A Million Person Study Innovation: Evaluating Cognitive Impairment and other Morbidity Outcomes from Chronic Radiation Exposure Through Linkages with the Centers for Medicaid and Medicare Services Assessment and Claims Data.

The study of One Million U.S. Radiation Workers and Veterans, the Million Person Study (MPS), examines the health consequences, both cancer and non-cancer, of exposure to ionizing radiation received gradually over time. Recently the MPS has focused on mortality patterns from neurological and behavioral conditions, e.g., Parkinson's disease, Alzheimer's disease, dementia, and motor neuron disease such as amyotrophic lateral sclerosis. A fuller picture of radiation-related late effects comes from studying both mortality and the occurrence (incidence) of conditions not leading to death. Accordingly, the MPS is identifying neurocognitive diagnoses from fee-for-service insurance claims from the Centers for Medicare and Medicaid Services (CMS), among Medicare beneficiaries beginning in 1999 (the earliest date claims data are available). Linkages to date have identified ∼540,000 workers with available health information. Such linkages provide individual information on important co-factor and confounding variables such as smoking, alcohol consumption, blood pressure, obesity, diabetes and many other health and demographic characteristics. The total person-level set of time-dependent variables, outcomes, organ-specific dose measures, co-factors, and demographics will be massive and much too large to be evaluated with standard software. Thus, development of specialized open-source software designed for large datasets (Colossus) is nearly complete. The wealth of information available from CMS claims data, coupled with individual dose reconstructions, will thus greatly enhance the quality and precision of health evaluations for this new field of low-dose radiation and neurocognitive effects.

Assessing the impact of neutron relative biological effectiveness on all solid cancer mortality risks in the Japanese atomic bomb survivors.

PURPOSE: Risk analyses, based on relative biological effectiveness (RBE) estimates for neutrons relative to gammas, were performed; and the change in the curvature of the risk to dose response with increasing neutron RBE was analyzed using all solid cancer mortality data from the Radiation Effect Research Foundation (RERF). Results were compared to those based on incidence data. MATERIALS AND METHODS: This analysis is based on RERF mortality data with separate neutron and gamma doses for colon doses, from which organ averaged doses could be calculated. A model for risk ratio variation with RBE was developed. RESULTS: The best estimate of the neutron RBE considering mortality data was 200 (95% confidence interval (CI): 50-1010) for colon dose using the weighted-dose approach and for organ averaged dose 110 (95% CI: 30-350). The ERR risk ratios for all solid cancers combined, for the best fitting neutron RBE estimate and the neutron RBE of 10 result in a ratio of 0.54 (95% CI: 0.17-0.85) for colon dose and 0.55 (95% CI: 0.18-0.87) for organ averaged dose. The risk to dose response curvature became significantly negative (concave down) with increasing RBE, at a neutron RBE of 170 using colon dose and at an RBE of 90 using organ averaged dose for males when fitting a linear-quadratic dose response. For females, the curvature decreased toward linearity with increasing neutron RBE and remained significantly positive until RBE of 80 and 40 using colon and organ averaged dose, respectively. For higher neutron RBEs, no significant conclusion could be drawn about the shape of the dose-response curve. CONCLUSIONS: Application of neutron RBE values higher than 10 results in substantially reduced cancer mortality risk estimates and a significant reduction in curvature of the risk to dose responses for males. Using mortality data, the best fitting neutron RBE is much higher than when incidence data is used. The neutron RBE ranges covered by the overlap in the CIs from both the mortality and incidence analyses are 50-190 using colon dose and in all cases, the best fitting neutron RBE and lower 95% CI are higher than the value of 10 traditionally applied by the RERF. Therefore, it is recommended to consider uncertainties in neutron RBE values when calculating radiation risks and discussing the shape of dose responses using Japanese A-bomb survivors data.

Application of multi-method-multi-model inference to radiation related solid cancer excess risks models for astronaut risk assessment.

The impact of including model-averaged excess radiation risks (ER) into a measure of radiation attributed decrease of survival (RADS) for the outcome all solid cancer incidence and the impact on the uncertainties is demonstrated. It is shown that RADS applying weighted model averaged ER based on AIC weights result in smaller risk estimates with narrower 95% CI than RADS using ER based on BIC weights. Further a multi-method-multi-model inference approach is introduced that allows calculating one general RADS estimate providing a weighted average risk estimate for a lunar and a Mars mission. For males the general RADS estimate is found to be 0.42% (95% CI: 0.38%; 0.45%) and for females 0.67% (95% CI: 0.59%; 0.75%) for a lunar mission and 2.45% (95% CI: 2.23%; 2.67%) for males and 3.91% (95% CI: 3.44%; 4.39%) for females for a Mars mission considering an age at exposure of 40 years and an attained age of 65 years. It is recommended to include these types of uncertainties and to include model-averaged excess risks in astronaut risk assessment.

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.

European astronaut radiation related cancer risk assessment using dosimetric calculations of organ dose equivalents.

An illustrative sample mission of a Mars swing-by mission lasting one calendar year was chosen to highlight the application of European risk assessment software to cancer (all solid cancer plus leukaemia) risks from radiation exposures in space quantified with organ dose equivalent rates from model calculations based on the quantity Radiation Attributed Decrease of Survival (RADS). The relevant dose equivalent to the colon for radiation exposures from this Mars swing-by mission were found to vary between 198 and 482 mSv. These doses depend on sex and the two other factors investigated here of: solar activity phase (maximum or minimum); and the choice of space radiation quality factor used in the calculations of dose equivalent. Such doses received at typical astronaut ages around 40 years old will result in: the probability of surviving until retirement age (65 years) being reduced by a range from 0.38% (95%CI: 0.29; 0.49) to 1.29% (95%CI: 1.06; 1.56); and the probability of surviving cancer free until retirement age being reduced by a range from 0.78% (95%CI: 0.59; 0.99) to 2.63% (95%CI: 2.16; 3.18). As expected from the features of the models applied to quantify the general dosimetric and radiation epidemiology parameters, the cancer incidence risks in terms of surviving cancer free, are higher than the cancer mortality risks in terms of surviving, the risks for females are higher than for males, and the risks at solar minimum are higher than at solar maximum.

A Hybrid Effectiveness/Implementation Clinical Trial of Adherence to Long-Term Oxygen Therapy for Chronic Obstructive Pulmonary Disease.

Rationale: Interventions to promote adherence to long-term oxygen therapy (LTOT) in chronic obstructive pulmonary disease (COPD) are needed. Objectives: To examine the real-world effectiveness of phone-based peer coaching on LTOT adherence and other outcomes in a pragmatic trial of patients with COPD. Methods: In a hybrid effectiveness/implementation pragmatic trial, patients were randomized to receive phone-based proactive coaching (educational materials, five phone-based peer coaching sessions over 60 d), reactive coaching (educational materials, peer coaching when requested), or usual care. Study staff members collected baseline and outcome data via phone at 30, 60, and 90 days after randomization. Adherence to LTOT over 60 days, the primary effectiveness outcome, was defined as mean LTOT use ⩾17.7 h/d. LTOT use was calculated using information about home oxygen equipment use in worksheets completed by study participants. Comparisons of adherence to LTOT between each coaching group and the usual care group using multivariable logistic regression models were prespecified as the primary analyses. Secondary effectiveness outcomes included Patient Reported Outcome Management Information System measures for physical, emotional, and social health. We assessed early implementation domains in the reach, adoption, and implementation framework. Results: In 444 participants, the proportions who were adherent to LTOT at 60 days were 74% in usual care, 84% in reactive coaching, and 70% in proactive coaching groups. Although reach, adoption by stakeholder partners, and intervention fidelity were acceptable, complete LTOT adherence data were available in only 73% of participants. Reactive coaching (adjusted odds ratio, 1.77; 97.5% confidence interval, 0.80-3.90) and proactive coaching (adjusted odds ratio, 0.70; 97.5% confidence interval, 0.34-1.46) did not improve adherence to LTOT compared with usual care. However, proactive coaching significantly reduced depressive symptoms and sleep disturbance compared with usual care and reduced depressive symptoms compared with reactive coaching. Unexpectedly, LTOT adherence was significantly lower in the proactive compared with the reactive coaching group. Conclusions: The results were inconclusive about whether a phone-based peer coaching strategy changed LTOT adherence compared with usual care. Further studies are needed to confirm the potential benefits of proactive peer coaching on secondary effectiveness outcomes and differences in LTOT adherence between proactive and reactive peer coaching. Clinical trial registered with ClinicalTrials.gov (NCT02098369).

Comparison and multi-model inference of excess risks models for radiation-related solid cancer.

In assessments of detrimental health risks from exposures to ionising radiation, many forms of risk to dose-response models are available in the literature. The usual practice is to base risk assessment on one specific model and ignore model uncertainty. The analysis illustrated here considers model uncertainty for the outcome all solid cancer incidence, when modelled as a function of colon organ dose, using the most recent publicly available data from the Life Span Study on atomic bomb survivors of Japan. Seven recent publications reporting all solid cancer risk models currently deemed plausible by the scientific community have been included in a model averaging procedure so that the main conclusions do not depend on just one type of model. The models have been estimated with different baselines and presented for males and females at various attained ages and ages at exposure, to obtain specially computed model-averaged Excess Relative Risks (ERR) and Excess Absolute Risks (EAR). Monte Carlo simulated estimation of uncertainty on excess risks was accounted for by applying realisations including correlations in the risk model parameters. Three models were found to weight the model-averaged risks most strongly depending on the baseline and information criteria used for the weighting. Fitting all excess risk models with the same baseline, one model dominates for both information criteria considered in this study. Based on the analysis presented here, it is generally recommended to take model uncertainty into account in future risk analyses.

Towards sustainable human space exploration-priorities for radiation research to quantify and mitigate radiation risks.

Human spaceflight is entering a new era of sustainable human space exploration. By 2030 humans will regularly fly to the Moon's orbit, return to the Moon's surface and preparations for crewed Mars missions will intensify. In planning these undertakings, several challenges will need to be addressed in order to ensure the safety of astronauts during their space travels. One of the important challenges to overcome, that could be a major showstopper of the space endeavor, is the exposure to the space radiation environment. There is an urgent need for quantifying, managing and limiting the detrimental health risks and electronics damage induced by space radiation exposure. Such risks raise key priority topics for space research programs. Risk limitation involves obtaining a better understanding of space weather phenomena and the complex radiation environment in spaceflight, as well as developing and applying accurate dosimetric instruments, understanding related short- and long-term health risks, and strategies for effective countermeasures to minimize both exposure to space radiation and the remaining effects post exposure. The ESA/SciSpacE Space Radiation White Paper identifies those topics and underlines priorities for future research and development, to enable safe human and robotic exploration of space beyond Low Earth Orbit.

Assessing the impact of different neutron RBEs on the all solid cancer radiation risks obtained from the Japanese A-bomb survivors data.

PURPOSE: Development of a model characterizing risk variation with RBE to investigate how the incidence risk for all solid cancers combined varies with higher neutron RBEs and different organ dose types. MATERIAL AND METHODS: The model is based on RERF data with separate neutron and gamma dose information. RESULTS: For both additive and multiplicative linear excess risks per unit organ averaged dose, a reduction of 50% in the risk coefficient per weighted dose arises when a neutron RBE of 110 is used instead of 10. Considering risk per unit liver dose, this reduction occurs for an RBE of 130 and for risks per unit colon dose for an RBE of 190. The change in the shape of the dose response curve when using higher neutron RBEs is evaluated. The curvature changed and became significantly negative for males at an RBE of 140 for colon dose, 100 for liver dose and 80 for organ averaged dose. For females this is the case at an RBE of 110, 80 and 60, respectively. CONCLUSIONS: Uncertainties in neutron RBE values should be considered when radiation risks and the shape of dose responses are deduced from cancer risk data from the atomic bomb survivors.

Tobacco industry ownership of pharmaceutical companies: an international survey of people with respiratory disease.

The 2021 purchase of the respiratory pharmaceutical company Vectura by Phillip Morris International has been criticised by the public health and medical community, as a conflict of interest, with little input to date, from the patient community or the public. To address this gap, the COPD Foundation, along with global partners, surveyed 1196 people with chronic respiratory disease. 70% were bothered by a tobacco company making an inhaler to treat lung conditions and 48% reported that they would want to switch inhalers if they knew that a tobacco company made or sold their inhaler devices. Patients care about who makes the therapies used to treat their diseases.

The effect of COVID-19 on children with congenital talipes equinovarus in a tertiary service in the United Kingdom.

During the coronavirus disease 2019 (COVID-19) pandemic, many aspects of healthcare have been hindered. The primary aim of this study was to identify what the impact of COVID-19 was on the delivery of outpatient care for children with congenital talipes equinovarus deformity (CTEV) at a large tertiary hospital in the UK. This study reviewed the patients who commenced their Ponseti treatment between March and September 2020, representing the cohort who received hands-on care during the first wave of the COVID-19 pandemic. Equivalent 6-month periods were searched in 2019 and 2018 as control cohorts. This study included a total of 45 children (72 affected feet) presenting for treatment of clubfoot. Twenty-three babies were seen with CTEV in 2020. For the same time period in 2018 and 2019, 11 babies were treated each year. The distance commuted to by families was higher in 2020 compared to 2019 and 2018, although the difference did not reach statistical significance (P = 0.301). Treatment with Ponseti casting was commenced at a mean age of 52 days, with no statistically significant differences between cohorts (P = 0.758). Using strict precautions, the Ponseti service at a large tertiary hospital in the UK grew in size and successfully provided treatment for children presenting with CTEV during the first wave of the COVID-19 pandemic. This study has shown that with careful protocols in place, children with CTEV can be treated successfully during times of pandemic, thereby reducing the post-pandemic burden of older children requiring treatment.

Can volumetric modulated arc radiation therapy reduce organ at risk dose in stage 4 sinonasal tumors in dogs treated with boost irradiation?

Intensity modulated radiation therapy (IMRT) introduced marked changes to cancer treatment in animals by reducing dose to organs at risk (OAR). As the next technological step, volumetric modulated arc therapy (VMAT) has advantages (increased degrees-of-freedom, faster delivery) compared to fixed-field IMRT. Our objective was to investigate a possible advantage of VMAT over IMRT in terms of lower OAR doses in advanced-disease sinonasal tumors in dogs treated with simultaneously-integrated boost radiotherapy. A retrospective, analytical, observational study design was applied using 10 pre-existing computed tomography datasets on dogs with stage 4 sinonasal tumors. Each dataset was planned with both, 5-field IMRT and 2 arc VMAT with 10x4.83 Gy to the gross tumor volume and 10x4.2 Gy to the planning target volume. Adequate target dose coverage and normal tissue complication probability of brain ≤5% was required. Dose constraints aspired to were D60 <15 Gy for eyes, D2 <35.4 Gy for corneae, and Dmean <20 Gy for lacrimal glands. OAR dose was statistically significantly higher in IMRT plans than in VMAT plans. Median eye D60% was 18.5 Gy (interquartile range (IQR) 17.5) versus 16.1 Gy (IQR 7.4) (p = 0.007), median lacrimal gland dose 21.8 Gy (IQR 20.5) versus 18.6 Gy (IQR 7.0) (p = 0.013), and median cornea D2% 45.5 Gy (IQR 6.8) versus 39.9 Gy (IQR 10.0) (p<0.005) for IMRT versus VMAT plans, respectively. Constraints were met in 21/40 eyes, 7/40 corneae, and 24/40 lacrimal glands. Median delivery time was significantly longer for IMRT plans than for VMAT plans (p<0.01). Based on these results, VMAT plans were found to be superior in sparing doses to eyes, lacrimal glands, corneae. However, not all ocular OAR constraints could be met while ensuring adequate dose coverage and restricting brain toxicity risk for both planning techniques.

Valid versus invalid radiation cancer risk assessment methods illustrated using Swiss population data.

After the nuclear accident in Fukushima, the public interest in radiation related cancer-risk assessment increased. However, interpretations of results from epidemiological studies and comprehension of cancer risk assessment methods can be unclear and involve questions about correctness and validity of the approaches. To shed some light on this potential lack of clarity, valid versus invalid radiation cancer risk assessments methods are illustrated here using Swiss population data. This involves a comparison of the cancer risk assessment method based on collective dose and the cumulative risk assessment method, where the latter is recommended with regard to uncertainties and risk of misinterpretation. Further, risk assessment in different dose ranges is discussed and it is concluded that below 100 mSv it cannot be appropriately stated that an adequate strength of evidence of a causal relationship between cancer and radiation is provided, because of the large uncertainties in this dose range. However, the linear non-threshold (LNT) model can be used to model the dose response, because it represents a prudent and parsimonious model, that fits the data well and lies within the given uncertainties. Additionally, treatments of uncertainties in the risk models are illustrated. The EU-project CONFIDENCE software is applied here to obtain example radiation related lifetime cancer risks for exposures of 20 mSv and 5 mSv. Furthermore, the impact of different dosimetry errors on the uncertainties in the cancer lifetime risk calculation is analysed, by including different standard deviations (SD) and by comparing the sampling of the doses from a normal and a lognormal distribution. Using the normal distribution, for females exposed to 20 mSv, the 95% confidence interval (CI) on the cancer lifetime risk increases, when compared to using a SD of 4 mSv, by a factor of 1.5 using a SD of 8 mSv and by a factor of 1.7 using a SD of 10 mSv. The corresponding factors for males for the same exposure are 1.3 and 1.5 respectively. For exposure to 5 mSv, the 95% CIs on the risk increase by a factor of 1.2 for females and 1.4 for men for a SD of 2 mSv using the normal distribution compared to the lognormal distribution and by a factor of 1.5 and 1.8 for a SD of 3 mSv compared to a SD of 1 mSv respectively. Furthermore, differences in the resulting 95% CI on the risk, using different distributions for the dose sampling are visible.

A Just-in-Time Implementation of an Extension for Community Health Outcomes (ECHO) Program for Support of Primary Care During the COVID-19 Pandemic.

As was experienced across the country, the COVID-19 pandemic reached Colorado in early spring 2020. Yet, unlike many of the early hotspots in other states, the initial cases in Colorado surfaced in rural areas. It was evident early on it would be a public health crisis unlike anything Colorado had ever faced. There was an urgent need for rapid dissemination of up-to-date information and practice support provided by a multidisciplinary task force of academic health center and state public health experts working collaboratively to meet these needs. This article provides a roadmap for the development of a similar model, a community-connected Extension for Community Health Outcomes (ECHO) program based at an academic medical center and its ability to facilitate the service rapidly and scale to need.

On the choice of methodology for evaluating dose-rate effects on radiation-related cancer risks.

Recently, several compilations of individual radiation epidemiology study results have aimed to obtain direct evidence on the magnitudes of dose-rate effects on radiation-related cancer risks. These compilations have relied on meta-analyses of ratios of risks from low dose-rate studies and matched risks from the solid cancer Excess Relative Risk models fitted to the acutely exposed Japanese A-bomb cohort. The purpose here is to demonstrate how choices of methodology for evaluating dose-rate effects on radiation-related cancer risks may influence the results reported for dose-rate effects. The current analysis is intended to address methodological issues and does not imply that the authors recommend a particular value for the dose and dose-rate effectiveness factor. A set of 22 results from one recent published study has been adopted here as a test set of data for applying the many different methods described here, that nearly all produced highly consistent results. Some recently voiced concerns, involving the recalling of the well-known theoretical point-the ratio of two normal random variables has a theoretically unbounded variance-that could potentially cause issues, are shown to be unfounded when aimed at the published work cited and examined in detail here. In the calculation of dose-rate effects for radiation protection purposes, it is recommended that meta-estimators should retain the full epidemiological and dosimetric matching information between the risks from the individual low dose-rate studies and the acutely exposed A-bomb cohort and that a regression approach can be considered as a useful alternative to current approaches.

A bespoke health risk assessment methodology for the radiation protection of astronauts.

An alternative approach that is particularly suitable for the radiation health risk assessment (HRA) of astronauts is presented. The quantity, Radiation Attributed Decrease of Survival (RADS), representing the cumulative decrease in the unknown survival curve at a certain attained age, due to the radiation exposure at an earlier age, forms the basis for this alternative approach. Results are provided for all solid cancer plus leukemia incidence RADS from estimated doses from theoretical radiation exposures accumulated during long-term missions to the Moon or Mars. For example, it is shown that a 1000-day Mars exploration mission with a hypothetical mission effective dose of 1.07 Sv at typical astronaut ages around 40 years old, will result in the probability of surviving free of all types of solid cancer and leukemia until retirement age (65 years) being reduced by 4.2% (95% CI 3.2; 5.3) for males and 5.8% (95% CI 4.8; 7.0) for females. RADS dose-responses are given, for the outcomes for incidence of all solid cancer, leukemia, lung and female breast cancer. Results showing how RADS varies with age at exposure, attained age and other factors are also presented. The advantages of this alternative approach, over currently applied methodologies for the long-term radiation protection of astronauts after mission exposures, are presented with example calculations applicable to European astronaut occupational HRA. Some tentative suggestions for new types of occupational risk limits for space missions are given while acknowledging that the setting of astronaut radiation-related risk limits will ultimately be decided by the Space Agencies. Suggestions are provided for further work which builds on and extends this new HRA approach, e.g., by eventually including non-cancer effects and detailed space dosimetry.