[Effects of chronic uranium internal exposure on mortality: results of a pilot study among French nuclear workers]. / Effets de la contamination chronique à l'uranium sur la mortalité : bilan d'une étude-pilote chez les travailleurs de l'industrie nucléaire en France.

BACKGROUND: This article presents the mortality data compiled among a cohort of workers at risk of internal uranium exposure and discusses the extent to which this exposure might differentiate them from other nuclear workers. METHODS: The cohort consisted of 2897 Areva-NC-Pierrelatte plant workers, followed from 1st January 1968 through 31st December 2006 (79,892 person-years). Mortality was compared with that of the French population, by calculating Standardized Mortality Ratios (SMR) and 95% confidence intervals (CI95%). External radiation exposure was reconstructed using external dosimetry archives. Internal uranium exposure was assessed using a plant-specific job-exposure-matrix, considering six types of uranium compounds according to their nature (natural and reprocessed uranium [RPU] and solubility [fast-F, moderate-M, and slow-S]). Exposure-effect analyses were performed for causes of death known to be related to external radiation exposure (all cancers and circulatory system diseases) and cancer of uranium target-organs (lung and hematopoietic and lymphatic tissues, HLT). RESULTS: A significant deficit of mortality from all causes (SMR=0.58; CI95% [0.53-0.63]), all cancers (SMR=0.72; CI95% [0.63-0.82]) and smoking related cancers was observed. Non-significant 30%-higher increase of mortality was observed for cancer of pleura (SMR=2.32; CI95 % [0.75-5.41]), rectum and HLT, notably non-Hodgkin's lymphoma (SMR=1.38; CI95 % [0.63-2.61]) and chronic lymphoid leukemia (SMR=2.36; CI95% [0.64-6.03]). No exposure-effect relationship was found with external radiation cumulative dose. A significant exposure-effect relationship was observed for slowly soluble uranium, particularly RPU, which was associated with an increase in mortality risk reaching 8 to 16% per unit of cumulative exposure score and 10 to 15% per year of exposure duration. CONCLUSION: The Areva-NC-Pierrelatte workers cohort presents a non-significant over-mortality from HLT cancers, notably of lymphoid origin, unrelated to external radiation exposure. The pilot study suggests an association between mortality from the HLT and lung cancers and exposure to slowly soluble RPU compounds. The results of this study should be investigated further in more powerful studies, with a dose-response analysis based on individual assessment of uranium absorbed dose to uranium-target organs.

Mortality associated with chronic external radiation exposure in the French combined cohort of nuclear workers.

OBJECTIVE: The long-term effects of protracted low level ionising radiation exposure are investigated in a combined analysis of French nuclear workers employed by the Commissariat à l'Energie Atomique (CEA), AREVA Nuclear Cycle (AREVA NC) and Electricité de France (EDF). Associations between cumulative external radiation dose and mortality due to solid cancers, leukaemia and circulatory disease were examined. METHODS: All workers hired by CEA, AREVA NC and EDF between 1950 and 1994 who were employed for at least 1 year, badge-monitored for radiation exposure and alive on 1 January 1968 were included. Individual data of annual exposure to penetrating photons (X-rays and gamma rays) were reconstructed for each worker. Estimates of radiation dose-mortality associations were obtained using a linear excess relative risk (ERR) Poisson regression model. RESULTS: Among the 59 021 nuclear workers, 2312 died of solid cancer, 78 of leukaemia and 1468 of circulatory diseases during the 1968-2004 period. Approximately 72% of the cohort had a non-zero cumulative radiation dose estimate, with a mean cumulative dose of 22.5 mSv. Positive but non-significant ERR/Sv were observed for all solid cancers, leukaemia excluding chronic lymphocytic leukaemia (CLL), ischaemic heart diseases and cerebrovascular diseases. A significant ERR/Sv was found for myeloid leukaemia. CONCLUSIONS: This is the first combined analysis of major French cohorts of nuclear workers. Results were consistent with risks estimated in other nuclear worker cohorts and illustrate the potential of a further joint international study to yield direct risk estimates in support to radiation protection standards.

Three-Year Rates of Reoperation and Revision Following Mobile Versus Fixed-Bearing Total Ankle Arthroplasty: A Cohort of 302 Patients with 2 Implants of Similar Design.

BACKGROUND: Currently, the implants utilized in total ankle arthroplasty (TAA) are divided between mobile-bearing 3-component and fixed-bearing 2-component designs. The literature evaluating the influence of this mobility difference on implant survival is sparse. The purpose of the present study was therefore to compare the short-term survival of 2 implants of similar design from the same manufacturer, surgically implanted by the same surgeons, in fixed-bearing or mobile-bearing versions. METHODS: All patients were enrolled who underwent TAA with either the mobile-bearing Salto (Tornier and Integra) or the fixed-bearing Salto Talaris (Integra) in 3 centers by 2 surgeons between January 2004 and March 2018. All patients who underwent TAA from January 2004 to April 2013 received the Salto implant, and all patients who underwent TAA after November 2012 received the Salto Talaris implant. The primary outcome was time, within 3 years, to first all-cause reoperation, revision of any metal component, and revision of any component, including the polyethylene insert. Secondary outcomes included the frequency, cause, and type of reoperation. RESULTS: A total of 302 consecutive patients were included, of whom 171 received the mobile-bearing and 131 received the fixed-bearing implant. The adjusted hazard ratio for all-cause reoperation was 1.42 (95% confidence interval [CI], 0.67 to 3.00; p = 0.36); for component revision, 3.31 (95% CI, 0.93 to 11.79; p = 0.06); and for metal component revision, 2.78 (95% CI, 0.58 to 13.33; p = 0.20). A total of 31 reoperations were performed in the mobile-bearing group compared with 14 in the fixed-bearing group (p = 0.07). More extensive reoperation procedures were performed in the mobile-bearing group. CONCLUSIONS: With the largest comparison of 2 implants of similar design from the same manufacturer, the present study supports the use of a fixed-bearing design in terms of short-term failure. We found a 3-times higher rate of revision among mobile-bearing implants compared with fixed-bearing implants at 3 years after TAA. Reoperations, including first and subsequent procedures, tended to be less common and the causes and types of reoperations less extensive among fixed-bearing implants. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Seven ways to get a grip on implementing Competency-Based Medical Education at the program level.

Competency-based medical education (CBME) curricula are becoming increasingly common in graduate medical education. Put simply, CBME is focused on educational outcomes, is independent of methods and time, and is composed of achievable competencies.1 In spite of widespread uptake, there remains much to learn about implementing CBME at the program level. Leveraging the collective experience of program leaders at Queen's University, where CBME simultaneously launched across 29 specialty programs in 2017, this paper leverages change management theory to provide a short summary of how program leaders can navigate the successful preparation, launch, and initial implementation of CBME within their residency programs.

Les programmes de formation médicale fondée sur les compétences (FMFC) sont de plus en plus répandus dans les études supérieures en médecine. En termes simples, la FMFC est centrée sur les résultats scolaires, elle est indépendante des méthodes et du temps, et est constituée de compétences réalisables.1 Malgré cette adoption généralisée, il reste encore beaucoup à apprendre sur la mise en œuvre de la FMFC au niveau des programmes. Tirant profit de l'expérience collective des responsables de programmes à l'Université Queen, où la FMFC a été lancée simultanément dans 29 programmes de spécialité en 2017,le présent article s'appuie sur la théorie de la gestion du changement pour produire un court résumé de la manière dont les responsables de programmes peuvent gérer avec succès la préparation, le lancement et la mise en œuvre initiale de la FMFC au sein de leurs programmes de résidence.

Mortality risk in the French cohort of uranium miners: extended follow-up 1946-1999.

OBJECTIVES: This paper presents the risk of death from lung cancer and from other causes of death for the French cohort of uranium miners through 1999 and estimates associations with radon exposure. METHODS: The cohort includes men employed as uranium miners for at least 1 year between 1946 and 1990. For each miner, vital status and cause of death were obtained from the national registry, and radon exposure was reconstructed for each year. Standardised mortality ratios were computed with national mortality rates as references. Exposure-risk relationships were estimated by Poisson regression, with a linear excess relative risk (ERR) model and a 5-year lag. RESULTS: The cohort included 5086 miners and 153 063 person-years of exposure. The mean duration of follow-up was 30.1 years. In all 4140 miners exposed to radon, the average cumulative exposure was 36.6 working level months (WLM). There were 1411 deaths of miners <85 years of age. The miners did not differ significantly in overall mortality from the general male population. The analysis confirmed an excess risk of lung cancer death (n = 159; SMR = 1.43; 95% CI: 1.22 to 1.68), which increased significantly with cumulative radon exposure (ERR per 100 WLM = 0.71; 95% CI: 0.29 to 1.35). The ERR per unit exposure was much higher after 1955, when the accuracy of exposure measurement improved substantially (ERR per 100 WLM = 2.00; 95% CI: 0.91 to 3.65). A significant excess of kidney cancer deaths was observed (n = 20; SMR = 2.0; 95% CI: 1.22 to 3.09), which was not associated with cumulative radon exposure. No excess was observed for other causes of death, except silicosis (n = 23; SMR = 7.12; 95% CI: 4.51 to 10.69). CONCLUSIONS: The analysis confirmed the excess risk of death from lung cancer associated with low radon exposure. An excess risk of death from kidney cancer was also observed, apparently not associated with cumulative radon exposure.

The roles for innate lymphoid cells in the human immune system.

From constituting a novel and obscure cell population, innate lymphoid cells (ILCs) are now accepted as a self-evident part of the immune system, contributing with unique and complementary functions to immunity by production of effector cytokines and interaction with other cell types. In this review, we discuss the redundant and complementary roles of the highly plastic human ILCs and their interaction with other immune cells with the ultimate aim of placing ILCs in a wider context within the human immune system.

Immediate percutaneous sacroiliac screw insertion for unstable pelvic fractures: is it safe enough?

OBJECTIVES: The purpose of this study was to compare the results of immediate and delayed percutaneous sacroiliac screws surgery for unstable pelvic fractures, regarding technical results and complication rate. DESIGN: Retrospective study. SETTING: The study was conducted at the Soroka University Medical center, Beer Sheva, Israel, which is a level 1 trauma Center. PATIENTS: 108 patients with unstable pelvic injuries were operated by the orthopedic department at the Soroka University Medical Center between the years 1999-2010. A retrospective analysis found 50 patients with immediate surgery and 58 patients with delayed surgery. Preoperative and postoperative imaging were analyzed and data was collected regarding complications. INTERVENTION: All patients were operated on by using the same technique-percutaneous fixation of sacroiliac joint with cannulated screws. MAIN OUTCOME MEASUREMENTS: The study's primary outcome measure was the safety and quality of the early operation in comparison with the late operation. RESULTS: A total of 156 sacroiliac screws were inserted. No differences were found between the immediate and delayed treatment groups regarding technical outcome measures (P value = 0.44) and complication rate (P value = 0.42). CONCLUSIONS: The current study demonstrated that immediate percutaneous sacroiliac screw insertion for unstable pelvic fractures produced equally good technical results, in comparison with the conventional delayed operation, without additional complications.

Total hip arthroplasty using a cementless dual-mobility cup provides increased stability and favorable gait parameters at five years follow-up.

BACKGROUND: Rates of dislocation following primary total hip arthroplasty (THA) vary from 0.5 to 10%. Dual-mobility cups in THA demonstrate increased stability. Clinical outcomes following THA with dual-mobility cups have been reported, but gait has not been assessed. Therefore we performed a retrospective case control study to answer: (1) is gait better in patients following THA with a dual-mobility cup than in frail, elderly patients of the same age? (2) Are clinical outcomes better in patients following THA with a dual-mobility cup than in frail, elderly patients? (3) What is the dislocation rate following THA with a dual-mobility cup? HYPOTHESIS: We hypothesized that patients who underwent THA with a dual-mobility cup have a better gait compared to frail, elderly patients of the same age. PATIENTS AND METHODS: Twenty patients (22 hips), mean age 79.9±7.7 (range, 62.3-88.3) years were assessed in this retrospective case-control series 5.6±1.4 (range: 4.1-8.8) years following dual-mobility cup THA. A reference group consisted of 72 "frail elderly" patients in a rehabilitation hospital for health problems unrelated to the lower limb, with no lower limb surgery or neurological conditions. Temporal and spatial gait performance were measured with four miniature gyroscopes, mounted on each thigh and calf, while patients walked freely along a 30m corridor. Harris Hip Score, WOMAC, radiological outcomes, and dislocation rate were determined. RESULTS: All gait parameters were better in the dual-mobility group compared to the frail elderly group. The dual-mobility group had a higher cadence (100.3 steps/minute versus 75.6 steps/minute), shorter (relative to gait cycle time) stance (61.6% versus 67.8%), shorter (relative to gait cycle time) double stance (23.3% versus 36.0%), longer stride (1.13m versus 0.80m), and faster walking speed (0.96m/s versus 0.52m/s). Range of motion of the shank, thigh and knee were better in the dual-mobility group. Harris Hip Score was 87.6±13.9 (range 51-100) and WOMAC score was 11.3±12.1 (range 0-34) in the THA group. We observed no dislocations. DISCUSSION: Gait patterns five years following THA with the dual-mobility cup were better or comparable to published study populations. LEVEL OF EVIDENCE: III, retrospective case-control series.

Age-related changes in the metabolism and body composition of three dog breeds and their relationship to life expectancy.

We measured body composition and resting metabolic rates (RMR) of three dog breeds (Papillons, mean body mass 3.0 kg (n = 35), Labrador retrievers, mean body mass 29.8 kg (n = 35) and Great Danes, mean body mass 62.8 kg (n = 35)) that varied between 0.6 and 14.3 years of age. In Papillons, lean body mass (LBM) increased with age but fat mass (FBM) was constant; in Labradors, both LBM and FBM were constant with age, and in Great Danes, FBM increased with age but LBM was constant. FBM averaged 14.8% and 15.7% of body mass in Papillons and Labradors, respectively. Great Danes were leaner and averaged only 10.5% FBM. Pooling the data for all individuals, the RMR was significantly and positively associated with LBM and FBM and negatively associated with age. Once these factors had been taken into account there was still a significant breed effect on RMR, which was significantly lower in Labradors than in the other two breeds. Using the predictive multiple regression equation for RMR and the temporal trends in body composition, we modelled the expenditure of energy (at rest) over the first 8 years of life, and over the entire lifespan for each breed. Over the first 8 years of life the average expenditure of energy per kg LBM were 0.985, 0.675 and 0.662 GJ for Papillons, Labradors and Great Danes, respectively. This energy expenditure was almost 60% greater for the smallest compared with the largest breed. On average, however, the life expectancy for the smallest breed was a further 6 years (i.e. 14 years in total), whereas for the largest breed it was only another 6 months (i.e. 8.5 years in total). Total lifetime expenditure of energy at rest per kg LBM averaged 1.584, 0.918 and 0.691 GJ for Papillons, Labradors and Great Danes, respectively. In Labradors, total daily energy expenditure, measured by the doubly labelled water method in eight animals, was only 16% greater than the observed RMR. High energy expenditure in dogs appears positively linked to increased life expectancy, contrary to the finding across mammal species and within exotherms, yet resembling observations in other intra-specific studies. These contrasting correlations suggest that metabolism is affecting life expectancy in different ways at these different levels of enquiry.

Efficacy of antisense morpholino oligomer targeted to c-myc in prostate cancer xenograft murine model and a Phase I safety study in humans.

PURPOSE: The overexpression of c-myc associated with uncontrolled cell proliferation is a frequent genetic event in androgen-refractory prostatic neoplasia. The purpose of this study was to evaluate the bioavailability and efficacy of a novel antisense phosphorodiamidate morpholino oligomer directed against c-myc, AVI-4126, in PC-3 androgen-independent human prostate cancer xenograft murine model and its safety in a Phase I human clinical study. EXPERIMENTAL DESIGN: AVI-4126 administration in athymic mice bearing s.c. PC-3 xenografts was carried out to determine the bioavailability, tolerance, antitumor activity, and histological changes induced by targeted inhibition of c-Myc expression using a specific morpholine antisense oligomer. The Phase I safety study involved a single center, open label, dose-escalating design in healthy volunteers after i.v. administration of AVI-4126. RESULTS: The data reveal that AVI-4126 targets and inhibits c-myc translation in a sequence-specific manner and causes significant growth inhibition and apoptosis in prostate cancer cells and in s.c. tumor xenografts. A 75-80% reduction in tumor burden was observed in AVI-4126-treated animals compared with the scrambled oligomer and saline control groups. Histologically, tumors grown in the athymic mice treated with AVI-4126 were less cellular and vascular than those in control mice and showed an increased level of cellular degeneration, cytoplasmic vacuoles, and hyperchromatic nuclei. Phase I safety trials in humans via i.v. route of administration showed no toxicity or serious adverse events. CONCLUSIONS: The present study demonstrates that inhibition of c-Myc expression by antisense phosphorodiamidate morpholino oligomer is a promising new and safe therapeutic strategy for prostate cancer.

The effect of social environment on the immune response of female common voles in matriarchal laboratory groups.

We used the hemagglutination test to investigate differences in the specific immune response to sheep red blood cells (SRBC) of female common voles living in matriarchal groups. The applied test proved to be a useful tool for studying the effect of the social environment on the immune response in small mammals. The required blood sampling method did not affect reproductive traits. Young female common voles showed a higher immune response than their mothers, which could have been caused by their age and/or by the reproductive and social dominance of their mothers. In non-breeding groups, the lower immune response of mothers could be attributed to their increased activity in advertising their dominance thus leading to an energy reallocation with consequent immunosuppression. Social stress, caused by crowded conditions, can lower the immune response and the growth of young females, which cannot leave the dams' proximity. The results are discussed regarding their relevance to the population regulation of the common vole and the spread of diseases to humans.

Monitoring of a long survival myeloma patient.

Monitoring with anti-idiotypic sera has been applied to identify tumoral cells in a myeloma patient still alive in complete remission 9 years after diagnosis. Monoclonal plasma cells displayed a labeling index that decreased in complete remission below 1%. The great majority of B lymphocytes belonged to the tumoral clone even in complete remission and were therefore not affected by conventional chemotherapy. Some aspects of this myeloma patient are discussed in the light of these immunologic and kinetic findings. In addition, it is suggested that the therapeutic management of the complete remission should be re-examined, by considering a lymphocytolytic therapy.

Leukemia risk associated with chronic external exposure to ionizing radiation in a French cohort of nuclear workers.

Leukemia is one of the earliest cancer effects observed after acute exposure to relatively high doses of ionizing radiation. Leukemia mortality after external exposure at low doses and low-dose rates has been investigated at the French Atomic Energy Commission (CEA) and Nuclear Fuel Company (AREVA NC) after an additional follow-up of 10 years. The cohort included radiation-monitored workers employed for at least one year during 1950-1994 at CEA or AREVA NC and followed during 1968-2004. Association between external exposure and leukemia mortality was estimated with excess relative risk (ERR) models and time-dependent modifying factors were investigated with time windows. The cohort included 36,769 workers, followed for an average of 28 years, among whom 73 leukemia deaths occurred. Among the workers with a positive recorded dose, the mean cumulative external dose was 21.7 mSv. Results under a 2-year lag assumption suggested that the risk of leukemia (except chronic lymphatic leukemia) increased significantly by 8% per 10 mSv. The magnitude of the association for myeloid leukemia was larger. The higher ERR/Sv for doses received 2-14 years earlier suggest that time since exposure modifies the effect. The ERR/Sv also appeared higher for doses received at exposure rates ≥20 mSv per year. These results are consistent with those found in other studies of nuclear workers. However, confidence intervals are still wide. Further analyses should be conducted in pooled cohorts of nuclear workers.

Solid cancer mortality associated with chronic external radiation exposure at the French atomic energy commission and nuclear fuel company.

Studies of nuclear workers make it possible to directly quantify the risks associated with ionizing radiation exposure at low doses and low dose rates. Studies of the CEA (Commissariat à l'Energie Atomique) and AREVA Nuclear Cycle (AREVA NC) cohort, currently the most informative such group in France, describe the long-term risk to nuclear workers associated with external exposure. Our aim is to assess the risk of mortality from solid cancers among CEA and AREVA NC nuclear workers and its association with external radiation exposure. Standardized mortality ratios (SMRs) were calculated and internal Poisson regressions were conducted, controlling for the main confounding factors [sex, attained age, calendar period, company and socioeconomic status (SES)]. During the period 1968-2004, there were 2,035 solid cancers among the 36,769 CEA-AREVA NC workers. Cumulative external radiation exposure was assessed for the period 1950-2004, and the mean cumulative dose was 12.1 mSv. Mortality rates for all causes and all solid cancers were both significantly lower in this cohort than in the general population. A significant excess of deaths from pleural cancer, not associated with cumulative external dose, was observed, probably due to past asbestos exposure. We observed a significant excess of melanoma, also unassociated with dose. Although cumulative external dose was not associated with mortality from all solid cancers, the central estimated excess relative risk (ERR) per Sv of 0.46 for solid cancer mortality was higher than the 0.26 calculated for male Hiroshima and Nagasaki A-bomb survivors 50 years or older and exposed at the age of 30 years or older. The modification of our results after stratification for SES demonstrates the importance of this characteristic in occupational studies, because it makes it possible to take class-based lifestyle differences into account, at least partly. These results show the great potential of a further joint international study of nuclear workers, which should improve knowledge about the risks associated with chronic low doses and provide useful risk estimates for radiation protection.

Mortality among workers monitored for radiation exposure at the French nuclear fuel company.

A cohort of 9,285 nuclear workers employed at the French company AREVA NC specializing in the nuclear fuel cycle was established. Vital status, causes of death, employment characteristics and annual exposure to ionizing radiation were reconstructed for each individual over the time period 1977-2004. Standardized mortality ratios (SMRs) were computed using national mortality rates as an external reference. Tests for trends in mortality with duration of employment and cumulative external dose were performed. The all-cause and all-cancer mortality was significantly lower than expected from the French population. No significant excess among cancer sites studied was observed. Significant positive trends with cumulative dose were observed for colon and liver cancer and for respiratory diseases. Isolated significant trends should be carefully interpreted and considered in line with the large number of trend tests performed.

Gametic Differentiation of Chlamydomonas reinhardtii: Control by Nitrogen and Light.

Gametic differentiation of the unicellular green alga Chlamydomonas reinhardtii proceeds in two steps controlled by the extrinsic signals nitrogen deficiency and light. Nitrogen deprivation induces the differentiation of vegetative cells to sexually immature pregametes. A light signal is required to convert the pregametes to gametes. Both signals are also required for the maintenance of mating competence. Two converging signal transduction chains are proposed to control gamete formation. For the differentiation of pregametes to gametes, a fluence rate-dependent reaction, requiring continuous irradiation, is suggested by photobiological experiments.

A medical school fellowship program for minority high school students.

The effectiveness of a research program for minority high school students was evaluated. The program, supported by funding from the National Institutes of Health, was begun in 1982; during the subsequent five years, there were 59 applicants and 38 participants in the program. Of the responding 20 participants, 12 were pursuing careers in science and medicine, and half of the 16 respondents with career plans reported that the program had influenced their career decisions. Overall and in each year, black male students were underrepresented in both the applicant pool and the participants as compared with the metropolitan high school population.