The effect of bovine dairy products and their components on the incidence and natural history of infection: a systematic literature review.

BACKGROUND: Dairy products and their components may impact immune function, although the current evidence base has some research gaps. As part of a larger systematic literature review of dairy products/components (including probiotics, dairy proteins, and dairy fats) and immune function, we identified the available epidemiologic research on the impact of dairy products/components on incidence and natural history of infectious diseases. METHODS: PubMed and Embase databases were systematically searched through May 2022 to identify eligible studies using pre-defined Population, Intervention, Comparator, Outcomes, and Study design criteria. Herein, we focused on describing the impacts of dairy product/component on infectious disease outcomes, including the effect on leukocyte and cytokine response in humans. Risk of bias assessment was performed using the Academy of Nutrition and Dietetics Quality Criteria Checklist. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. RESULTS: Among 9,832 studies identified from the larger literature search, 133 relevant publications from 128 studies reported on dairy product/component and infectious disease outcomes. Few studies are available on the impact of non-fermented milk and traditional yogurt on infectious disease. Evidence was identified to suggest milk and yogurt drinks fermented with Lactobacillus strains reduce the risk and burden of common infectious diseases (CIDs), although the findings are mixed and difficult to reconcile due to heterogenous study populations, bacterial strains, and study methods. Few studies are available on the impact of dairy products/components on the natural history of infection, with the available findings indicating probiotics may both improve gastrointestinal symptoms among HIV-infected persons and help eradicate and alleviate the symptoms of Heliobacter (H.) pylori. The available evidence also suggests lactoferrin may reduce the virological burden of COVID-19 and hepatitis C virus. No consistent changes in leukocytes or cytokine production were observed for any type of dairy product or their components, but probiotics appeared to enhance natural killer cell levels/activity and the phagocytic process. CONCLUSIONS: Dairy products, particularly those with added probiotics, may represent an easily accessible nutritional intervention to prevent and improve the course of infectious diseases. This review highlights the need for additional research in this potentially impactful area. PROSPERO REGISTRATION: CRD42022333780.

The OPTIFAST total and partial meal replacement programme reduces cardiometabolic risk in adults with obesity: Secondary and exploratory analysis of the OPTIWIN study.

AIM: The effects of weight loss with a partial or total meal replacement programme (MRP) on atherosclerotic cardiovascular disease (ASCVD) risk factors are not fully understood, in particular in people at higher CV risk. In the 52-week randomized controlled OPTIWIN study in men and women with obesity, meal replacement programme (total for first 26 weeks, partial for the ensuing 26 weeks) with OPTIFAST (OP) resulted in significantly greater weight loss compared with a low-calorie food-based (FB) dietary plan, both as part of a comprehensive lifestyle intervention [OP (n = 135)/FB (n = 138) week 26: -12.4%/-6.0%, p < .001; week 52: -10.5%/-5.5%, p < .001]. Here, we examined effects on ASCVD risk factors and 10-year ASCVD risk. MATERIALS AND METHODS: Participants with body mass index 30-55 kg/m2 and age 18-70 years, and not on anti-obesity medications, were recruited. The effects on systolic and diastolic blood pressure (SBP, DBP), lipid parameters and 10-year ASCVD risk were analysed as changes over time using linear mixed models. Subgroup analyses were conducted for changes in SBP, DBP and ASCVD risk by categories of age (<40, 40-59, ≥60 years), baseline SBP (

Moon, Mars and Minds: Evaluating Parkinson's disease mortality among U.S. radiation workers and veterans in the million person study of low-dose effects.

BACKGROUND: Radiation is one of the most important stressors related to missions in space beyond Earth's orbit. Epidemiologic studies of exposed workers have reported elevated rates of Parkinson's disease. The importance of cognitive dysfunction related to low-dose rate radiation in humans is not defined. A meta-analysis was conducted of six cohorts in the Million Person Study (MPS) of low-dose health effects to learn whether there is consistent evidence that Parkinson's disease is associated with radiation dose to brain. MATERIALS AND METHODS: The MPS evaluates all causes of death among U.S. radiation workers and veterans, including Parkinson's disease. Systematic and consistent methods are applied to study all categories of workers including medical radiation workers, industrial radiographers, nuclear power plant workers, atomic veterans, and Manhattan Projects workers at the Los Alamos National Laboratory and at Rocky Flats. Consistent methods for all cohorts are used to estimate organ-specific doses and to obtain vital status and cause of death. RESULTS: The meta-analysis include 6 cohorts within the MPS, consisting of 517,608 workers and 17,219,001 person-years of observation. The mean dose to brain ranged from 6.9 to 47.6 mGy and the maximum dose from 0.76 to 2.7 Gy. Five of the 6 cohorts revealed positive associations with Parkinson's disease. The overall summary estimate from the meta-analysis was statistically significant based on 1573 deaths due to Parkinson's disease. The summary excess relative risk at 100 mGy was 0.17 (95% CI: 0.05; 0.29). CONCLUSIONS: Parkinson's disease was positively associated with radiation in the MPS cohorts indicating the need for careful evaluation as to causality in other studies, delineation of possible mechanisms, and assessing possible implications for space travel as well as radiation protection guidance for terrestrial workers.

Third mortality follow-up of the Mallinckrodt uranium processing workers, 1942-2019.

INTRODUCTION: Mallinckrodt Chemical Works was a uranium processing facility during the Manhattan Project from 1942 to 1966. Thousands of workers were exposed to low-dose-rates of ionizing radiation from external and internal sources. This third follow-up of 2514 White male employees updates cancer and noncancer mortality potentially associated with radiation and silica dust. MATERIALS AND METHODS: Individual, annualized organ doses were estimated from film badge records (n monitored = 2514), occupational chest x-rays (n = 2514), uranium urinalysis (n = 1868), radium intake through radon breath measurements (n = 487), and radon ambient measurements (n = 1356). Silica dust exposure from pitchblende processing was estimated (n = 1317). Vital status and cause of death determination through 2019 relied upon the National Death Index and Social Security Administration Epidemiological Vital Status Service. The analysis included standardized mortality ratios (SMRs), Cox proportional hazards, and Poisson regression models. RESULTS: Vital status was confirmed for 99.4% of workers (84.0% deceased). For a dose weighting factor of 1 for intakes of uranium, radium, and radon decay products, the mean and median lung doses were 65.6 and 29.9 mGy, respectively. SMRs indicated a difference in health outcomes between salaried and hourly workers, and more brain cancer deaths than expected [SMR: 1.79; 95% confidence interval (CI): 1.14, 2.70]. No association was seen between radiation and lung cancer [hazard ratio (HR) at 100 mGy: 0.93; 95%CI: 0.78, 1.11]. The relationship between radiation and kidney cancer observed in the previous follow-up was maintained (HR at 100 mGy: 2.07; 95%CI: 1.12, 3.79). Cardiovascular disease (CVD) also increased significantly with heart dose (HR at 100 mGy: 1.11; 95%CI: 1.02, 1.21). Exposures to dust ≥23.6 mg/m3-year were associated with nonmalignant kidney disease (NMKD) (HR: 3.02; 95%CI: 1.12, 8.16) and kidney cancer combined with NMKD (HR: 2.46; 95%CI: 1.04, 5.81), though without evidence of a dose-response per 100 mg/m3-year. CONCLUSIONS: This third follow-up of Mallinckrodt uranium processors reinforced the results of the previous studies. There was an excess of brain cancers compared with the US population, although no radiation dose-response was detected. The association between radiation and kidney cancer remained, though potentially due to few cases at higher doses. The association between levels of silica dust ≥23.6 mg/m3-year and NMKD also remained. No association was observed between radiation and lung cancer. A positive dose-response was observed between radiation and CVD; however, this association may be confounded by smoking, which was unmeasured. Future work will pool these data with other uranium processing worker cohorts within the Million Person Study.

Dietary eating patterns, dairy consumption, and anxiety: A systematic literature review.

BACKGROUND: Nutrition affects both physical and mental health but evidence is mixed regarding potential associations between anxiety and diet, particularly dairy consumption. We conducted a systematic literature review (SLR) of dairy consumption and/or various dietary patterns and risk of anxiety. METHODS: Literature searches were conducted in PubMed and Embase. All study designs except case reports, small case series, and SLRs were considered for inclusion. Reference lists of previously published SLRs were reviewed for any relevant additional studies. Studies of populations without dairy sensitivities exploring the association between dietary patterns and/or dairy consumption and anxiety published through May 2022 were identified using predefined eligibility criteria. Study quality was determined using the Academy of Nutrition and Dietetics Quality Criteria Checklist. RESULTS: For this SLR, 132 studies were included; 80 were cross-sectional. Studies examined different dietary patterns (e.g., Mediterranean, gluten-free) and anxiety using various anxiety scales, with 19 studies specifically reporting on whole dairy consumption and anxiety. Dairy consumption was significantly associated with a lower risk of anxiety in 7 studies, while the remaining 12 studies showed no significant associations. Evidence was mixed for the association between various dietary patterns and anxiety, but more studies observed a lower risk of anxiety with greater adherence to "healthy" diets (e.g., Mediterranean, diet quality score, vegetarian/vegan) than a higher risk. Notable heterogeneity in study populations, time periods, geographical locations, dietary assessment methods, and anxiety scales was observed. CONCLUSIONS: The results of this SLR suggest a potential link between diet including diary consumption and anxiety, but future studies, especially with longitudinal designs that measure diet and anxiety at several timepoints and comprehensively adjust for confounders, are needed to fully understand the relationship between diet and anxiety.

Updated systematic assessment of human, animal and mechanistic evidence demonstrates lack of human carcinogenicity with consumption of aspartame.

Aspartame has been studied extensively and evaluated for its safety in foods and beverages yet concerns for its potential carcinogenicity have persisted, driven primarily by animal studies conducted at the Ramazzini Institute (RI). To address this controversy, an updated systematic review of available human, animal, and mechanistic data was conducted leveraging critical assessment tools to consider the quality and reliability of data. The evidence base includes 12 animal studies and >40 epidemiological studies reviewed by the World Health Organization which collectively demonstrate a lack of carcinogenic effect. Assessment of >1360 mechanistic endpoints, including many guideline-based genotoxicity studies, demonstrate a lack of activity associated with endpoints grouped to key characteristics of carcinogens. Other non-specific mechanistic data (e.g., mixed findings of oxidative stress across study models, tissues, and species) do not provide evidence of a biologically plausible carcinogenic pathway associated with aspartame. Taken together, available evidence supports that aspartame consumption is not carcinogenic in humans and that the inconsistent findings of the RI studies may be explained by flaws in study design and conduct (despite additional analyses to address study limitations), as acknowledged by authoritative bodies.

Radiation and CNS effects: summary of evidence from a recent symposium of the Radiation Research Society.

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.

Mortality among Tennessee Eastman Corporation (TEC) uranium processing workers, 1943-2019.

BACKGROUND: There are few occupational studies of women exposed to ionizing radiation. During World War II, the Tennessee Eastman Corporation (TEC) operated an electromagnetic field separation facility of 1152 calutrons to obtain enriched uranium (235U) used for the Hiroshima atomic bomb. Thousands of women were involved in these operations. MATERIALS AND METHODS: A new study was conducted of 13,951 women and 12,699 men employed at TEC between 1943 and 1947 for at least 90 days. Comprehensive dose reconstruction techniques were used to estimate lung doses from the inhalation of uranium dust based on airborne measurements. Vital status through 2018/2019 was obtained from the National Death Index, Social Security Death Index, Tennessee death records and online public record databases. Analyses included standardized mortality ratios (SMRs) and Cox proportional hazards models. RESULTS: Most workers were hourly (77.7%), white (95.6%), born before 1920 (58.3%), worked in dusty environments (57.0%), and had died (94.9%). Vital status was confirmed for 97.4% of the workers. Women were younger than men when first employed: mean ages 25.0 years and 33.0 years, respectively. The estimated mean absorbed dose to the lung was 32.7 mGy (max 1048 mGy) for women and 18.9 mGy (max 501 mGy) for men. The mean dose to thoracic lymph nodes (TLNs) was 127 mGy. Statistically significant SMRs were observed for lung cancer (SMR 1.25; 95% CI 1.19, 1.31; n = 1654), nonmalignant respiratory diseases (NMRDs) (1.23; 95% CI 1.19, 1.28; n = 2585), and cerebrovascular disease (CeVD) (1.13; 95% CI 1.08, 1.18; n = 1945). For lung cancer, the excess relative rate (ERR) at 100 mGy (95% CI) was 0.01 (-0.10, 0.12; n = 652) among women, and -0.15 (-0.38, 0.07; n = 1002) among men based on a preferred model for men with lung doses <300 mGy. NMRD and non-Hodgkin lymphoma were not associated with estimated absorbed dose to the lung or TLN. CONCLUSIONS: There was little evidence that radiation increased the risk of lung cancer, suggesting that inhalation of uranium dust and the associated high-LET alpha particle exposure to lung tissue experienced over a few years is less effective in causing lung cancer than other types of exposures. There was no statistically significant difference in the lung cancer risk estimates between men and women. The elevation of certain causes of death such as CeVD is unexplained and will require additional scrutiny of workplace or lifestyle factors given that radiation is an unlikely contributor since only the lung and lymph nodes received appreciable dose.

Mortality among medical radiation workers in the United States, 1965-2016.

BACKGROUND: Estimates of radiation risks following prolonged exposures at low doses and low-dose rates are uncertain. Medical radiation workers are a major component of the Million Person Study (MPS) of low-dose health effects. Annual personal dose equivalents, HP(10), for individual workers are available to facilitate dose-response analyses for lung cancer, leukemia, ischemic heart disease (IHD) and other causes of death. MATERIALS AND METHODS: The Landauer, Inc. dosimetry database identified 109,019 medical and associated radiation workers first monitored 1965-1994. Vital status and cause of death were determined through 2016. Mean absorbed doses to red bone marrow (RBM), lung, heart, and other organs were estimated by adjusting the recorded HP(10) for each worker by scaling factors, accounting for exposure geometry, the energy of the incident photon radiation, sex of the worker and whether an apron was worn. There were 4 exposure scenarios: general radiology characterized by low-energy x-ray exposure with no lead apron use, interventional radiologists/cardiologists who wore aprons, nuclear medicine personnel and radiation oncologists exposed to high-energy photon radiation, and other workers. Standardized mortality ratio (SMR) analyses were performed. Cox proportional hazards models were used to estimate organ-specific radiation risks. RESULTS: Overall, 11,433 deaths occurred (SMR 0.60; 95%CI 0.59,0.61), 126 from leukemia other than chronic lymphocytic leukemia (CLL), 850 from lung cancer, and 1654 from IHD. The mean duration of monitoring was 23.7 y. The excess relative rate (ERR) per 100 mGy was estimated as 0.10 (95% CI -0.34, 0.54) for leukemia other than CLL, 0.15 (0.02, 0.27) for lung cancer, and -0.10 (-0.27, 0.06) for IHD. The ERR for lung cancer was 0.16 (0.01, 0.32) among the 55,218 male workers and 0.09 (-0.19, 0.36) among the 53,801 female workers; a difference that was not statistically significant (p-value = 0.23). CONCLUSIONS: Medical radiation workers were at increased risk for lung cancer that was higher among men than women, although this difference was not statistically significant. In contrast, the study of Japanese atomic bomb survivors exposed briefly to radiation in 1945 found females to be nearly 3 times the radiation risk of lung cancer compared with males on a relative scale. For medical workers, there were no statistically significant radiation associations with leukemia excluding CLL, IHD or other specific causes of death. Combining these data with other cohorts within the MPS, such as nuclear power plant workers and nuclear submariners, will enable more precise estimates of radiation risks at relatively low cumulative doses.

Benefit-risk of coffee consumption and all-cause mortality: A systematic review and disability adjusted life year analysis.

BACKGROUND: Recommendations and guidance from scientific bodies do not provide clear messages about potential health risks or benefits of coffee consumption. Numerous studies have demonstrated inverse (beneficial) effects of coffee consumption for many adverse outcomes such as cancer and cardiovascular disease; fewer studies demonstrate risks. However, the risk-benefit relationship has not yet been fully assessed using quantitative metrics preferred by policy makers (disability-adjusted life years [DALYs]). OBJECTIVE: Conduct a quantitative analysis of the risk-benefit for coffee consumption and all-cause mortality using the Benefit-Risk Analysis for Foods (BRAFO) framework and the DALY as a quantitative metric. METHOD: A systematic search and appraisal of meta-analyses investigating coffee consumption and all-cause mortality was conducted. Using the BRAFO framework, evidence was assessed in context of potential risks or benefits associated with the reference scenario - coffee consumption (assessed by varying the consumption level in three analyses) in adults aged 15+ versus the alternative scenario of no coffee consumption. DALYs were used to quantify risks and benefits based on risk ratios from meta-analyses with populations from the United States. RESULTS: Meta-analyses consistently report an inverse (beneficial) relationship between coffee consumption and all-cause mortality; subsequently, even while varying consumption amounts and prevalence of coffee consumption, DALYs calculated consistently demonstrated findings in the direction of prevention of healthy years of life lost with variable magnitude. More than 3.5 million DALYs, or ∼3.35% of estimated years of healthy life lost could be prevented by consuming one cup of coffee per day, up to 4.7% of estimated years of healthy life lost could be prevented at current consumption rates ranging from 1 to 8 cups/day, and even more benefit could be seen (prevention of an estimated 6% of years of healthy life lost) if consumers all drank 3 cups of coffee per day. IMPACT: Policy that directs consumers to avoid drinking coffee may be a detriment to the overall health of the population given the substantial potential benefits of coffee consumption on all-cause mortality for adults.

Theoretical attributable risk analysis and Disability Adjusted Life Years (DALYs) based on increased dairy consumption.

BACKGROUND: Identification of modifiable risk factors that may impact chronic disease risk is critical to public health. Our study objective was to conduct a theoretical population attributable risk analysis to estimate the burden of disease from low dairy intake and to estimate the impact of increased dairy intake on United States (US)-based disability adjusted life years (DALYs). METHODS: We conducted a comprehensive literature review to identify statistically significant summary relative risk estimates (SRREs) from recent meta-analyses of dairy consumption and key chronic disease outcomes. The SRREs were applied to preventive fractions using a range of categories (low to high) for population consumption of dairy products. The preventive fraction estimates were then applied to the number of DALYs for each health outcome in the US based on 2019 WHO estimates. The population attributable risk proportion estimates were calculated using the inverse of the SRRE from each meta-analysis using the same range of categories of consumption. These values were subsequently applied to the DALYs estimates to estimate the theoretical burden of disease attributable to low dairy intake. RESULTS: Statistically significant SRREs were identified in recent meta-analyses of total dairy consumption in relation to breast cancer, colorectal cancer, cardiovascular disease (CVD), type 2 diabetes (T2D), stroke, and hypertension. In this theoretical analysis, nearly 850,000 DALYs (or 5.0% of estimated years of healthy life lost) due to CVD and 200,000 DALYs (4.5%) due to T2D may be prevented by increased dairy consumption. Approximately 100,000 DALYs due to breast cancer (7.5%) and approximately 120,000 DALYs (8.5%) due to colorectal cancer may be prevented by high dairy intake. The numbers of DALYs for stroke and hypertension that may be prevented by increased dairy consumption were approximately 210,000 (6.0%) and 74,000 (5.5%), respectively. CONCLUSIONS: Consumption of dairy products has been associated with decreased risk of multiple chronic diseases of significant public health importance. The burden of disease that may potentially be prevented by increasing dairy consumption is substantial, and population-wide improvement in meeting recommended daily dairy intake goals could have a notable public health impact. However, this analysis is theoretical, and thus additional studies providing empirical evidence are needed to further clarify potential relationships between dairy intake and various health outcomes.

Characterizing a Clinical Trial - Representative, Real-World Population with Heart Failure with Reduced Ejection Fraction.

PURPOSE: Given known differences between real-world and clinical trial populations, we characterized demographics, clinical characteristics, and outcomes using real-world (RW) data for patients with heart failure with reduced ejection fraction (HFrEF), including those similar to subjects enrolled in an HFrEF clinical trial to better understand patient populations that could benefit from novel therapies. PATIENTS AND METHODS: Using Vanderbilt University Medical Center electronic health records (2006-2019), two RW cohorts of HFrEF patients were identified. The "Clinical Cohort" was based on a validated HFrEF algorithm and left ventricular ejection fraction (LVEF) ≤40%. The "GALACTIC-HF-like Cohort" mirrored enrollment requirements of the GALACTIC-HF clinical trial including hospitalizations, medications, laboratory values, and LVEF ≤35%. RESULTS: Median age at index for the Clinical Cohort (N = 3954) and GALACTIC-HF-like Cohort (N = 1541) were 65 and 61 years, respectively; both were 67% male and 80% white. Over half had coronary artery disease (55% Clinical vs 64% GALACTIC-HF-like); hypercholesterolemia was common (69% Clinical vs 74% GALACTIC-HF-like). Chronic kidney disease (31 vs 21%), atrial fibrillation (32 vs 29%), and cardiac resynchronization or implantable cardioverter defibrillator (26 vs 23%) were higher in the GALACTIC-HF-like Cohort. ACE inhibitor use was high in both groups but more common in the GALACTIC-HF-like Cohort (71% and 82%, respectively). Beta-blockers or loop diuretics were used by >90% of both cohorts. HF hospitalization rates were 261 (95% CI 224, 297) per 1000 person-years in Clinical versus 523 (484, 562) in GALACTIC-HF-like Cohort (median follow-up of 2.9 and 4.2 years, respectively). CONCLUSION: Approximately 40% of RW HFrEF patients met criteria for the GALACTIC-HF trial. While findings of ongoing clinical trials may be directly generalizable to this sizable proportion of patients, future trials should examine whether the majority of patients with lower prevalence of comorbidities and rate of HF hospitalization could benefit from emerging HF treatments.

Relation of the Dietary Approaches to Stop Hypertension Dietary Pattern to Heart Failure Risk and Socioeconomic Status (from the Southern Community Cohort Study).

The Dietary Approaches to Stop Hypertension (DASH) dietary pattern has been associated with a lower risk of incident heart failure (HF); however, previous studies were conducted in mostly middle-income White populations. The association between DASH and incident HF risk in lower income and Black individuals is less well understood. We analyzed 25,300 White and Black adults without a history of HF at enrollment (2002 to 2009) in the Southern Community Cohort Study receiving Centers for Medicare and Medicaid Services. Alignment with DASH was assessed at enrollment using a validated food frequency questionnaire. Incident HF was ascertained from Centers for Medicare and Medicaid Services claims through 2016. The association between DASH diet alignment and incident HF was examined in multivariable-adjusted Cox proportional hazards regression models, including an interaction term testing effect modification by income. The cohort was predominantly middle-aged (median 54 years), Black (68%), female (63%), and low-income (88% <$25,000/year/household). Socioeconomic factors, including education and annual income, were larger contributors to the variance in DASH score than were cardiovascular co-morbidities. The association between DASH dietary alignment and HF risk was not significant overall (hazard ratio [HR] 1.00; 95% confidence interval [CI] 0.96 to 1.04) or in race-sex groups. However, the association between alignment with the DASH diet and HF risk significantly varied by income (interaction p = 0.030), with neutral and inverse associations in lower (<$25,000/year) and higher ($≥25,000) income participants, respectively. In conclusion, income modified the association between healthier dietary patterns and risk of incident HF. In lower income participants, greater alignment with the DASH diet was not associated with lower HF risk.

Obtaining vital status and cause of death on a million persons.

PURPOSE: To present the methodology used to determine vital status and obtain cause of death (COD) within the Million Person Study of Low-Dose Health Effects (MPS). Data sources and vital status tracing techniques used to obtain vital status and COD for six (n = 424,238 subjects) of the ∼20+ cohorts under study are described. METHODS AND MATERIALS: A multistage approach using multiple sources of vital status information was used to determine vital status (or 'trace') study participants from as early as 1940 to the present. Mortality records from state departments of vital statistics and the Social Security Administration Death Master File (SSA-DMF) were matched to study participants by Social Security Number (SSN), full name, date of birth (DOB), and/or sex using deterministic and probabilistic algorithms. The National Death Index (NDI) and SSA Service for Epidemiological Researchers (SSA-SER) were used to obtain COD (after 1978) and verification of alive status, respectively. Online public records and ancestry services, death certificates, and specialized mortality sources were also utilized. RESULTS: For the MPS cohorts traced to date (nuclear power plant workers, industrial radiographers, atomic veterans, and workers at Rocketdyne/Atomics International, Mound nuclear facility, and Mallinckrodt Chemical Works), vital status was confirmed for over 90% of all study subjects in all but one cohort (88%). The ascertainment of COD was over 96% for all cohorts. CONCLUSIONS: A hallmark of a high-quality epidemiologic cohort mortality study is a low percentage of subjects with unknown vital status and a low percentage of deaths without a COD. The sources and methods used for vital status tracing and COD determination for the MPS have been successful and should be useful for other investigators tracing large, historic study populations. Some of the approaches would be applicable for use in all cohort studies using regional-specific mortality data or modifications to the approach.

Validating the use of census data on education as a measure of socioeconomic status in an occupational cohort.

PURPOSE: Adjusting for smoking status or a reliable surrogate [such as socioeconomic status (SES)] is critically important in occupational epidemiology studies when any smoking-related cancer or cardiovascular disease is an outcome of interest. Sometimes, however, data on smoking patterns or individual-level smoking surrogates such as job title, education, pay scale or other measures of SES are not readily available in occupational cohorts. METHODS AND MATERIALS: To obtain a surrogate measure for missing smoking or individual-level SES data, we demonstrate a method used to obtain and geocode residential address histories which were then linked to area-level SES measures from the United States Census in three test samples and then in a full cohort of workers from the Mound nuclear weapons facility in Dayton, Ohio, USA. The mean educational attainment of the Census Block Group was used to derive a categorical estimate of educational attainment which was compared to self-reported (SR) education available from Mound worker histories using Kappa statistics. Lung cancer mortality patterns between area-derived (AD) and SR education were investigated using Standardized Mortality Ratios (SMR) and Cox Proportional Hazards models with stratification or adjustment by either SR or AD education. RESULTS: Home address histories were obtained from linkages of individual worker data to online resources. In the test cohorts, mean educational attainment was the Census Block Group measure found to have the largest magnitude association with individual-level SES measures. Among 7251 Mound workers, 5685 (78.4%) had at least one residential address match (mean 4.9 addresses) identified. The SR and AD educational attainment measures were highly correlated (weighted Kappa coefficient 0.10, p < .0001). SMR patterns by SR and AD educational attainment were similar, with steadily decreasing mortality with increased educational attainment by either measure. Cox models for lung cancer using AD education produced similar results as those using SR education as an adjustment factor. CONCLUSION: When individual-level SES indicators are not available for statistical adjustment, area-level SES measures can serve as a reliable surrogate when investigating outcomes that are affected by lifestyle factors such as smoking.

Evaluation of statistical modeling approaches for epidemiologic studies of low-dose radiation health effects.

PURPOSE: A substantial body of epidemiologic literature addresses risks associated with occupational radiation exposure but comparing results between studies is often difficult as different statistical models are commonly used. It is unclear whether different methods produce similar results for estimates of radiation risk when applied to the same data. The goal of this study was to compare the radiation risk estimates for leukemia other than chronic lymphocytic leukemia (non-CLL) and ischemic heart disease (IHD) produced by both Cox and Poisson regression models for time-dependent dose-response analyses of occupational exposure. MATERIALS AND METHODS: For brevity, this methods paper presents the results from one cohort, the Nuclear Power Plant workers (NPP), though the evaluation considered five cohorts of varying size and exposure as part of the Million Worker Study. Cox Proportional Hazards models, with age as the underlying timescale for hazard, were conducted using three computer software programs: SAS, R, and Epicure. Doses lagged 2 years for non-CLL and 10 years for ischemic heart disease were treated as time-dependent exposures at the annual level and were examined both in categories and as a continuous term. Hazard ratios (HR) and 95% confidence intervals (CI) were reported for each model in SAS and R, while the Peanuts program of Epicure was utilized to produce Excess Relative Risk (ERR) estimates and 95% CI. All models were adjusted for gender and year of birth. Four piece-wise exponential Poisson models (log-linear regression for rate) were developed with varying cutpoints for age strata from very fine to broad categories using both R and the Amfit program in Epicure for ERR estimates. RESULTS: Comparable estimates of risk (both RR and ERR) were observed from Cox and Poisson models, regardless of software utilized, as long as appropriately narrow categories of age were utilized to control the confounding of age in Poisson models. The ERR estimates produced in Epicure tended to agree very closely with the HR or RR estimates, and the statistical software program used had no impact to risk estimates for the same model. CONCLUSIONS: As computational power is no longer the burden today as it has been in the past, the results of this evaluation support the use of the Cox proportional hazards or the ungrouped Poisson approach to analyzing time-dependent dose-response relationships to ensure that maximum control over the confounding of age is achieved in studies of mortality for cohorts occupationally exposed to radiation.

Sex-specific lung cancer risk among radiation workers in the million-person study and patients TB-Fluoroscopy.

BACKGROUND: The 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 MATERIALS: Five 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. RESULTS: Overall, 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. CONCLUSIONS: There 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.

Updated mortality analysis of the Mallinckrodt uranium processing workers, 1942-2012.

PURPOSE: Mallinckrodt Chemical Works (MCW) was the earliest uranium processing facility in the United States, and in 1942 produced the uranium oxide used for the first sustained and controlled nuclear fission chain-reaction at the University of Chicago. A second follow-up through 2012 was conducted of 2514 White male workers employed 1942-1966 at the MCW for dose-response analyses for selected causes of death. MATERIALS AND METHODS: Organ/tissue-specific dose reconstruction included both external (12,686 MCW film badge records, 210 other facility film badge records, and 31,297 occupational chest x-rays) and internal sources of uranium and radium (39,451 urine bioassays, 2341 breath radon measurements, and 6846 ambient radon measurements). Dust measurements from pitchblende facilitated quantitative risk estimates for non-radiogenic effects on the lung and kidney. Vital status was determined from multiple sources including the National Death Index and the Social Security Administration. Cox regression models were used for dose response analyses. RESULTS: Vital status was determined for 99% of the workers, of whom 75% had died. The mean lung dose from all sources of external and internal radiation combined was 69.9 mGy (maximum 885 mGy; percent workers >100 mGy, 10%) and there was no evidence for a dose response for lung cancer (Hazard Ratio (HR) of 0.95 (95% CI = 0.81-1.12) at 100 mGy). A significant association with radiation was found for kidney cancer (HR of 1.73 (95% CI = 1.04-2.79) at 100 mGy) and suggested for nonmalignant kidney diseases (HR of 1.30 (95% CI = 0.96-1.76) at 100 mGy). A non-radiation etiology could not be discounted, however, because of the possible renal toxicities of uranium, a heavy metal, and silica, a component of pitchblende dust. Non-significant HRs at 100 mGy for other sites of a priori interest were 0.36 (0.06-2.03) for leukemia other than CLL, 0.68 (0.17-2.77) for liver cancer, and 1.23 (0.79-1.90) for non-Hodgkin lymphoma. The HR at 100 mGy was 1.09 (0.99-1.20) for ischemic heart disease. An association was seen between dust and combined malignant and non-malignant lung disease, HR at 10 mgm-3year-1 of 1.01 (1.00-1.02). CONCLUSIONS: A positive radiation dose response was observed for malignant and non-malignant kidney disease, and a negative dose response for malignant and non-malignant lung disease. Cumulative measures of dust were significantly associated with malignant and non-malignant lung disease and suggested for malignant and non-malignant kidney disease. Small numbers preclude definitive interpretations which will await the combination with similar studies of early uranium processing workers.