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International audience; Background The COCCINELLE study is a nationwide retrospective French cohort set up to evaluate the risk of radiation associated cancer in patients who undergone cardiac catheterization (CC) procedures for diagnosis or treatment of congenital heart disease during childhood [1].Material and methods Children who undergone CC procedures from 01/01/2000 to 31/12/2013 before the age of 16 in one of the 15 pediatric cardiology departments which perform pediatric CC in mainland France were included. The follow-up started at the date of the first recorded CC procedure until the exit date, i.e. the date of death, the date of first cancer diagnosis, the date of the 18th birthday, or the 31/12/2015, whichever occurred first. The cohort was linked to the National Childhood Cancer Registry to identify patients diagnosed with cancer and with the French National Directory for the Identification of Natural Persons to retrieve the patients’ vital status. An external comparison was conducted using standardized incidence ratios (SIR). Breslow and Day’s approximation was used to estimate 95% confidence intervals (CI) for the SIRs [2]. Results A total of 17,104 children were included in the cohort and followed for 110,335 person-years, with 22,227 CC procedures collected. Among the patients, 81.6 % received only one procedure. Fifty-nine cancer cases were observed in the cohort. SIRs were increased for all-cancer (SIR = 3.8, 95% CI 2.9, 4.9), leukemia (SIR = 3.3, 95% CI 2.0, 5.4), lymphoma (SIR = 14.9, 95% CI 9.9, 22.5) and solid cancers excluding central nervous system tumors (SIR = 3.3, 95% CI 2.0, 5.5) compared with the general population. Conclusion Increased risks of cancer were observed. Potential explanations include shared genetic or environmental factors, immunosuppression drugs, and exposure to medical ionizing radiation procedures. The dose-response analysis between ionizing radiation doses received during CCs and cancer occurrence will allow to address this question.Keywords: Ionizing radiation, cardiac catheterization, congenital heart disease, cancerCompeting interestsThe authors declare that they have no competing of interest.References1.Baysson H, Nkoumazok B, Barnaoui S, Réhel J, Girodon B, Milani G, Boudjemline Y, Bonnet D, Laurier D, Bernier M (2015) Follow-up of children exposed to ionising radiation from cardiac catheterisation: the Coccinelle study. Radiation protection dosimetry 165:13–162.Breslow NE, Day NE (1987) Statistical Methods in Cancer Research Volume II: The Design and Analysis of Cohort Studies, IARC Scientific Publication. IARC Scientific Publication No. 82, Lyon, France: International Agency for Research on Cancer.NotesCOCCINELLE: French acronym for COhorte sur le risque de Cancer après Cardiologie INterventionnELLECC: Cardiac CatheterizationSIR: Standardized Incidence Ratios CI: Confidence IntervalsCNS: Central Nervous System

International audience; Within the European Epidemiological Study to Quantify Risks for Paediatric Computerized Tomography (EPI-CT study), a cohort was assembled comprising nearly one million children, adolescents and young adults who received over 1.4 million computed tomography (CT) examinations before 22 years of age in nine European countries from the late 1970s to 2014. Here we describe the methods used for, and the results of, organ dose estimations from CT scanning for the EPI-CT cohort members. Data on CT machine settings were obtained from national surveys, questionnaire data, and the Digital Imaging and Communications in Medicine (DICOM) headers of 437,249 individual CT scans. Exposure characteristics were reconstructed for patients within specific age groups who received scans of the same body region, based on categories of machines with common technology used over the time period in each of the 276 participating hospitals. A carefully designed method for assessing uncertainty combined with the National Cancer Institute Dosimetry System for CT (NCICT, a CT organ dose calculator), was employed to estimate absorbed dose to individual organs for each CT scan received. The two-dimensional Monte Carlo sampling method, which maintains a separation of shared and unshared error, allowed us to characterize uncertainty both on individual doses as well as for the entire cohort dose distribution. Provided here are summaries of estimated doses from CT imaging per scan and per examination, as well as the overall distribution of estimated doses in the cohort. Doses are provided for five selected tissues (active bone marrow, brain, eye lens, thyroid and female breasts), by body region (i.e., head, chest, abdomen/pelvis), patient age, and time period (1977-1990, 1991-2000, 2001-2014). Relatively high doses were received by the brain from head CTs in the early 1990s, with individual mean doses (mean of 200 simulated values) of up to 66 mGy per scan. Optimization strategies implemented since the late 1990s have resulted in an overall decrease in doses over time, especially at young ages. In chest CTs, active bone marrow doses dropped from over 15 mGy prior to 1991 to approximately 5 mGy per scan after 2001. Our findings illustrate patterns of age-specific doses and their temporal changes, and provide suitable dose estimates for radiation-induced risk estimation in epidemiological studies.

To describe computed tomography (CT) scanning parameters, volume CT dose index (CTDIvol) and dose-length product (DLP) in paediatric practice and compare them to current diagnostic reference levels (DRLs). The survey was conducted in radiology departments of six major university hospitals in France in 2010–2013. Data collection was automatised to extract and standardise information on scanning parameters from DICOM-header files. CTDIvol and DLP were estimated based on Monte Carlo transport simulation and computational reference phantoms. CTDIvol and DLP were derived for 4,300 studies, four age groups and 18 protocols. CTDIvol was lower in younger patients for non-head scans, but did not vary with age for routine head scans. Ratios of 95th to 5th percentile CTDIvol values were 2–4 for most body parts, but 5–7 for abdominal examinations and 4–14 for mediastinum CT with contrast, depending on age. The 75th percentile CTDIvol values were below the national DRLs for chest (all ages) and head and abdominal scans (≥10 years). The results suggest the need for a better optimisation of scanning parameters for routine head scans and infrequent protocols with patient age, enhanced standardisation of practices across departments and revision of current DRLs for children. • CTDIvol varied little with age for routine head scans. • CTDIvol was lowest in youngest children for chest or abdominal scans. • Individual and inter-department variability warrant enhanced standardisation of practices. • Recent surveys support the need for revised diagnostic reference levels. • More attention should be given to specific protocols (sinuses, neck, spine, mediastinum).

Background Long-term clinical effectiveness of biologics in psoriasis is needed. Objectives We aimed to assess the long-term persistence of biologics used to treat psoriasis in a real-life setting. Methods All adults with psoriasis having been registered in the French National Health Insurance database (SNIIRAM) between 2008 and 2016 were eligible for inclusion. Psoriasis was defined as the fulfilment of at least two prescriptions for topical formulations of a vitamin D derivative within a 2-year period. The study population comprised biologic-naive patients, i.e. those with a first prescription of etanercept, infliximab, adalimumab or ustekinumab. Persistence of treatment with a biologic was defined as the time interval between initiation and discontinuation. Results In this nationwide population-based cohort, 16 545 out of 874 549 patients with psoriasis were biologic-naive (mean age 48·6 years; males 57·3%, mean follow-up 3·6 years). The mean ± SD length of follow-up for biologic-naive patients was 3·6 ± 2·4 years. There were 9988 treatment discontinuations. Kaplan-Meier survival analyses revealed a persistence rate of 61·9% for the first, 33·3% for the third and 22·6% for the fifth year. Ustekinumab had a higher persistence rate than the other biologics. This finding should be interpreted with caution, in view of differences in administration between the biologics. About 85% of patients, having discontinued their first biologic, resumed systemic treatment of some type in the following year (biologics in 85% of cases). Conclusions Our data suggest that biologics are less effective than physicians have been led to believe in a real-life, nonselected population. Further, long-term disease control requires several courses of different biologics.

Background: Exposures to high-dose ionizing radiation and high-dose rate ionizing radiation are established risk factors for childhood acute leukemia (AL). The risk of AL following exposure to lower doses due to natural background radiation (NBR) has yet to be conclusively determined. Methods: AL cases diagnosed over 1990–2009 (9,056 cases) were identified and their municipality of residence at diagnosis collected by the National Registry of Childhood Cancers. The Geocap study, which included the 2,763 cases in 2002–2007 and 30,000 population controls, was used for complementary analyses. NBR exposures were modeled on a fine scale (36,326 municipalities) based on measurement campaigns and geological data. The power to detect an association between AL and dose to the red bone marrow (RBM) fitting UNSCEAR (United Nations Scientific Committee on the Effects of Atomic Radiation) predictions was 92%, 45% and 99% for exposure to natural gamma radiation, radon and total radiation, respectively. Results: AL risk, irrespective of subtype and age group, was not associated with the exposure of municipalities to radon or gamma radiation in terms of yearly exposure at age reached, cumulative exposure or RBM dose. There was no confounding effect of census-based socio-demographic indicators, or environmental factors (road traffic, high voltage power lines, vicinity of nuclear plants) related to AL in the Geocap study. Conclusions: Our findings do not support the hypothesis that residential exposure to NBR increases the risk of AL, despite the large size of the study, fine scale exposure estimates and wide range of exposures over France. However, our results at the time of diagnosis do not rule out a slight association with gamma radiation at the time of birth, which would be more in line with the recent findings in the UK and Switzerland. Citation: Demoury C, Marquant F, Ielsch G, Goujon S, Debayle C, Faure L, Coste A, Laurent O, Guillevic J, Laurier D, Hémon D, Clavel J. 2017. Residential exposure to natural background radiation and risk of childhood acute leukemia in France, 1990–2009. Environ Health Perspect 125:714–720; http://dx.doi.org/10.1289/EHP296

There are very few data on the prognosis of possible versus definite infective endocarditis (IE). We studied data from 365 consecutive patients with IE involving native heart valve seen in an academic institution from 1990 to 2012. Patients were classified according to the modified Duke criteria for IE: patients with possible IE (n = 101, 28%) and those with definite IE (n = 264, 72%). Patients with possible IE were older than those with definite IE (66 ± 15 vs 62 ± 16, p = 0.05). A causative microorganism was identified in 66% of patients with possible IE versus all patients with definite IE (p0.0001) and only 41% had major echocardiographic criteria (vs 100%; p0.0001). Overall, 139 patients died over a mean ± SD follow-up of 3.9 ± 4.5 years (median 2.2, interquartile range 5.9 years). Patients with possible and definite IE had a similar risk of death. Independent predictors of long-term mortality were increasing age (hazard ratio [HR] 1.02, 95% confidence interval [CI] 1.01 to 1.04; p = 0.0009), vegetation length15 mm (HR 1.87, 95% CI 1.14 to 3.06; p = 0.01), and stroke (HR 4.10, 95% CI 1.84 to 9.17; p = 0.0006), whereas infection of mitral valve (HR 0.57, 95% CI 0.34 to 0.94; p = 0.03) and surgery (HR 0.43, 95% CI 0.19 to 0.99; p = 0.05) were associated with a better prognosis. Patients with definite IE and those with possible IE who did not undergo surgery had a worse prognosis than their counterparts with surgery. In conclusion, unselected patients with possible IE (Duke criteria) had a similar prognosis than those with definite IE.

A "Facility-Exposure Matrix" (FEM) is proposed to assess exposure to chemical carcinogens and radionuclides in a cohort of nuclear workers. Exposures are to be attributed in the following way: a worker reports to an administrative unit and/or is monitored for exposure to ionising radiation in a specific workplace. These units are connected with a list of facilities for which exposure is assessed through a group of experts. The entire process of the FEM applied in one of the nuclear centres included in the study shows that the FEM is feasible: exposure durations as well as groups of correlated exposures are presented but have to be considered as possible rather than positive exposures. Considering the number of facilities to assess (330), ways to simplify the method are proposed: (i) the list of exposures will be restricted to 18 chemical products retained from an extensive bibliography study; (ii) for each of the following classes of facilities: nuclear reactors, fuel fabrication, high-activity laboratories and radiation chemistry, accelerators and irradiators, waste treatment, biology, reprocessing, fusion, occupational exposure will be deduced from the information already gathered by the initial method. Besides taking into account confusion factors in the low doses epidemiological study of nuclear workers, the matrix should help in the assessment of internal contamination and chemical exposures in the nuclear industry. © 2005 EDP Sciences.

International audience; A broad variety of methods for measurement error (ME) correction have been developed, but these methods have rarely been applied possibly because their ability to correct ME is poorly understood. We carried out a simulation study to assess the performance of three error-correction methods two variants of regression calibration (the substitution method and the estimation calibration method) and the simulation extrapolation (SIMEX) method. Features of the simulated cohorts were borrowed from the French Uranium Miners' Cohort in which exposure to radon had been documented from 1946 to 1999. In the absence of ME correction, we observed a severe attenuation of the true effect of radon exposure, with a negative relative bias of the order of 60% on the excess relative risk of lung cancer death. In the main scenario considered, that is, when ME characteristics previously determined as most plausible from the French Uranium Miners' Cohort were used both to generate exposure data and to correct for ME at the analysis stage, all three error-correction methods showed a noticeable but partial reduction of the attenuation bias, with a slight advantage for the SIMEX method. However, the performance of the three correction methods highly depended on the accurate determination of the characteristics of ME. In particular, we encountered severe overestimation in some scenarios with the SIMEX method, and we observed lack of correction with the three methods in some other scenarios. For illustration, we also applied and compared the proposed methods on the real data set from the French Uranium Miners' Cohort study. © 2012 John Wiley and Sons, Ltd.

Objective: To analyse the effectiveness and toxicity of aprotinin compared with tranexamic acid according to the type of cardiac surgery: coronary artery bypass or valve surgery. Setting: A French general hospital of 700 acute beds. Method: A retrospective study of benefit/risk ratio of aprotinin in adult cardiac surgery, which compare two periods (2000 vs. 2005) where mainly only anti-fibrinolytic treatment changed. Aprotinin was compared with tranexamic acid according to the type of surgery: coronary artery bypass or valve surgery. This study was conducted before the marketing application authorization of aprotinin was suspended. Main outcome measure: Blood loss during the first 24 h after intervention. The second outcome measures were mortality and spontaneous declaration of adverse drug effects. Results: Six hundred and seventy-six patients were included in our study. For coronary artery bypass, aprotinin appeared to be more effective than tranexamic acid to reduce blood loss after intervention (719 ± 41 mL vs. 947 ± 34 mL; p < 0.0001 during the first 24 h). For valvular surgery, there was no difference between the two anti-fibrinolytic drugs to decrease postoperative bleeding. No acute toxic effects were reported through the data bank of the department of cardiovascular surgery. Conclusions: Our preliminary results indicated that tolerance to aprotinin was as good as for tranexamic acid. Concerning its effectiveness, results differed according to the type of surgery. The benefit/risk ratio of aprotinin in our study was positive for coronary artery bypass surgery, but the use of tranexamic acid in valve surgery was as efficient and much less expensive than aprotinin. Our data suggest that even if the marketing application authorization of aprotinin was suspended, this drug should have clinical benefit for coronary artery bypass surgery. Therefore, our study shows that it is difficult to reach an unequivocal result about the use of aprotinin. Further investigations of aprotinin must be conducted in different types of cardiac surgery and among different patients populations like in pediatrics in which its efficiency and safety profiles are not clear. © 2010 Elsevier Masson SAS. All rights reserved.; Objectifs Étude de l’efficacité et de la toxicité de l’aprotinine comparativement à l’acide tranexamique selon deux types de chirurgie : pontage coronarien ou chirurgie valvulaire. Contexte Centre hospitalier français de 700 lits. Patients et méthode Étude rétrospective mesurant le rapport bénéfice/risque de l’aprotinine utilisée chez l’adulte en chirurgie cardiaque comparant deux périodes (2000 versus 2005) dont les changements en pratique concernaient essentiellement les traitements hémostatiques. L’aprotinine a été comparée à l’acide tranexamique selon deux types de chirurgie : le pontage coronarien et la chirurgie valvulaire. Cette étude a été effectuée avant le retrait de commercialisation de l’aprotinine. Principal critère d’évaluation Volume de perte sanguine durant les premières 24 heures après l’intervention. Les critères secondaires d’évaluation étaient le taux de mortalité et d’effets indésirables. Résultats Six cent soixante-seize patients ont été inclus dans l’étude. Dans le cas du pontage coronarien, l’aprotinine semblait diminuer les pertes sanguines plus efficacement que l’acide tranexamique (719 ± 41 mL versus 947 ± 34 mL ; p < 0,0001 durant les premières 24 heures). En chirurgie valvulaire, aucune différence significative n’a été observée entre les deux hémostatiques quant à la diminution des saignements postopératoires. Aucun effet indésirable aigu n’a été relevé dans la base de données du département de chirurgie cardiaque. Conclusions Cette étude a montré que l’aprotinine et l’acide tranexamique ont un profil de tolérance similaire. Concernant l’efficacité, nos résultats diffèrent selon le type de chirurgie. Le ratio bénéfice/risque est en faveur de l’aprotinine pour le pontage coronarien, mais l’utilisation de l’acide tranexamique en chirurgie valvulaire est aussi efficace mais beaucoup moins chère que l’aprotinine. Nos résultats suggèrent que même si l’aprotinine a été retirée du marché, elle pouvait présenter un intérêt clinique dans le pontage coronarien. Par conséquent, notre étude a montré qu’il est difficile d’aboutir à un résultat univoque concernant l’utilisation de l’aprotinine. D’autres investigations seraient nécessaires afin d’étudier l’aprotinine dans d’autres types de chirurgie cardiaque et chez différentes populations de patients, notamment chez les enfants dont les profils d’efficacité et de tolérance de l’aprotinine ne sont pas encore établis.

Objective: To analyse the effect of external radiation exposure on the mortality of French nuclear workers. Methods: A cohort of 29 204 workers employed between 1950 and 1994 at the French Atomic Energy Commission (Commissariat a l’Energie Atomique (CEA)) or at the General Company of Nuclear Fuel (COmpagnie GEnerale des MAtieres nucleaires (Cogema, now Areva NC)) was followed up for an average of 17.8 years. Standardised mortality ratios (SMRs) were computed with reference to French mortality rates. Dose-effect relationship were analysed through trend tests and Poisson regression, with linear and log-linear models. Results: The mean exposure to X and gamma radiation was 8.3 mSv (16.9 mSv for exposed worker population). A total of 1842 deaths occurred between 1968 and 1994. A healthy worker effect was observed, the number of deaths in the cohort being 59% of the number expected from national mortality statistics. Among the 21 main cancer sites studied, a statistically significant excess was observed only for skin melanoma, and an excess of borderline statistical significance was observed for multiple myeloma. A dose-effect relationship was observed for leukaemia after exclusion of chronic lymphoid leukaemia (CLL). The relative risk observed for non-CLL leukaemia, n = 20, was 4.1 per 100 mSv (90% CI 1.4 to 12.2), linear model and 2.2 per 100 mSv (90% CI 1.2 to 3.3), log-linear model. Significant dose-effect relationship were also observed for causes of deaths associated with alcohol consumption: mouth and pharynx cancer, cirrhosis and alcoholic psychosis and external causes of death. Conclusion: The risk of leukaemia increases with increasing exposure to external radiation; this is consistent with published results on other nuclear workers cohorts.

Objectives: To provide direct estimates of risk of cancer after protracted low doses of ionising radiation and to strengthen the scientific basis of radiation protection standards for environmental, occupational, and medical diagnostic exposures. Design: Multinational retrospective cohort study of cancer mortality. Setting: Cohorts of workers in the nuclear industry in 15 countries. Participants: 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person years. Main outcome measurements: Estimates of excess relative risks per sievert (Sv) of radiation dose for mortality from cancers other than leukaemia and from leukaemia excluding chronic lymphocytic leukaemia, the main causes of death considered by radiation protection authorities. Results: The excess relative risk for cancers other than leukaemia was 0.97 per Sv, 95% confidence interval 0.14 to 1.97. Analyses of causes of death related or unrelated to smoking indicate that, although confounding by smoking may be present, it is unlikely to explain all of this increased risk. The excess relative risk for leukaemia excluding chronic lymphocytic leukaemia was 1.93 per Sv (< 0 to 8.47). On the basis of these estimates, 1-2% of deaths from cancer among workers in this cohort may be attributable to radiation. Conclusions: These estimates, from the largest study of nuclear workers ever conducted, are higher than, but statistically compatible with, the risk estimates used for current radiation protection standards. The results suggest that there is a small excess risk of cancer, even at the low doses and dose rates typically received by nuclear workers in this study.