Parathyroidectomy and the Risk of Major Cerebrovascular and Cardiovascular Events in the Elderly.

OBJECTIVE: We aimed to determine the incidence of major cardiovascular and cerebrovascular events in elderly patients with primary hyperparathyroidism (pHPT) and the impact of parathyroidectomy. SUMMARY BACKGROUND DATA: pHPT is underdiagnosed and undertreated in the United States. It is associated with increased cardiovascular disease risk, but its association with cerebrovascular disease risk is not well-established. It is also unknown if parathyroidectomy reduces these risks. METHODS: The incidence of major cerebrovascular and cardiovascular events in 108,869 patients with pHPT diagnosed in the Medicare database between 2008 and 2018 and a matched comparison group of 1,088,690 Medicare subjects was prospectively evaluated. We estimated hazard ratios (HR) for the association of pHPT and parathyroidectomy for the risk of these outcomes from Cox proportional hazards models. Survival curves were calculated to obtain 5-year disease-free survival estimates. RESULTS: For patients with pHPT, five-year disease-free survival was lower, and HRs were higher than the comparison group for any outcome (75.9% vs. 78.4; HR 1.11, 95% confidence interval [CI] 1.09-1.13), major cerebrovascular events (84.5% vs. 86.3%; HR 1.14, 95% CI 1.12-1.17), and major cardiovascular events (87.7% vs. 88.8%; HR 1.06, 95% CI 1.03-1.08). However, in patients who had parathyroidectomy, the risks of major cerebrovascular and cardiovascular events did not differ from the comparison cohort. The lower risk in patients who had parathyroidectomy was maintained in subgroup analyses. CONCLUSIONS: Older patients with pHPT have an increased risk of major cerebrovascular and cardiovascular events compared with patients without the disease. Physicians treating older patients with primary hyperparathyroidism should consider parathyroidectomy.R.M.P. and N.N. contributed equally to the preparation of this manuscript.

Bayesian dose-response analysis for epidemiological studies with complex uncertainty in dose estimation.

Most conventional risk analysis methods rely on a single best estimate of exposure per person, which does not allow for adjustment for exposure-related uncertainty. Here, we propose a Bayesian model averaging method to properly quantify the relationship between radiation dose and disease outcomes by accounting for shared and unshared uncertainty in estimated dose. Our Bayesian risk analysis method utilizes multiple realizations of sets (vectors) of doses generated by a two-dimensional Monte Carlo simulation method that properly separates shared and unshared errors in dose estimation. The exposure model used in this work is taken from a study of the risk of thyroid nodules among a cohort of 2376 subjects who were exposed to fallout from nuclear testing in Kazakhstan. We assessed the performance of our method through an extensive series of simulations and comparisons against conventional regression risk analysis methods. When the estimated doses contain relatively small amounts of uncertainty, the Bayesian method using multiple a priori plausible draws of dose vectors gave similar results to the conventional regression-based methods of dose-response analysis. However, when large and complex mixtures of shared and unshared uncertainties are present, the Bayesian method using multiple dose vectors had significantly lower relative bias than conventional regression-based risk analysis methods and better coverage, that is, a markedly increased capability to include the true risk coefficient within the 95% credible interval of the Bayesian-based risk estimate. An evaluation of the dose-response using our method is presented for an epidemiological study of thyroid disease following radiation exposure.

NCICT: a computational solution to estimate organ doses for pediatric and adult patients undergoing CT scans.

We developed computational methods and tools to assess organ doses for pediatric and adult patients undergoing computed tomography (CT) examinations. We used the International Commission on Radiological Protection (ICRP) reference pediatric and adult phantoms combined with the Monte Carlo simulation of a reference CT scanner to establish comprehensive organ dose coefficients (DC), organ absorbed dose per unit volumetric CT Dose Index (CTDIvol) (mGy/mGy). We also developed methods to estimate organ doses with tube current modulation techniques and size specific dose estimates. A graphical user interface was designed to obtain user input of patient- and scan-specific parameters, and to calculate and display organ doses. A batch calculation routine was also integrated into the program to automatically calculate organ doses for a large number of patients. We entitled the computer program, National Cancer Institute dosimetry system for CT(NCICT). We compared our dose coefficients with those from CT-Expo, and evaluated the performance of our program using CT patient data. Our pediatric DCs show good agreements of organ dose estimation with those from CT-Expo except for thyroid. Our results support that the adult phantom in CT-Expo seems to represent a pediatric individual between 10 and 15 years rather than an adult. The comparison of CTDIvol values between NCICT and dose pages from 10 selected CT scans shows good agreements less than 12% except for two cases (up to 20%). The organ dose comparison between mean and modulated mAs shows that mean mAs-based calculation significantly overestimates dose (up to 2.4-fold) to the organs in close proximity to lungs in chest and chest-abdomen-pelvis scans. Our program provides more realistic anatomy based on the ICRP reference phantoms, higher age resolution, the most up-to-date bone marrow dosimetry, and several convenient features compared to previous tools. The NCICT will be available for research purpose in the near future.

Association of cardiovascular disease management drugs with Lewy body dementia: a case-control study.

Lewy body dementia is the second most common neurodegenerative dementia after Alzheimer's disease. Disease-modifying therapies for this disabling neuropsychiatric condition are critically needed. To identify drugs associated with the risk of developing Lewy body dementia, we performed a population-based case-control study of 148 170 US Medicare participants diagnosed with Lewy body dementia between 1 January 2008 and 31 December 2014 and of 1 253 043 frequency-matched controls. We estimated odds ratios and 95% confidence intervals for the association of Lewy body dementia risk with 1017 prescription drugs overall and separately for the three major racial groups (Black, Hispanic and White Americans). We identified significantly reduced Lewy body dementia risk associated with drugs used to treat cardiovascular diseases (anti-hypertensives: odds ratio = 0.72, 95% confidence interval = 0.70-0.74, P-value = 0; cholesterol-lowering agents: odds ratio = 0.85, 95% confidence interval = 0.83-0.87, P-value = 0; anti-diabetics: odds ratio = 0.83, 95% confidence interval = 0.62-0.72, P-value = 0). Notably, anti-diabetic medications were associated with a larger risk reduction among Black Lewy body dementia patients compared with other racial groups (Black: odds ratio = 0.67, 95% confidence interval = 0.62-0.72, P-value = 0; Hispanic: odds ratio = 0.86, 95% = 0.80-0.92, P-value = 5.16 × 10-5; White: odds ratio = 0.85, 95% confidence interval = 0.82-0.88, P-value = 0). To independently confirm the epidemiological findings, we looked for evidence of genetic overlap between Lewy body dementia and cardiovascular traits using whole-genome sequence data generated for 2591 Lewy body dementia patients and 4027 controls. Bivariate mixed modelling identified shared genetic risk between Lewy body dementia and low-density lipoprotein cholesterol levels, Type 2 diabetes and hypertension. By combining epidemiological and genomic data, we demonstrated that drugs treating cardiovascular diseases are associated with reduced Lewy body dementia risk, and these associations varied across racial groups. Future randomized clinical trials need to confirm our findings, but our data suggest that assiduous management of cardiovascular diseases may be beneficial in this understudied form of dementia.

ORGAN DOSE ESTIMATION ACCOUNTING FOR UNCERTAINTY FOR PEDIATRIC AND YOUNG ADULT CT SCANS IN THE UNITED KINGDOM.

Since our previous publication of organ dose for the pediatric CT cohort in the UK, there have been questions about the magnitude of uncertainty in our dose estimates. We therefore quantified shared and unshared uncertainties in empirical CT parameters extracted from 1073 CT films (1978-2008) from 36 hospitals in the study and propagated these uncertainties into organ doses using Monte Carlo random sampling and NCICT organ dose calculator. The average of 500 median brain and marrow doses for the full cohort was 35 (95% confidence interval: 30-40) mGy and 6 (5-7) mGy, respectively. We estimated that shared uncertainty contributed ~99% of coefficient of variation of median brain doses in brain scans compared to unshared uncertainty (1% contribution). We found that the previous brain doses were slightly underestimated for <1990 and overestimated for >1990 compared to the results in the current study due to the revised CTDI models based on CT films.

S values for 131I based on the ICRP adult voxel phantoms.

To improve the estimates of organ doses from nuclear medicine procedures using (131)I, the authors calculated a comprehensive set of (131)I S values, defined as absorbed doses in target tissues per unit of nuclear transition in source regions, for different source and target combinations. The authors used the latest reference adult male and female voxel phantoms published by the International Commission on Radiological Protection (ICRP Publication 110) and the (131)I photon and electron spectra from the ICRP Publication 107 to perform Monte Carlo radiation transport calculations using MCNPX2.7 to compute the S values. For each phantom, the authors simulated 55 source regions with an assumed uniform distribution of (131)I. They computed the S values for 42 target tissues directly, without calculating specific absorbed fractions. From these calculations, the authors derived a comprehensive set of S values for (131)I for 55 source regions and 42 target tissues in the ICRP male and female voxel phantoms. Compared with the stylised phantoms from Oak Ridge National Laboratory (ORNL) that consist of 22 source regions and 24 target regions, the new data set includes 1662 additional S values corresponding to additional combinations of source-target tissues that are not available in the stylised phantoms. In a comparison of S values derived from the ICRP and ORNL phantoms, the authors found that the S values to the radiosensitive tissues in the ICRP phantoms were 1.1 (median, female) and 1.3 (median, male) times greater than the values based on the ORNL phantoms. However, for several source-target pairs, the difference was up to 10-fold. The new set of S values can be applied prospectively or retrospectively to the calculation of radiation doses in adults internally exposed to (131)I, including nuclear medicine patients treated for thyroid cancer or hyperthyroidism.

Computational lymphatic node models in pediatric and adult hybrid phantoms for radiation dosimetry.

We developed models of lymphatic nodes for six pediatric and two adult hybrid computational phantoms to calculate the lymphatic node dose estimates from external and internal radiation exposures. We derived the number of lymphatic nodes from the recommendations in International Commission on Radiological Protection (ICRP) Publications 23 and 89 at 16 cluster locations for the lymphatic nodes: extrathoracic, cervical, thoracic (upper and lower), breast (left and right), mesentery (left and right), axillary (left and right), cubital (left and right), inguinal (left and right) and popliteal (left and right), for different ages (newborn, 1-, 5-, 10-, 15-year-old and adult). We modeled each lymphatic node within the voxel format of the hybrid phantoms by assuming that all nodes have identical size derived from published data except narrow cluster sites. The lymph nodes were generated by the following algorithm: (1) selection of the lymph node site among the 16 cluster sites; (2) random sampling of the location of the lymph node within a spherical space centered at the chosen cluster site; (3) creation of the sphere or ovoid of tissue representing the node based on lymphatic node characteristics defined in ICRP Publications 23 and 89. We created lymph nodes until the pre-defined number of lymphatic nodes at the selected cluster site was reached. This algorithm was applied to pediatric (newborn, 1-, 5-and 10-year-old male, and 15-year-old males) and adult male and female ICRP-compliant hybrid phantoms after voxelization. To assess the performance of our models for internal dosimetry, we calculated dose conversion coefficients, called S values, for selected organs and tissues with Iodine-131 distributed in six lymphatic node cluster sites using MCNPX2.6, a well validated Monte Carlo radiation transport code. Our analysis of the calculations indicates that the S values were significantly affected by the location of the lymph node clusters and that the values increased for smaller phantoms due to the shorter inter-organ distances compared to the bigger phantoms. By testing sensitivity of S values to random sampling and voxel resolution, we confirmed that the lymph node model is reasonably stable and consistent for different random samplings and voxel resolutions.

Evaluation of the use of surrogate tissues for calculating radiation dose to lymphatic nodes from external photon beams.

Lymphatic node chains of the human body are particularly difficult to realistically model in computational human phantoms. In the absence of a lymphatic node model, researchers have used the following surrogate tissues to calculate the radiation dose to the lymphatic nodes: blood vessels, muscle and the combination of the muscle and adipose tissues. In the present work, the authors investigated whether and in which extent the use of different surrogate tissues is appropriate to assess the lymph node dose, using a realistic model of lymphatic nodes that the authors recently reported. Using a Monte Carlo radiation transport method coupled with the adult male hybrid phantom that included the lymph node model, the air kerma-to-absorbed dose conversion coefficients (Gy Gy(-1)) to the lymph nodes and other tissues used as surrogates for external photon beams of 15 discrete energies (0.015-10 MeV) were computed using the following six idealised geometries: anterior-posterior (AP), posterior-anterior (PA), right lateral, left lateral, rotational and isotropic. To validate the results of this study, the lymph node dose calculated here was compared with the dose published by the International Commission on Radiological Protection for the adult male reference phantom. The lymph node dose conversion coefficients with the values calculated for the blood vessels, muscle, adipose tissue and the combination of muscle and adipose tissues were then compared. It was found that muscle was the best estimator for the lymph nodes, with a dose difference averaged across energies >0.08 MeV of <8 % in all irradiation geometries excluding the AP and PA geometries for which the blood vessels were found to be the best estimator. In conclusion, muscle and blood vessels may preferably be used as surrogate tissues in the absence of lymphatic nodes in a given voxel phantom. For energies <0.08 MeV, for which the authors observed a difference of up to 30-fold, an explicit lymph node model may be required to prevent increasing differences with the lymph node dose as the photon energy decreases, though the absolute values of the dose conversion coefficients are smaller than at higher energy.

Fallout deposition in the Marshall Islands from Bikini and Enewetak nuclear weapons tests.

Deposition densities (Bq m(-2)) of all important dose-contributing radionuclides occurring in nuclear weapons testing fallout from tests conducted at Bikini and Enewetak Atolls (1946-1958) have been estimated on a test-specific basis for 32 atolls and separate reef islands of the Marshall Islands. A complete review of various historical and contemporary data, as well as meteorological analysis, was used to make judgments regarding which tests deposited fallout in the Marshall Islands and to estimate fallout deposition density. Our analysis suggested that only 20 of the 66 nuclear tests conducted in or near the Marshall Islands resulted in substantial fallout deposition on any of the 23 inhabited atolls. This analysis was confirmed by the fact that the sum of our estimates of 137Cs deposition from these 20 tests at each atoll is in good agreement with the total 137Cs deposited as estimated from contemporary soil sample analyses. The monitoring data and meteorological analyses were used to quantitatively estimate the deposition density of 63 activation and fission products for each nuclear test, plus the cumulative deposition of 239+240Pu at each atoll. Estimates of the degree of fractionation of fallout from each test at each atoll, as well as of the fallout transit times from the test sites to the atolls were used in this analysis. The estimates of radionuclide deposition density, fractionation, and transit times reported here are the most complete available anywhere and are suitable for estimations of both external and internal dose to representative persons as described in companion papers.

Predictions of dispersion and deposition of fallout from nuclear testing using the NOAA-HYSPLIT meteorological model.

The NOAA Hybrid Single-Particle Lagrangian Integrated Trajectory Model (HYSPLIT) was evaluated as a research tool to simulate the dispersion and deposition of radioactive fallout from nuclear tests. Model-based estimates of fallout can be valuable for use in the reconstruction of past exposures from nuclear testing, particularly where little historical fallout monitoring data are available. The ability to make reliable predictions about fallout deposition could also have significant importance for nuclear events in the future. We evaluated the accuracy of the HYSPLIT-predicted geographic patterns of deposition by comparing those predictions against known deposition patterns following specific nuclear tests with an emphasis on nuclear weapons tests conducted in the Marshall Islands. We evaluated the ability of the computer code to quantitatively predict the proportion of fallout particles of specific sizes deposited at specific locations as well as their time of transport. In our simulations of fallout from past nuclear tests, historical meteorological data were used from a reanalysis conducted jointly by the National Centers for Environmental Prediction (NCEP) and the National Center for Atmospheric Research (NCAR). We used a systematic approach in testing the HYSPLIT model by simulating the release of a range of particle sizes from a range of altitudes and evaluating the number and location of particles deposited. Our findings suggest that the quantity and quality of meteorological data are the most important factors for accurate fallout predictions and that, when satisfactory meteorological input data are used, HYSPLIT can produce relatively accurate deposition patterns and fallout arrival times. Furthermore, when no other measurement data are available, HYSPLIT can be used to indicate whether or not fallout might have occurred at a given location and provide, at minimum, crude quantitative estimates of the magnitude of the deposited activity. A variety of simulations of the deposition of fallout from atmospheric nuclear tests conducted in the Marshall Islands (mid-Pacific), at the Nevada Test Site (U.S.), and at the Semipalatinsk Nuclear Test Site (Kazakhstan) were performed. The results of the Marshall Islands simulations were used in a limited fashion to support the dose reconstruction described in companion papers within this volume.