thyroid blocking. The excess risk of developing thyroid cancer was projected using the US National Cancer Institute's radiation risk assessment tool RadRAT.ResultsWe projected zero dose, and subsequently zero risk of developing thyroid cancer for people living within 10 km of the NPP, due to effective implementation of selected protective actions. Based on centreline doses, at the 12 km radius, excess childhood thyroid cancer risks of approximately 600% and 130% compared to the baseline were projected for the single- and multi-unit scenarios, respectively. The risk of developing thyroid cancer was projected to be low for adults for both scenarios.DiscussionThe results of this modelling study provide insights into the effectiveness of protective actions in reducing radiation-related thyroid cancer risk when considering hypothetical severe nuclear accidents. Implementation of select protective actions protects the population living near the Darlington NPP. The projected increase of developing thyroid cancer for children living beyond 10 km could potentially be eliminated with additional mitigation measures specified in the PNERP.

Background Evidence linking risk of lymphoma and B-cell lymphoma subtypes to ionizing radiation is inconclusive, particularly at low exposure levels. Methods We investigated risk of lymphoma (all subtypes), B-cell lymphomas, and its major subtypes, associated with low-level occupational exposure to ionizing radiation, in 2346 lymphoma cases and 2463 controls, who participated in the multicenter EpiLymph case-control study. We developed a job-exposure matrix to estimate exposure to ionizing radiation, distinguishing between internal and external radiation, and we applied it to the lifetime occupational history of study subjects, We calculated the Odds Ratio (OR) and its 95% confidence interval (95% CI) for lymphoma (all subtypes combined), B-cell lymphoma, and its major subtypes using unconditional, polytomous logistic regression adjusting for age, gender, and education. Results We did not observe an association between exposure metrics of external and internal radiation and risk of lymphoma (all subtypes), nor with B-cell lymphoma, or its major subtypes, at the levels regularly experienced in occupational settings. An elevated risk of diffuse large B cell lymphoma was observed among the most likely exposed study subjects with relatively higher exposure intensity, which would be worth further investigation. Conclusions Further investigation is warranted on risk of B cell lymphoma subtypes associated with low-level occupational exposure to external ionizing radiation, and to clarify whether lymphoma should be included among the cancer outcomes related to ionizing radiation.

ObjectivesEpidemiological studies of underground miners have provided clear evidence that inhalation of radon decay products causes lung cancer. Moreover, these studies have served as a quantitative basis for estimation of radon-associated excess lung cancer risk. However, questions remain regarding the effects of exposure to the low levels of radon decay products typically encountered in contemporary occupational and environmental settings on the risk of lung cancer and other diseases, and on the modifiers of these associations. These issues are of central importance for estimation of risks associated with residential and occupational radon exposures.MethodsThe Pooled Uranium Miner Analysis (PUMA) assembles information on cohorts of uranium miners in North America and Europe. Data available include individual annual estimates of exposure to radon decay products, demographic and employment history information on each worker and information on vital status, date of death and cause of death. Some, but not all, cohorts also have individual information on cigarette smoking, external gamma radiation exposure and non-radiological occupational exposures.ResultsThe PUMA study represents the largest study of uranium miners conducted to date, encompassing 124 507 miners, 4.51 million person-years at risk and 54 462 deaths, including 7825 deaths due to lung cancer. Planned research topics include analyses of associations between radon exposure and mortality due to lung cancer, cancers other than lung, non-malignant disease, modifiers of these associations and characterisation of overall relative mortality excesses and lifetime risks.ConclusionPUMA provides opportunities to evaluate new research questions and to conduct analyses to assess potential health risks associated with uranium mining that have greater statistical power than can be achieved with any single cohort.

Summary Background Substantial evidence links exposure to moderate or high doses of ionising radiation, particularly in childhood, with increased risk of leukaemia. The association of leukaemia with exposure to low-dose (

Author(s): Chirikova, Ekaterina; Cahoon, Elizabeth K; Rozhko, Alexander; Drozdovitch, Vladimir; Little, Mark P; McConnell, Robert J; Minenko, Victor; Veyalkin, Ilya; Yauseyenka, Vasilina; Hatch, Maureen; O’Kane, Patrick; Zablotska, Lydia B | Abstract: Abstract Thyroid enlargement can cause problems with swallowing or breathing and a decrease in accuracy of screening for thyroid cancer. Exposure to radioactive iodines after the 1986 Chernobyl accident is known to increase risk of thyroid cancer in those exposed at a young age, but little is known about its effects on thyroid volume, which could have important clinical implications. The objective of this study is to characterize the dose-response association between iodine-131 (131I) exposure and thyroid volume using data from a Belarusian-American cohort study of residents of Belarus exposed during childhood. Persons exposed to Chernobyl fallout in Belarus at the age of 18 years or younger had individual 131I doses to the thyroid gland estimated from direct thyroid activity measurements, radioecological and biokinetic models, and interview data on whereabouts and dietary habits collected during baseline screening in 1996-2001 (N=11,970; median age 21 years). Thyroid volume was estimated from thyroid ultrasound measurements during screening. Individuals with diagnoses of benign or malignant tumors of thyroid gland, any thyroid surgery or aplasia, and missing thyroid volume measurements were excluded (n=1,104). Dose and thyroid volume were log-transformed due to right-skewed distributions. We used a multivariable linear regression to estimate the dose-response association between 131I dose to the thyroid and thyroid volume accounting for confounding effects of sex, age at screening, and place of residence at the time of screening, a proxy for endemic iodine deficiency. To examine nonlinear effects, we added a quadratic term for the log-transformed dose. Among 10,866 participants, dose to thyroid ranged from 0.0005 to 39 gray (Gy) (median=0.3 Gy). In a linear regression model adjusted for confounders, log thyroid volume was best described by a linear-quadratic function of log dose (pl0.001 for log dose and log dose-squared coefficients). The largest effect was observed for doses 0.3-0.6 Gy (14%), then gradually decreased. Subjects with thyroid dose of 1 Gy had an average thyroid volume 13.6% (95% CI 8- 19.2%) higher compared to those with dose 1 mGy. Thyroid volume increased with age and was significantly higher for males compared to females and for those from Minsk city and area compared to other regions (both pl0.001). The adjusted R2-value was 30%, suggesting unaccounted factors that might better explain this association. This is the first study to assess the dose-response association between exposure to 131I and thyroid volume. Although statistically significant, the observed increase in thyroid volume with dose was small. Availability of measurements of iodine deficiency and dietary habits around the time of an accident in the future studies of nuclear accidents will be essential for understanding the mechanism of association between radiation dose and thyroid volume in young people.

ObjectivesThere is growing evidence of an association between low-dose external γ-radiation and circulatory system diseases (CSDs), yet sparse data exist about an association with chronic internal uranium exposure and the role of non-radiation risk factors. We conducted a nested case–control study of French AREVA NC Pierrelatte nuclear workers employed between 1960 and 2005 to estimate CSD risks adjusting for major CSD risk factors (smoking, blood pressure, body mass index, total cholesterol and glycaemia) and external γ-radiation dose.MethodsThe study included 102 cases of death from CSD and 416 controls individually matched on age, gender, birth cohort and socio-professional status. Information on CSD risk factors was collected from occupational medical records. Organ-specific absorbed doses were estimated using biomonitoring data, taking into account exposure regime and uranium physicochemical properties. External γ-radiation was measured by individual dosimeter badges. Analysis was conducted with conditional logistic regression.ResultsWorkers were exposed to very low radiation doses (mean γ-radiation dose 2 and lung uranium dose 1 mGy). A positive but imprecise association was observed (excess OR per mGy 0.2, 95% CI 0.004 to 0.5). Results obtained after adjustment suggest that uranium exposure might be an independent CSD risk factor.ConclusionsOur results suggest that a positive association might exist between internal uranium exposure and CSD mortality, not confounded by CSD risk factors. Future work should focus on numerous uncertainties associated with internal uranium dose estimation and on understanding biological pathway of CSD after protracted low-dose internal radiation exposure.

Author(s): Cahoon, Elizabeth K; Nadyrov, Eldar A; Polyanskaya, Olga N; Yauseyenka, Vasilina V; Veyalkin, Ilya V; Yeudachkova, Tamara I; Maskvicheva, Tamara I; Minenko, Victor F; Liu, Wayne; Drozdovitch, Vladimir; Mabuchi, Kiyohiko; Little, Mark P; Zablotska, Lydia B; McConnell, Robert J; Hatch, Maureen; Peters, Kamau O; Rozhko, Alexander V; Brenner, Alina V | Abstract: ContextAlthough radiation exposure is an important predictor of thyroid cancer on diagnosis of a thyroid nodule, the relationship between childhood radiation exposure and thyroid nodules has not been comprehensively evaluated.ObjectiveTo examine the association between internal I-131 thyroid dose and thyroid nodules in young adults exposed during childhood.Design, setting, and participantsIn this cross-sectional study, we screened residents of Belarus aged ≤18 years at the time of the Chernobyl nuclear accident for thyroid disease (median age, 21 years) with thyroid palpation, ultrasonography, blood/urine analysis, and medical follow-up when appropriate. Eligible participants (N = 11,421) had intact thyroid glands and doses based on direct individual thyroid activity measurements.Main outcome measuresExcess odds ratios per Gray (EOR/Gy, scaled at age 5 years at exposure) for any thyroid nodule and for nodules grouped by cytology/histology, diameter size, and singularity.ResultsRisk of any thyroid nodule increased significantly with I-131 dose and, for a given dose, with younger age at exposure. The EOR/Gy (95% confidence intervals) for neoplastic nodules (3.82; 0.87 to 15.52) was significantly higher than for nonneoplastic nodules (0.32; l0.03 to 0.70) and did not vary by size; whereas the EOR/Gy for nonneoplastic nodules did vary by size (P = 0.02) and was 1.55 (0.36 to 5.46) for nodules ≥10 mm and 0.02 (l-0.02 to 0.70) for nodules l10 mm. EORs/Gy for single and multiple nodules were comparable.ConclusionsChildhood exposure to internal I-131 is associated with increased risk of neoplastic thyroid nodules of any size and nonneoplastic nodules ≥10 mm.

This paper describes a study to estimate absorbed doses to various organs from film-based chest radiographs and their uncertainties in the periods 1930 to 1948, 1949 to 1955, and 1956 to 1969. Estimated organ doses will be used in new analyses of risks of cancer and other diseases in tuberculosis patients in Canada who had chest fluoroscopic and radiographic examinations in those periods. In this paper, doses to lungs, female breast, active bone marrow, and heart from a single chest radiograph in adults and children of ages 1, 5, 10, and 15 y in the Canadian cohort and their uncertainties are estimated using (1) data on the tube voltage (kV), total filtration (mm Al), tube-current exposure-time product (mA s), and tube output (mR [mA s]−1) in each period; (2) assumptions about patient orientation, distance from the source to the skin of a patient, and film size; and (3) new calculations of sex- and age-specific organ dose conversion coefficients (organ doses per dose in air at skin entrance). Variations in estimated doses to each organ across the three periods are less than 20% in adults and up to about 30% at younger ages. Uncertainties in estimated organ doses are about a factor of 2 to 3 in adults and up to a factor of 4 at younger ages and are due mainly to uncertainties in the tube voltage and tube-current exposure-time product.

International audience; Background: The Pooled Uranium Miners Analysis (PUMA) study draws together information about workers employed in uranium mining in Canada, the Czech Republic, France, Germany, and the United States. We compared mortality in PUMA to expectations based upon national mortality rates.Methods: The cohort includes over 120,000 uranium miners and over 50,000 deaths. Vital status and cause of death were ascertained and standardized mortality ratios (SMRs) were computed; SMRs were tabulated by categories of attained age, calendar period of follow-up, duration of employment as a miner, and calendar period of first employment as a miner. Results: Overall, the miners in PUMA experienced all cause mortality rates near those for the general population (SMR=1.0; 95%CI: 1.0, 1.0). There were more deaths than expected due to cancer of the lung (SMR=1.8; 95%CI: 1.8, 1.9), larynx (SMR=1.1; 95%CI: 0.9, 1.3), and liver (SMR=1.1; 95%CI: 0.9, 1.2). Non-malignant respiratory disease mortality also was in excess in PUMA (SMR=1.1; 95%CI: 1.0, 1.2). The relative excesses of mortality due to lung cancer and non-malignant respiratory disease persisted into more recent decades of follow-up, tended to increase with duration of employment as a uranium miner, and tended to decrease with more recent year of first employment as a uranium miner. While lung cancer was elevated in all of the PUMA cohorts, the relative excess of lung cancer was greatest among US Colorado Plateau (SMR=4.7; 95%CI: 4.3, 5.1) and Czech miners (SMR=2.9; 95%CI: 2.8, 3.1), intermediate for US New Mexico (SMR=1.9; 95%CI: 1.6, 2.1) and German Wismut (SMR=1.9; 95%CI: 1.8, 1.9) miners, and smallest among French (SMR=1.3; 95%CI:1.2, 1.5), Canadian Ontario (SMR=1.3; 95%CI: 1.3, 1.4), and Canadian Eldorado (SMR=1.3; 95%CI: 1.2, 1.4) miners. Conclusions: PUMA provides evidence of excess mortality among uranium miners and underscores the importance of long term follow-up to identify the effects of occupational exposures.

Genetic studies provide valuable information to assess if the effect of genetic variants varies by the non-genetic (“environmental”) variables, what is traditionally defined to be gene-environment interaction. A common complication is that multiple disease states present with the same set of symptoms, and hence share the clinical diagnosis. Because 1) disease states might have distinct genetic bases; and 2) frequencies of the disease states within the clinical diagnosis vary by the environmental variables, analyses of association with the clinical diagnosis as an outcome variable might result in false positive or false negative findings. We develop estimates for assessment of GxE in a case-only study and compare the case-control and case-only estimates. We report extensive simulation studies that evaluate empirical properties of the estimates and show the application to a study of Alzheimer’s disease.

This work provides dose coefficients necessary to reconstruct doses used in epidemiological studies of tuberculosis patients treated from the 1930s through the 1960s, who were exposed to diagnostic imaging while undergoing treatment. We made use of averaged imaging parameters from measurement data, physician interviews, and available literature of the Canadian Fluoroscopy Cohort Study and, on occasion, from a similar study of tuberculosis patients from Massachusetts, United States, treated between 1925 and 1954. We used computational phantoms of the human anatomy and Monte Carlo radiation transport methods to compute dose coefficients that relate dose in air, at a point 20 cm away from the source, to absorbed dose in 58 organs. We selected five male and five female phantoms, based on the mean height and weight of Canadian tuberculosis patients in that era, for the 1-, 5-, 10-, 15-year old and adult ages. Using high-performance computers at the National Institutes of Health, we simulated 2,400 unique fluoroscopic and radiographic exposures by varying x-ray beam quality, field size, field shuttering, imaged anatomy, phantom orientation, and computational phantom. Compared with previous dose coefficients reported for this population, our dosimetry system uses improved anatomical phantoms constructed from computed tomography imaging datasets. The new set of dose coefficients includes tissues that were not previously assessed, in particular, for tissues outside the x-ray field or for pediatric patients. In addition, we provide dose coefficients for radiography and for fluoroscopic procedures not previously assessed in the dosimetry of this cohort (i.e. pneumoperitoneum and chest aspirations). These new dose coefficients would allow a comprehensive assessment of exposures in the cohort. In addition to providing newly derived dose coefficients, we believe the automation and methods developed to complete these dosimetry calculations are generalizable and can be applied to other epidemiological studies interested in an exposure assessment from medical x-ray imaging. These epidemiological studies provide important data for assessing health risks of radiation exposure to help inform the current system of radiological protection and efforts to optimize the use of radiation in medical studies.

BACKGROUND Frailty is common in adults with advanced lung disease and is associated with death before and after lung transplantation. We aimed to determine whether frailty changes from before to after the lung transplant. METHODS In a single-center, prospective cohort study among adults undergoing lung transplantation from 2010 to 2017, we assessed frailty by the Short Physical Performance Battery (SPPB; higher scores reflect less frailty) and Fried Frailty Phenotype (FFP; higher scores reflect greater frailty) before and repeatedly up to 36 months after transplant. We tested for changes in frailty scores over time using segmented mixed effects models, adjusting for age, sex, and diagnosis. We quantified the proportion of subjects transitioning between frailty states (frail vs not frail) from before to after the transplant. RESULTS In 246 subjects, changes in frailty occurred within the first 6 post-operative months and remained stable thereafter. The overall change in frailty was attributable to improvements among those subjects who were frail before transplant. They experienced a 5.1-point improvement in SPPB (95% confidence interval [CI] 4.6–5.7) and a 1.8-point improvement in FFP (95% CI −2.1 to −1.6) during the early period. Frailty by SPPB and FFP did not change in those who were not frail before transplant. Approximately 84% of survivors who were frail before transplant became not frail after transplant. CONCLUSIONS Pre-operative frailty resolves in many patients after lung transplantation. Because a large proportion of frailty may be attributable to advanced lung disease, frailty alone should not be an absolute contraindication to transplantation.

It is well established that high radon exposures increase the risk of lung cancer mortality. The effects of low occupational exposures and the factors that confound and modify this risk are not clear and are needed to inform current radiation protection of miners. The risk of lung cancer mortality at low radon exposures (

Genetic studies provide valuable information to assess if the effect of genetic variants varies by the nongenetic "environmental" variables, what is traditionally defined to be gene-environment interaction (GxE). A common complication is that multiple disease states present with the same set of symptoms, and hence share the clinical diagnosis. Because (a) disease states might have distinct genetic bases; and (b) frequencies of the disease states within the clinical diagnosis vary by the environmental variables, analyses of association with the clinical diagnosis as an outcome variable might result in false positive or false negative findings. We develop estimates for this setting to be able to assess GxE in a case-only study and we compare the case-control and case-only estimates. We report extensive simulation studies that evaluate empirical properties of the estimates and show the application to a study of Alzheimer's disease.

Author(s): Afshar, Armin R; Damato, Bertil E; Stewart, Jay M; Zablotska, Lydia B; Roy, Ritu; Olshen, Adam B; Joseph, Nancy M; Bastian, Boris C | Abstract: PurposeTo clinically use the UCSF500, a pancancer, next-generation sequencing assay in uveal melanoma (UM) and to correlate results with gene expression profiling (GEP) and predictive factors for metastasis.MethodsCohort study. Tumor samples of adult UM patients were analyzed with the UCSF500 and GEP. Main outcomes were copy number changes in chromosomes 1, 3, 6, and 8 and mutations in GNAQ, GNA11, SF3B1, EIF1AX, BAP1, SRSF2, U2AF1, and PLCB4. Chromosome 3 loss (a metastasis predictor) was tested for correlation with GEP class, tumor characteristics (largest basal diameter, thickness, ciliary body involvement, and extraocular extension), and histology (presence of epithelioid cells, closed loops, and mitotic count).ResultsThe 62 patients had a mean age of 59 years (range, 24-89 years). Chromosome 3 loss was detected in 30 patients and was associated with larger basal tumor diameter (Wilcoxon rank sum test, P = 0.015), greater thickness (Wilcoxon rank sum test, P = 0.016) and tumor, node, metastasis stage (Fisher test, P = 0.006), epithelioid cytology (Fisher test, P l 0.001), BAP1 mutation (Fisher test, P l 0.001), and chromosome 8q gain (Fisher test, P l 0.001). Class 2 tumors were much more likely to have chromosome 3 loss than class 1 (odds ratio, 121; P l 0.001). Eleven patients developed metastatic UM, of which five died during the study. All metastatic cases had chromosome 3 loss, 8 gain, BAP1 mutation, and class 2 GEP. Five class 1 tumors had chromosome 3 loss.ConclusionsUCSF500 detects chromosomal copy number changes and missense mutations that correlate strongly with metastasis predictors, including GEP.Translational relevanceNext-generation sequencing of UM should enhance survival prognostication.

Author(s): Karpov, Andrey; Takhauov, Ravil; Zerenkov, Andrey; Dolgopolov, Yuriy; Izmestev, Konstantin; Blinov, Aleksey; Zablotska, Lydia

Author(s): Rage, Estelle; Do, Minh; Demers, Paul A; Fenske, Nora; Kreuzer, Michaela; Laurier, Dominique; Samet, Jon; Schubauer-Berigan, Mary; Sobotzki, Christina; Tomasek, Ladislav; Zablotska, Lydia; Richardson, David

BackgroundWhile an increased risk of thyroid cancer from post-Chernobyl exposure to Iodine-131 (I-131) in children and adolescents has been well-documented, risks of other cancers or leukemia as a result of residence in radioactively contaminated areas remain uncertain.MethodsWe studied non-thyroid cancer incidence in a cohort of about 12,000 individuals from Belarus exposed under age of 18 years to Chernobyl fallout (median age at the time of Chernobyl accident of 7.9 years). During 15 years of follow-up from1997 through 2011, 54 incident cancers excluding thyroid were identified in the study cohort with 142,968 person-years at risk. We performed Standardized Incidence Ratio (SIR) analysis of all solid cancers excluding thyroid (n=42), of leukemia (n=6) and of lymphoma (n=6).ResultsWe found no significant increase in the incidence of non-thyroid solid cancer (SIR=0.83, 95% Confidence Interval [CI]: 0.61; 1.11), lymphoma (SIR=0.66, 95% CI: 0.26; 1.33) or leukemia (SIR=1.78, 95% CI: 0.71; 3.61) in the study cohort as compared with the sex-, age- and calendar-time-specific national rates. These findings may in part reflect the relatively young age of study subjects (median attained age of 33.4 years), and long latency for some radiation-related solid cancers.ConclusionsWe found no evidence of statistically significant increases in solid cancer, lymphoma and leukemia incidence 25 years after childhood exposure in the study cohort; however, it is important to continue follow-up non-thyroid cancers in individuals exposed to low-level radiation at radiosensitive ages.

Background Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. Methods A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). Results Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p

Background: Competency-based education is essential to prepare future nurse scientists to compete in the world of data-driven science. Yet, few schools of nursing have developed core competencies that guide quantitative research instruction. We described development of new competency-based curriculum in quantitative research for doctor of philosophy (PhD) nursing students. Method: We assessed quantitative research methods curricula from among top National Institutes of Health-ranked research-intensive Schools of Nursing. At the University of California, San Francisco School of Nursing, we administered a survey to PhD students and alumni, and interviewed program faculty about current quantitative courses and perceived needs. A committee of PhD faculty framed competencies. Results: Core competencies for quantitative methods training were developed. Faculty modified courses to align with core competencies. This allowed an outcome-based approach to design, implement, and evaluate coursework. Conclusion: This effort at generating core quantitative research skills competencies could be useful for other nursing schools interested in redesigning PhD training programs. [ J Nurs Educ. 2018;57(8):483–488.]

Purpose Long-term health risks of occupational exposures to uranium processing were examined to better understand potential differences with uranium underground miners and nuclear reactor workers. Methods A cohort study of mortality of workers from Port Hope, Canada (1950–1999) and Wismut, Germany (1946–2008) employed in uranium milling, refining, and processing was conducted. Poisson regression was used to evaluate the association between cumulative exposures to radon decay products (RDP) and gamma-rays and causes of death potentially related to uranium processing. Results The pooled cohort included 7431 workers (270,201 person-years of follow-up). Mean RDP exposures were lower than in miners while gamma-ray doses were higher than in reactor workers. Both exposures were highly correlated (weighted rho = 0.81). Radiation risks of lung cancer and cardiovascular diseases (CVD) in males were increased but not statistically significant and compatible with risks estimated for miners and reactor workers, respectively. Higher RDP-associated CVD risks were observed for exposures 5–14 years prior to diagnosis compared to later exposures and among those employed