Occupational Radiation Dose Trends in U.S. Radiologic Technologists Assisting with Fluoroscopically Guided Interventional Procedures, 1980-2020.

PURPOSE: To summarize dose trends from 1980 to 2020 for 19,651 U.S. Radiologic Technologists who reported assisting with fluoroscopically guided interventional procedures (FGIPs), overall and by work history characteristics. MATERIALS AND METHODS: A total of 762,310 annual personal dose equivalents at a 10-mm reference depth (doses) during 1980-2020 for 43,823 participants of the U.S. Radiologic Technologists (USRT) cohort who responded to work history questionnaires administered during 2012-2014 were summarized. This population included 19,651 technologists who reported assisting with FGIP (≥1 time per month for ≥12 consecutive months) at any time during the study period. Doses corresponding to assistance with FGIP were estimated in terms of proximity to patients, monthly procedure frequency, and procedure type. Box plots and summary statistics (eg, medians and percentiles) were used to describe annual doses and dose trends. RESULTS: Median annual dose corresponding to assistance with FGIP was 0.65 mSv (interquartile range [IQR], 0.60-1.40 mSv; 95th percentile, 6.80). Higher occupational doses with wider variability were associated with close proximity to patients during assistance with FGIP (median, 1.20 mSv [IQR, 0.60-4.18 mSv]; 95th percentile, 12.66), performing ≥20 FGIPs per month (median, 0.75 mSv [IQR, 0.60-2.40 mSv]; 95th percentile, 9.44), and assisting with high-dose FGIP (median, 0.70 mSv [IQR, 0.60-1.90 mSv]; 95th percentile, 8.30). CONCLUSIONS: Occupational doses corresponding to assistance with FGIP were generally low but varied with exposure frequency, procedure type, and proximity to patients. These results highlight the need for vigilant dose monitoring, radiation safety training, and proper protective equipment.

Radiation exposure and leukaemia risk among cohorts of persons exposed to low and moderate doses of external ionising radiation in childhood.

BACKGROUND: Many high-dose groups demonstrate increased leukaemia risks, with risk greatest following childhood exposure; risks at low/moderate doses are less clear. METHODS: We conducted a pooled analysis of the major radiation-associated leukaemias (acute myeloid leukaemia (AML) with/without the inclusion of myelodysplastic syndrome (MDS), chronic myeloid leukaemia (CML), acute lymphoblastic leukaemia (ALL)) in ten childhood-exposed groups, including Japanese atomic bomb survivors, four therapeutically irradiated and five diagnostically exposed cohorts, a mixture of incidence and mortality data. Relative/absolute risk Poisson regression models were fitted. RESULTS: Of 365 cases/deaths of leukaemias excluding chronic lymphocytic leukaemia, there were 272 AML/CML/ALL among 310,905 persons (7,641,362 person-years), with mean active bone marrow (ABM) dose of 0.11 Gy (range 0-5.95). We estimated significant (P < 0.005) linear excess relative risks/Gy (ERR/Gy) for: AML (n = 140) = 1.48 (95% CI 0.59-2.85), CML (n = 61) = 1.77 (95% CI 0.38-4.50), and ALL (n = 71) = 6.65 (95% CI 2.79-14.83). There is upward curvature in the dose response for ALL and AML over the full dose range, although at lower doses (<0.5 Gy) curvature for ALL is downwards. DISCUSSION: We found increased ERR/Gy for all major types of radiation-associated leukaemia after childhood exposure to ABM doses that were predominantly (for 99%) <1 Gy, and consistent with our prior analysis focusing on <100 mGy.

Causes of cardiovascular and noncardiovascular death in the ISCHEMIA trial.

BACKGROUND: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial demonstrated no overall difference in the composite primary endpoint and the secondary endpoints of cardiovascular (CV) death/myocardial infarction or all-cause mortality between an initial invasive or conservative strategy among participants with chronic coronary disease and moderate or severe myocardial ischemia. Detailed cause-specific death analyses have not been reported. METHODS: We compared overall and cause-specific death rates by treatment group using Cox models with adjustment for pre-specified baseline covariates. Cause of death was adjudicated by an independent Clinical Events Committee as CV, non-CV, and undetermined. We evaluated the association of risk factors and treatment strategy with cause of death. RESULTS: Four-year cumulative incidence rates for CV death were similar between invasive and conservative strategies (2.6% vs 3.0%; hazard ratio [HR] 0.98; 95% CI [0.70-1.38]), but non-CV death rates were higher in the invasive strategy (3.3% vs 2.1%; HR 1.45 [1.00-2.09]). Overall, 13% of deaths were attributed to undetermined causes (38/289). Fewer undetermined deaths (0.6% vs 1.3%; HR 0.48 [0.24-0.95]) and more malignancy deaths (2.0% vs 0.8%; HR 2.11 [1.23-3.60]) occurred in the invasive strategy than in the conservative strategy. CONCLUSIONS: In International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, all-cause and CV death rates were similar between treatment strategies. The observation of fewer undetermined deaths and more malignancy deaths in the invasive strategy remains unexplained. These findings should be interpreted with caution in the context of prior studies and the overall trial results.

Collar Badge Lens Dose Equivalent Values among United States Physicians Performing Fluoroscopically Guided Interventional Procedures.

PURPOSE: To describe the range of occupational badge dose readings and annualized dose records among physicians performing fluoroscopically guided interventional (FGI) procedures using job title information provided by the same 3 major medical institutions in 2009, 2012, and 2015. MATERIALS AND METHODS: The Radiation Safety Office of selected hospitals was contacted to request assistance with identifying physicians in a large commercial dosimetry database. All entries judged to be uninformative of occupational doses to FGI procedure staff were excluded. Monthly and annualized doses were described with univariate statistics and box-and-whisker plots. RESULTS: The dosimetry data set of interventional radiology staff contained 169 annual dose records from 77 different physicians and 698 annual dose records from 455 nonphysicians. The median annualized lens dose equivalent values among physicians (11.9 mSv; interquartile range [IQR], 6.9-20.0 mSv) was nearly 3-fold higher than those among nonphysician medical staff assisting with FGI procedures (4.0 mSv; IQR, 1.8-6.7 mSv) (P < .001). During the study period, without eye protection, 25% (23 of 93) of the physician annualized lens dose equivalent values may have exceeded 20 mSv; for nonphysician medical staff, this value may have been exceeded 3.5% (6 of 173) of the time. However, these values did not account for eye protection. CONCLUSIONS: The findings from this study highlight the importance of mitigating occupational dose to the eyes of medical staff, particularly physicians, performing or assisting with FGI procedures. Training on radiation protection principles, the use of personal protective equipment, and patient radiation dose management can all help ensure that the occupational radiation dose is adequately controlled.

Trends in Occupational Radiation Doses for U.S. Radiologic Technologists Performing General Radiologic and Nuclear Medicine Procedures, 1980-2015.

Background Occupational doses to most medical radiation workers have declined substantially since the 1950s because of improvements in radiation protection practices. However, different patterns may have emerged for radiologic technologists working with nuclear medicine because of the higher per-procedure doses and increasing workloads. Purpose To summarize annual occupational doses during a 36-year period for a large cohort of U.S. radiologic technologists and to compare dose between general radiologic technologists and those specializing in nuclear medicine procedures. Materials and Methods Annual personal dose equivalents (referred to as doses) from 1980 to 2015 were summarized for 58 434 (62%) participants in the U.S. Radiologic Technologists (USRT) cohort who responded to the most recent mailed work history survey (years 2012-2014) and reported never regularly performing interventional procedures. Doses were partitioned according to the performance of nuclear medicine (yes or no, frequency, procedure type) by calendar year. Annual dose records were described by using summary statistics (eg, median and 25th and 75th percentiles). Results Median annual doses related to performance of general radiologic procedures decreased from 0.60 mSv (interquartile range [IQR], 0.10-1.9 mSv) in 1980 to levels below the limits of detection by 2015, whereas annual doses related to performance of nuclear medicine procedures remained relatively high during this period (median, 1.2 mSv; IQR, 0.12-3.0 mSv). Higher median annual doses were associated with more frequent (above vs below the median) performance of diagnostic nuclear medicine procedures (≥35 vs <35 times per week; 1.6 mSv [IQR, 0.30-3.3 mSv] and 0.9 mSv [IQR, 0.10-2.6 mSv]). Higher and more variable annual doses were associated with more frequent performance of cardiac nuclear medicine (≥10 times per week) and PET (nine or more times per week) examinations (median, 1.6 mSv [IQR, 0.30-2.2 mSv] and 2.2 mSv [IQR, 0.10-4.6 mSv], respectively). Conclusion Annual doses to U.S. radiologic technologists performing general radiologic procedures declined during a 36-year period. However, consistently higher and more variable doses were associated with the performance of nuclear medicine procedures, particularly cardiac nuclear medicine and PET procedures. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Mettler and Guiberteau in this issue.

Occupational Doses to Medical Staff Performing or Assisting with Fluoroscopically Guided Interventional Procedures.

Background Staff who perform fluoroscopically guided interventional (FGI) procedures are among the most highly radiation-exposed groups in medicine. However, there are limited data on monthly or annual doses (or dose trends over time) for these workers. Purpose To summarize occupational badge doses (lens dose equivalent and effective dose equivalent values) for medical staff performing or assisting with FGI procedures in 3 recent years after accounting for uninformative values and one- versus two-badge monitoring protocol. Materials and Methods Badge dose entries of medical workers believed to have performed or assisted with FGI procedures were retrospectively collected from the largest dosimetry provider in the United States for 49 991, 81 561, and 125 669 medical staff corresponding to years 2009, 2012, and 2015, respectively. Entries judged to be uninformative of occupational doses to FGI procedures staff were excluded. Monthly and annual occupational doses were described using summary statistics. Results After exclusions, 22.2% (153 033 of 687 912) of the two- and 32.9% (450 173 of 1 366 736) of the one-badge entries were judged to be informative. There were 335 225 and 916 563 of the two- and one-badge entries excluded, respectively, with minimal readings in the above-apron badge. Among the two-badge entries, 123 595 were incomplete and 76 059 had readings indicating incorrect wear of the badges. From 2009 to 2015 there was no change in lens dose equivalent values among workers who wore one badge (P = .96) or those who wore two badges (P = .23). Annual lens dose equivalents for workers wearing one badge (median, 6.9 mSv; interquartile range, 3.8213.8 mSv; n = 6218) were similar to those of staff wearing two badges (median, 7.1 mSv; interquartile range, 4.6-11.2 mSv; n = 1449) (P = .18), suggesting a similar radiation environment. Conclusion These workers are among the highest exposed to elevated levels of ionizing radiation, although their occupational doses are within U.S. regulatory limits. This is a population that requires consistent and accurate dose monitoring; however, failure to return one or both badges, reversal of badges, and improper badge placement are a major hindrance to this goal. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Karellas in this issue.

The HARMONIC project: study design for the assessment of radiation doses and associated cancer risks following cardiac fluoroscopy in childhood.

The HARMONIC project (Health Effects of Cardiac Fluoroscopy and Modern Radiotherapy in Paediatrics) is a European study aiming to improve our understanding of the long-term health risks from radiation exposures in childhood and early adulthood. Here, we present the study design for the cardiac fluoroscopy component of HARMONIC. A pooled cohort of approximately 100 000 patients who underwent cardiac fluoroscopy procedures in Belgium, France, Germany, Italy, Norway, Spain or the UK, while aged under 22 years, will be established from hospital records and/or insurance claims data. Doses to individual organs will be estimated from dose indicators recorded at the time of examination, using a lookup-table-based dosimetry system produced using Monte Carlo radiation transport simulations and anatomically realistic computational phantom models. Information on beam geometry and x-ray energy spectra will be obtained from a representative sample of radiation dose structured reports. Uncertainties in dose estimates will be modelled using 2D Monte Carlo methods. The cohort will be followed up using national registries and insurance records to determine vital status and cancer incidence. Information on organ transplantation (a major risk factor for cancer development in this patient group) and/or other conditions predisposing to cancer will be obtained from national or local registries and health insurance data, depending on country. The relationship between estimated radiation dose and cancer risk will be investigated using regression modelling. Results will improve information for patients and parents and aid clinicians in managing and implementing changes to reduce radiation risks without compromising medical benefits.

Cataract risk in US radiologic technologists assisting with fluoroscopically guided interventional procedures: a retrospective cohort study.

OBJECTIVES: To assess radiation exposure-related work history and risk of cataract and cataract surgery among radiologic technologists assisting with fluoroscopically guided interventional procedures (FGIP). METHODS: This retrospective study included 35 751 radiologic technologists who reported being cataract-free at baseline (1994-1998) and completed a follow-up questionnaire (2013-2014). Frequencies of assisting with 21 types of FGIP and use of radiation protection equipment during five time periods (before 1970, 1970-1979, 1980-1989, 1990-1999, 2000-2009) were derived from an additional self-administered questionnaire in 2013-2014. Multivariable-adjusted relative risks (RRs) for self-reported cataract diagnosis and cataract surgery were estimated according to FGIP work history. RESULTS: During follow-up, 9372 technologists reported incident physician-diagnosed cataract; 4278 of incident cases reported undergoing cataract surgery. Technologists who ever assisted with FGIP had increased risk for cataract compared with those who never assisted with FGIP (RR: 1.18, 95% CI 1.11 to 1.25). Risk increased with increasing cumulative number of FGIP; the RR for technologists who assisted with >5000 FGIP compared with those who never assisted was 1.38 (95% CI 1.24 to 1.53; p trend <0.001). These associations were more pronounced for FGIP when technologists were located ≤3 feet (≤0.9 m) from the patient compared with >3 feet (>0.9 m) (RRs for >5000 at ≤3 feet vs never FGIP were 1.48, 95% CI 1.27 to 1.74 and 1.15, 95% CI 0.98 to 1.35, respectively; pdifference=0.04). Similar risks, although not statistically significant, were observed for cataract surgery. CONCLUSION: Technologists who reported assisting with FGIP, particularly high-volume FGIP within 3 feet of the patient, had increased risk of incident cataract. Additional investigation should evaluate estimated dose response and medically validated cataract type.

Organ-specific dose coefficients derived from Monte Carlo simulations for historical (1930s to 1960s) fluoroscopic and radiographic examinations of tuberculosis patients.

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.

Occupational radiation exposure and risk of cataract incidence in a cohort of US radiologic technologists.

It has long been known that relatively high-dose ionising radiation exposure (> 1 Gy) can induce cataract, but there has been no evidence that this occurs at low doses (< 100 mGy). To assess low-dose risk, participants from the US Radiologic Technologists Study, a large, prospective cohort, were followed from date of mailed questionnaire survey completed during 1994-1998 to the earliest of self-reported diagnosis of cataract/cataract surgery, cancer other than non-melanoma skin, or date of last survey (up to end 2014). Cox proportional hazards models with age as timescale were used, adjusted for a priori selected cataract risk factors (diabetes, body mass index, smoking history, race, sex, birth year, cumulative UVB radiant exposure). 12,336 out of 67,246 eligible technologists reported a history of diagnosis of cataract during 832,479 person years of follow-up, and 5509 from 67,709 eligible technologists reported undergoing cataract surgery with 888,420 person years of follow-up. The mean cumulative estimated 5-year lagged eye-lens absorbed dose from occupational radiation exposures was 55.7 mGy (interquartile range 23.6-69.0 mGy). Five-year lagged occupational radiation exposure was strongly associated with self-reported cataract, with an excess hazard ratio/mGy of 0.69 × 10-3 (95% CI 0.27 × 10-3 to 1.16 × 10-3, p < 0.001). Cataract risk remained statistically significant (p = 0.030) when analysis was restricted to < 100 mGy cumulative occupational radiation exposure to the eye lens. A non-significantly increased excess hazard ratio/mGy of 0.34 × 10-3 (95% CI - 0.19 × 10-3 to 0.97 × 10-3, p = 0.221) was observed for cataract surgery. Our results suggest that there is excess risk for cataract associated with radiation exposure from low-dose and low dose-rate occupational exposures.

Physical validation of UF-RIPSA: A rapid in-clinic peak skin dose mapping algorithm for fluoroscopically guided interventions.

PURPOSE: The purpose of this study was to experimentally validate UF-RIPSA, a rapid in-clinic peak skin dose mapping algorithm developed at the University of Florida using optically stimulated luminescent dosimeters (OSLDs) and tissue-equivalent phantoms. METHODS: The OSLDs used in this study were InLightTM Nanodot dosimeters by Landauer, Inc. The OSLDs were exposed to nine different beam qualities while either free-in-air or on the surface of a tissue equivalent phantom. The irradiation of the OSLDs was then modeled using Monte Carlo techniques to derive correction factors between free-in-air exposures and more complex irradiation geometries. A grid of OSLDs on the surface of a tissue equivalent phantom was irradiated with two fluoroscopic x ray fields generated by the Siemens Artis zee bi-plane fluoroscopic unit. The location of each OSLD within the grid was noted and its dose reading compared with UF-RIPSA results. RESULTS: With the use of Monte Carlo correction factors, the OSLD's response under complex irradiation geometries can be predicted from its free-in-air response. The predicted values had a percent error of -8.7% to +3.2% with a predicted value that was on average 5% below the measured value. Agreement within 9% was observed between the values of the OSLDs and RIPSA when irradiated directly on the phantom and within 14% when the beam first traverses the tabletop and pad. CONCLUSIONS: The UF-RIPSA only computes dose values to areas of irradiated skin determined to be directly within the x ray field since the algorithm is based upon ray tracing of the reported reference air kerma value, with subsequent corrections for air-to-tissue dose conversion, x ray backscatter, and table/pad attenuation. The UF-RIPSA algorithm thus does not include the dose contribution of scatter radiation from adjacent fields. Despite this limitation, UF-RIPSA is shown to be fairly robust when computing skin dose to patients undergoing fluoroscopically guided interventions.

Body-weight dependent dose coefficients for adults exposed to idealised external photon fields.

In epidemiological investigations of cancer risk from occupational exposure, it is important to obtain an organ-specific dose for each cohort member for accurate risk analysis. To date, dose conversion coefficients, which convert physical dose measurement to organ dose, are only available for individuals with reference body size, which can differentially bias the estimated organ dose depending on the body mass index of cohort members. In the current study, we calculated the organ dose coefficients applicable to adult males and females with various body weights by using the Monte Carlo radiation transport technique combined with a library of body size-dependent hybrid computational phantoms exposed in six idealised irradiation geometries. We adapted the eight adult male phantoms, 175 cm tall with weights of 60, 70, 80, 90, 100, 110, 120 and 130 kg, and the nine adult female phantoms, 165 cm tall with weights of 50, 60, 70, 80, 90, 100, 110, 120 and 130 kg. The radiation transport was simulated using MCNPX 2.7 Monte Carlo code. Phantoms were irradiated by external photon fields in anterior posterior (AP), posterior-anterior, right and left lateral, rotational, and isotropic geometries. The results showed that the 60 kg adult male phantom shows 1.33-, 1.43-, 1.44- and 1.52-fold greater dose coefficients for the lungs, heart, stomach, and liver, respectively, than the 120 kg adult male phantom at 0.1 MeV in AP geometry. We derived exponential correlation between organ dose coefficients and body weight to facilitate calculation of organ dose coefficients for a given weight. The comprehensive organ dose coefficients and exponential regression model can be used to estimate more accurate organ dose for individuals of the two genders with various body weights exposed to external photon radiation.

Science-informed Policy Making for Protecting People and the Environment from Radiation.

ABSTRACT: The process to arrive at the radiation protection practices of today to protect workers, patients, and the public, including sensitive populations, has been a long and deliberative one. This paper presents an overview of the US Environmental Protection Agency's (US EPA) responsibility in protecting human health and the environment from unnecessary exposure to radiation. The origins of this responsibility can be traced back to early efforts, a century ago, to protect workers from x rays and radium. The system of radiation protection we employ today is robust and informed by the latest scientific consensus. It has helped reduce or eliminate unnecessary exposures to workers, patients, and the public while enabling the safe and beneficial uses of radiation and radioactive material in diverse areas such as energy, medicine, research, and space exploration. Periodic reviews and analyses of research on health effects of radiation by scientific bodies such as the National Academy of Sciences, National Council on Radiation Protection and Measurements, United Nations Scientific Committee on the Effects of Atomic Radiation, and the International Commission on Radiological Protection continue to inform radiation protection practices while new scientific information is gathered. As a public health agency, US EPA is keenly interested in research findings that can better elucidate the effects of exposure to low doses and low dose rates of radiation as applicable to protection of diverse populations from various sources of exposure. Professional organizations such as the Health Physics Society can provide radiation protection practitioners with continuing education programs on the state of the science and describe the key underpinnings of the system of radiological protection. Such efforts will help equip and prepare radiation protection professionals to more effectively communicate radiation health information with their stakeholders.

Cause-Specific Mortality in Patients With Advanced Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

BACKGROUND: In ISCHEMIA-CKD, 777 patients with advanced chronic kidney disease and chronic coronary disease had similar all-cause mortality with either an initial invasive or conservative strategy (27.2% vs 27.8%, respectively). OBJECTIVES: This prespecified secondary analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) was conducted to determine whether an initial invasive strategy compared with a conservative strategy decreased the incidence of cardiovascular (CV) vs non-CV causes of death. METHODS: Three-year cumulative incidences were calculated for the adjudicated cause of death. Overall and cause-specific death by treatment strategy were analyzed using Cox models adjusted for baseline covariates. The association between cause of death, risk factors, and treatment strategy were identified. RESULTS: A total of 192 of the 777 participants died during follow-up, including 94 (12.1%) of a CV cause, 59 (7.6%) of a non-CV cause, and 39 (5.0%) of an undetermined cause. The 3-year cumulative rates of CV death were similar between the invasive and conservative strategies (14.6% vs 12.6%, respectively; HR: 1.13, 95% CI: 0.75-1.70). Non-CV death rates were also similar between the invasive and conservative arms (8.4% and 8.2%, respectively; HR: 1.25; 95% CI: 0.75-2.09). Sudden cardiac death (46.8% of CV deaths) and infection (54.2% of non-CV deaths) were the most common cause-specific deaths and did not vary by treatment strategy. CONCLUSIONS: In ISCHEMIA-CKD, CV death was more common than non-CV or undetermined death during the 3-year follow-up. The randomized treatment assignment did not affect the cause-specific incidences of death in participants with advanced CKD and moderate or severe myocardial ischemia. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease [ISCHEMIA-CKD]; NCT01985360).

Design, synthesis, and biological evaluation of novel double-winged galloyl derivatives as HIV-1 RNase H inhibitors.

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not clinically validated as an antiviral target. We have previously reported that the galloyl derivative II-25 had RNase H inhibitory activity in enzymatic assays but showed weak antiviral activity in phenotypic assays due its large polarity and poor membrane permeability. In this report, we report on a series of II-25 derivatives, obtained by addition of different hydrophobic moieties ("the wings") at the C-2 and C-3 positions of the piperazine ring that showed improved RNase H inhibitory activity. Six compounds showed strong inhibitory activity and were found to be more potent than ß-thujaplicinol in enzymatic assays. The most potent compound was IA-6 and exhibited the best inhibitory activity (IC50 = 0.067 ± 0.02 µM). IA-6 was around 11 and 30 times more potent than II-25 and ß-thujaplicinol, respectively. Molecular modeling studies predict a strong hydrophobic interaction between the furylmethylaminyl group of IA-6 and the side chain of His539, explaining the potent HIV-1 RNase H inhibition. Unfortunately, none of the derivatives showed significant antiviral activity in cell culture. It is worth emphasizing that most of the obtained compounds show low cytotoxicity (CC50 > 20 µM), which confirms the significance of identifying galloyl derivatives as valuable leads for further optimization.

The impact of anthropometric patient-phantom matching on organ dose: a hybrid phantom study for fluoroscopy guided interventions.

PURPOSE: To investigate the benefits and limitations of patient-phantom matching for determining organ dose during fluoroscopy guided interventions. METHODS: In this study, 27 CT datasets representing patients of different sizes and genders were contoured and converted into patient-specific computational models. Each model was matched, based on height and weight, to computational phantoms selected from the UF hybrid patient-dependent series. In order to investigate the influence of phantom type on patient organ dose, Monte Carlo methods were used to simulate two cardiac projections (PA/left lateral) and two abdominal projections (RAO/LPO). Organ dose conversion coefficients were then calculated for each patient-specific and patient-dependent phantom and also for a reference stylized and reference hybrid phantom. The coefficients were subsequently analyzed for any correlation between patient-specificity and the accuracy of the dose estimate. Accuracy was quantified by calculating an absolute percent difference using the patient-specific dose conversion coefficients as the reference. RESULTS: Patient-phantom matching was shown most beneficial for estimating the dose to heavy patients. In these cases, the improvement over using a reference stylized phantom ranged from approximately 50% to 120% for abdominal projections and for a reference hybrid phantom from 20% to 60% for all projections. For lighter individuals, patient-phantom matching was clearly superior to using a reference stylized phantom, but not significantly better than using a reference hybrid phantom for certain fields and projections. CONCLUSIONS: The results indicate two sources of error when patients are matched with phantoms: Anatomical error, which is inherent due to differences in organ size and location, and error attributed to differences in the total soft tissue attenuation. For small patients, differences in soft tissue attenuation are minimal and are exceeded by inherent anatomical differences. For large patients, difference in soft tissue attenuation can be large. In these cases, patient-phantom matching proves most effective as differences in soft tissue attenuation are mitigated. With increasing obesity rates, overweight patients will continue to make up a growing fraction of all patients undergoing medical imaging. Thus, having phantoms that better represent this population represents a considerable improvement over previous methods. In response to this study, additional phantoms representing heavier weight percentiles will be added to the UFHADM and UFHADF patient-dependent series.

Skin dose mapping for fluoroscopically guided interventions.

PURPOSE: To introduce a new skin dose mapping software system for interventional fluoroscopy dose assessment and to analyze the benefits and limitations of patient-phantom matching. METHODS: In this study, a new software system was developed for visualizing patient skin dose during interventional fluoroscopy procedures. The system works by translating the reference point air kerma to the location of the patient's skin, which is represented by a computational model. In order to orient the model with the x-ray source, geometric parameters found within the radiation dose structured report (RDSR) are used along with a limited number of in-clinic measurements. The output of the system is a visual indication of skin dose mapped onto an anthropomorphic model at a resolution of 5 mm. In order to determine if patient-dependent and patient-sculpted models increase accuracy, peak skin dose was calculated for each of 26 patient-specific models and compared with doses calculated using an elliptical stylized model, a reference hybrid model, a matched patient-dependent model and one patient-sculpted model. Results were analyzed in terms of a percent difference using the doses calculated using the patient-specific model as the true standard. RESULTS: Anthropometric matching, including the use of both patient-dependent and patient-sculpted phantoms, was shown most beneficial for left lateral and anterior-posterior projections. In these cases, the percent difference using a reference model was between 8 and 20%, using a patient-dependent model between 7 and 15%, and using a patient-sculpted model between 3 and 7%. Under the table tube configurations produced errors less than 5% in most situations due to the flattening affects of the table and pad, and the fact that table height is the main determination of source-to-skin distance for these configurations. In addition to these results, several skin dose maps were produced and a prototype display system was placed on the in-clinic monitor of an interventional fluoroscopy system. CONCLUSIONS: The skin dose mapping program developed in this work represents a new tool that, as the RDSR becomes available through automated export or real-time streaming, can provide the interventional physician information needed to modify behavior when clinically appropriate. The program is nonproprietary and transferable, and also functions independent to the software systems already installed on the control room workstation. The next step will be clinical implementation where the workflow will be optimized along with further analysis of real-time capabilities.

Fluoroscopy X-Ray Organ-Specific Dosimetry System (FLUXOR) for Estimation of Organ Doses and Their Uncertainties in the Canadian Fluoroscopy Cohort Study.

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.

Lymphoma and multiple myeloma in cohorts of persons exposed to ionising radiation at a young age.

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 <21 years using active bone marrow (ABM) and, where available, lymphoid system doses, and harmonised outcome classification. Relative and absolute risk models were fitted. Years of entry spanned 1916-1981. At the end of follow-up (mean 42.1 years) there were 593 lymphoma (422 non-Hodgkin (NHL), 107 Hodgkin (HL), 64 uncertain subtype), 66 chronic lymphocytic leukaemia (CLL) and 122 multiple myeloma (MM) deaths and incident cases among 143,136 persons, with mean ABM dose 0.14 Gy (range 0-5.95 Gy) and mean age at first exposure 6.93 years. Excess relative risk (ERR) was not significantly increased for lymphoma (ERR/Gy = -0.001; 95% CI: -0.255, 0.279), HL (ERR/Gy = -0.113; 95% CI: -0.669, 0.709), NHL + CLL (ERR/Gy = 0.099; 95% CI: -0.149, 0.433), NHL (ERR/Gy = 0.068; 95% CI: -0.253, 0.421), CLL (ERR/Gy = 0.320; 95% CI: -0.678, 1.712), or MM (ERR/Gy = 0.149; 95% CI: -0.513, 1.063) (all p-trend > 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, and CLL. Further pooled epidemiological studies are needed with longer follow-up, central outcome review by expert hematopathologists, and assessment of radiation doses to lymphoid tissues.