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The consequences of the withdrawal of marketing authorisation of drugs have mostly been studied considering drug prescription patterns for the therapeutic alternatives of the withdrawn drugs. The potential concomitant changes in the reporting of adverse reactions concerning these alternatives have been studied less often. The objective of this study was to analyse the changes in the reporting of adverse events (AEs) for therapeutic alternatives after the withdrawal of three medicines (dextropropoxyphene, pioglitazone and tetrazepam) from the market for safety reasons. This study was performed using both the French pharmacovigilance database and the Echantillon Generaliste des Beneficiaires (a random sample of French health insurance affiliates). For dextropropoxyphene, pioglitazone and tetrazepam alternatives, the number and types of case reports were studied for both the year preceding the first official safety warning and the year following the withdrawal. Reporting rates expressed per 10,000 reimbursements (RRReimb) and per 10,000 treated patients (RRPat) were also compared for the two periods. After dextropropoxyphene withdrawal, case reports and reimbursements increased for tramadol (case reports: +23%, reimbursements: +13%) and codeine (case reports: +74%, reimbursements: +47%), RRPat being significantly increased for tramadol (0.92 vs. 1.06, p = 0.02). After pioglitazone withdrawal, case reports increased for dipeptidyl peptidase-4 (DPP-4) inhibitors, glinides, and glucagon-like peptide 1 (GLP-1) analogues (+84%, +22% and +5%, respectively) and reimbursements (+55, +11 and +50%, respectively); both decreased for sulfonylureas (case reports: −6%, reimbursements: −2%). RRPat increased for DPP-4 inhibitors (1.63 vs. 2.26, p = 0.008). After tetrazepam withdrawal, case reports increased for diazepam, methocarbamol and thiocolchicoside (+110, +86 and +157%, respectively), as lesser did reimbursements. RRPat increased for diazepam (1.78 vs. 2.41, p = 0.054) and thiocolchicoside (0.14 vs. 0.24, p = 0.013). For the three drug withdrawals investigated, the number of case reports involving alternatives increased to a larger extent than the numbers of prescriptions. This could relate to a higher occurrence of AEs in new users of alternatives who switched from the withdrawn medicines or to an increased awareness of possible AEs.

Non-compliance situations happen when patients do not follow their prescriptions and take actions that lead to potentially harmful situations. Although such situations are dangerous, patients usually do not report them to their physicians. Hence, it is necessary to study other sources of information. We propose to study online health fora. The purpose of our work is to explore online health fora with supervised classification and information retrieval methods in order to identify messages that contain drug non-compliance. The supervised classification method permits detection of non-compliance with up to 0.824 F-measure, while the information retrieval method permits detection non-compliance with up to 0.529 F-measure. For some fine-grained categories and new data, it shows up to 0.65-0.70 Precision.

Resume Objectif Le devenir professionnel des asthmatiques est souvent defavorable avec des consequences frequentes de l’asthme sur le statut socioeconomique (diminution de revenus et/ou perte de l’emploi). L’objectif de ce travail etait d’etudier l’itineraire socioprofessionnel des asthmatiques a partir des donnees de l’enquete Sante et itineraire professionnel. Methodes En 2006, 13 648 individus de 20 a 74 ans vivant en France metropolitaine en menage ordinaire ont participe a l’enquete. En 2010, ils ont ete recontactes et 11 220 individus ont ete reinterroges. La presente analyse a porte sur les 11 068 individus ayant participe aux deux vagues de l’enquete et ayant un itineraire professionnel. L’asthme aux differents moments de la vie a ete repere par les declarations des individus. Les antecedents professionnels et medicaux ont ete recueillis. Resultats Chez les femmes, apres ajustement sur l’âge, la probabilite d’etre asthmatique etait plus elevee chez celles ayant eu au moins une periode de chomage au cours de leur itineraire professionnel, une duree de periodes de chomage de plus d’un an et une duree d’emploi plus courte, et etait plus faible chez celles ayant les revenus les plus eleves. Entre 2006 et 2010, les femmes asthmatiques ont connu plus frequemment des periodes de chomage et des arrets maladie que les non-asthmatiques. Aucune difference statistiquement significative n’etait observee chez les hommes. Conclusions Ces resultats suggerent que les femmes asthmatiques comparees au non-asthmatiques, connaissent des parcours professionnels plus instables et ont des revenus inferieurs, ce qui n’est pas observe chez les hommes. Les cohortes Coset et Constances devraient permettre d’etudier plus en detail l’impact de l’asthme sur la carriere professionnelle des travailleurs.

International audience; Misuses occur when patients do not respect prescriptions and commit actions which can lead to harmful results. Even if such situations are dangerous, patients do not inform medical doctors about such events. To obtain some information on misuses, it becomes necessary to study other sources of information. We propose to concentrate on discussion fora. The purpose of our work is to explore health fora with machine learning methods and to identify messages where users describe or mention drug misuses. Our approach detects the mesuses with up to 0.773 F-measure. This approach can help in routine detection of misuses and to provide material exploitable by health professionals.

International audience

International audience; The relatively recent development of industries working with nanomaterials has created challenges for exposure assessment. In this article, we propose a relatively simple approach to assessing nanomaterial exposures for the purposes of epidemiological studies of workers in these industries. This method consists of an onsite industrial hygiene visit of facilities carried out individually and a description of workstations where nano-objects and their agglomerates and aggregates (NOAA) are present using a standardized tool, the Onsite technical logbook. To assess its reliability, we implemented this approach for assessing exposure to NOAA in workplaces at seven workstations which synthesize and functionalize carbon nanotubes. The prediction of exposure to NOAA using this method exhibited substantial agreement with that of the reference method, the latter being based on an onsite group visit, an expert’s report and exposure measurements (Cohen kappa = 0.70, sensitivity = 0.88, specificity = 0.92). Intramethod comparison of results for exposure prediction showed moderate agreement between the three evaluators (two program team evaluators and one external evaluator) (weighted Fleiss kappa = 0.60, P = 0.003). Interevaluator reliability of the semiquantitative exposure characterization results was excellent between the two evaluators from the program team (Spearman rho = 0.93, P = 0.03) and fair when these two evaluators’ results were compared with the external evaluator’s results. The project was undertaken within the framework of the French epidemiological surveillance program EpiNano. This study allowed a first reliability assessment of the EpiNano method. However, to further validate this method a comparison with robust quantitative exposure measurement data is necessary.

Purpose of the study. To develop an operational method for identifying workers potentially exposed to manufactured nano-objects and their aggregates and agglomerates (NOAA) and assessing their potential exposure in frame of epidemiological surveillance program EpiNano. Method. The method was developed by a multidisciplinary working group. It consists of a company visit guided by a standardized tool "Field technical logbook". This tool enables assessing a set of parameters necessary for identification and characterization of workstations concerned with NOAA exposure, namely a detailed description of tasks and processes, personal and collective protection equipment, NOAA characteristics before and after transformation and other exposure surrounding conditions. The method was tested in ten companies. After each visit, all information collected in the logbook was computerized via a friendly-using application. A pdf copy of data was sent to the company along with proceedings of the visit listing workstations classified as concerned with NOAA exposure, for verification and validation. Results. All proceedings were validated. Among 53 workstations. observed during all the visits, 30 (57 %) were classified as concerned with NOAA exposure, namely workstations dealing with NOAA synthesis, sampling, transfer and functionalization. In private companies, there were 60 % of workstations classified as concerned with NOAA exposure versus 54 % in public companies. Numerous parameters were likely to determine the exposure classification, particularly humidity and dustiness of the NOAA powders. The assessment of these parameters might be useful for all companies since it also serves in implementing exposure control banding. Conclusion. This simple and non-instrumental method (without aerosol sampling and measurements) was developed for epidemiologists but could be useful to all occupational health actors in the field of nanotechnology.; Objectif : Proposer une méthode opérationnelle pour identifier les travailleurs potentiellement exposés aux nano-objets manufacturés, leurs agrégats et agglomérats (NOAA) et caractériser leur exposition potentielle dans le dispositif de surveillance épidémiologique EpiNano. Méthode : La méthode a été conçue par un groupe de travail pluridisciplinaire. Elle repose sur une visite d’entreprise, guidée par un outil intitulé carnet d’observation technique (COT). Il permet de relever, dans un ordre logique, des éléments nécessaires au repérage et à la caractérisation des postes exposants, notamment les procédés mis en œuvre, l’aéraulique des ateliers, les équipements de protection, les caractéristiques des NOAA à l’entrée et à la sortie du poste, les conditions de leur manipulation, de la tenue du poste et de sa maintenance. La méthode a été testée au sein de dix entreprises. À l’issue de chaque visite, un compte rendu de mission listant les postes potentiellement exposant aux NOAA était envoyé à l’entreprise visitée. La copie des informations informatisées du COT était jointe au compte rendu pour vérification et validation. Résultats : L’ensemble des comptes rendus des missions a été validé. Parmi les 53 postes observés, 30 (57 %) ont été classés potentiellement exposant, notamment les postes de synthèse, d’échantillonnage, de transfert et de fonctionnalisation des NOAA. La proportion de postes de travail potentiellement exposant aux NOAA était de 54 % dans les entreprises privées et de 60 % dans les entreprises publiques. De nombreux paramètres semblent déterminants dans le classement d’un poste de travail, notamment la pulvérulence et la teneur en humidité des NOAA. La connaissance de ces paramètres peut également servir dans l’application de l’approche de gestion graduée du risque, et par conséquent être utile à l’entreprise. Conclusion : Cette méthode simple et non instrumentale (sans prélèvement et sans mesure de l’aérosol) conçue pour des épidémiologistes pourrait servir à l’ensemble des acteurs en santé et prévention au travail impliqués dans la gestion des risques liés aux nanomatériaux.

Cet article présente la méthode ayant été testée et optimisée dans le cadre du dispositif de surveillance épidémiologique des travailleurs potentiellement exposés aux nanomateriaux en France, EpiNano. Cette méthode intègre les préconisations de l'INRS, de l'INERIS et du CEA dans l'étude dite de situation préalable à une campagne de mesurage. Elle se matérialise par un outil pragmatique : le Carnet d'observation technique (COT). Il s'agit d'un outil de collecte d'informations, conçu pour des épidémiologistes, qui pourrait servir à l'ensemble des acteurs de la santé et prévention au travail impliqués dans la gestion des risques liés aux nanomatériaux.

The fibrogenicity and carcinogenicity of asbestos fibers are dependent on several fiber parameters including fiber dimensions. Based on the WHO (World Health Organization) definition, the current regulations focalise on long asbestos fibers (LAF) (Length: L ≥ 5 μm, Diameter: D < 3 μm and L/D ratio > 3). However air samples contain short asbestos fibers (SAF) (L < 5 μm). In a recent study we found that several air samples collected in buildings with asbestos containing materials (ACM) were composed only of SAF, sometimes in a concentration of ≥10 fibers.L-1. This exhaustive review focuses on available information from peer-review publications on the size-dependent pathogenetic effects of asbestos fibers reported in experimental in vivo and in vitro studies. In the literature, the findings that SAF are less pathogenic than LAF are based on experiments where a cut-off of 5 μm was generally made to differentiate short from long asbestos fibers. Nevertheless, the value of 5 μm as the limit for length is not based on scientific evidence, but is a limit for comparative analyses. From this review, it is clear that the pathogenicity of SAF cannot be completely ruled out, especially in high exposure situations. Therefore, the presence of SAF in air samples appears as an indicator of the degradation of ACM and inclusion of their systematic search should be considered in the regulation. Measurement of these fibers in air samples will then make it possible to identify pollution and anticipate health risk. © 2014 Boulanger et al. licensee BioMed Central Ltd., SCOPUS: re.j, info:eu-repo/semantics/published

MSD represents the primary cause of occupational illness and the occupational health physician would appear to be a determining stakeholder in prevention. The studies of risk factors of MSD are important but the studies of intervention are limited. The objective of our research is double: understand the practices of occupational health physician and give the means of activity development. Theoretical framework is multidisciplinary approach about activity analysis. The problematic is to produce knowledge of activity of occupational health physicians to take into account their activity in the debate of professional evolution and pluridisciplinarity in health of work. The disciplinary skills of each equip of research produce some methods. Fifty physicians participate in our research. We have observed during 60 day with ergonomics methods, notably 200 sequences of medical consultation with protocol to record data, confirmed by institutions of protection of physician profession and protection of data. Some types of interview are realized (65): semi-directive, clarification, simple self-confrontation, cross self-confrontation. Furthermore, our research is based on the objective to develop the activity of occupational health physicians. To do this, we set up four groups of volunteer occupational health physicians. The discussion of groups is based on objective data of activity (14 discussion sessions) and on instruction of double (15 discussions sessions). All equips of our research have building a common reference to facilitate the data exploitation. Each equip has written one or some articles (in annex of report) to keep this specificity of data production based of disciplinary approach. The first result is that there are some skills of occupational health physicians to make prevention. Someone physicians prefer to realize their action in consultation while the others prefer make intervention in company. The professionals styles of physicians according to the gender building with experience and training depend on context of company, legislative prevention system, relationship between stakeholders and operators, which facilitate or slow down to built the room of maneuver to exercise these professional styles. The activity of physician can be to hamper in certain conditions. The occupational health physicians are the only one to follow the operators, the story of company and relationships of stakeholders, the evolution of health and work. They use their knowledge about work in company to help operator to understand the relation between work and health. They mobilize the words using by operators in consultation, with respected the medical secret, to modify the stakeholders representation of the interaction between work and health. In the other words, it is impossible to separate the individual approach and collective approach in prevention activity of occupational health physician. These different approaches organize the actions of physician. The discussion of research led to questioning the legislative evolution and comparing our French system with de others system like Quebec system.; Les TMS constituent l'une des premières maladies professionnelles et les médecins du travail jouent un rôle important dans la prévention. Aujourd'hui les connaissances sur les facteurs de risque à l'origine de cette pathologie font l'objet de débats sur la prévention des TMS. Les recherches ont besoin d'évoluer vers une meilleure connaissance des modalités de prise en charge de ce risque par les professionnels de la prévention. L'objectif de notre recherche est donc double : comprendre les pratiques des médecins du travail et participer au développement de leur activité de prévention. Notre cadre théorique multidisciplinaire (ergonomie, clinique du travail, sociologie du travail) est celui de l'analyse du travail. Notre problématique est la production de connaissances sur l'activité réelle du médecin afin de contribuer au débat sur les évolutions de leur métier et la pluridisciplinarité en santé au travail. Plusieurs méthodologies ont été mises en œuvre selon les compétences et les disciplines de chaque équipe de recherche. Une cinquantaine de médecins volontaires ont participé à notre recherche. Nous avons fait plus de 60 jours d'observation ergonomique du travail sur le terrain, dont 200 observations de consultation avec un protocole validé par le conseil de l'ordre et la CNIL. Différentes formes d'entretiens (au total 65) ont été réalisés (semi-directif, d'explicitation, d'auto-confrontation simple et croisé). Afin de contribuer au développement de l'activité de prévention des médecins du travail, nous avons constitué quatre groupes de pairs qui ont pu échanger sur les traces de leur activité réelle (au total, 14 réunions collectives) et à partir des méthodologies d'instruction du sosie (au total, 15 réunions collectives). Nos équipes de recherche ont partagé un référentiel commun afin de faciliter l'exploitation des données. Pour ne pas perdre la spécificité de chaque discipline, chaque équipe a écrit un ou plusieurs textes (en annexes du rapport) qui constituent la base d'un document de synthèse. Premier résultat, il existe plusieurs manières et façons de faire de la prévention des TMS chez les médecins du travail. Certains médecins privilégient une action en consultation alors que d'autres sont plus dans une action en entreprise. Mais ces styles, s'ils correspondent à des postures professionnelles construites avec l'expérience et le parcours de formation, sont très dépendants du contexte de l'entreprise, des dispositifs légales de prévention et du type de relations avec les salariés, les acteurs de l'entreprise et de la prévention, qui rendent plus ou moins possibles leurs mises en œuvre. L'activité du médecin dans certaines conditions est empêchée. Les médecins du travail sont les seuls intervenants de la prévention à tenir dans la continuité l'histoire de l'entreprise, des relations, de la santé. Ils ramènent leurs connaissances sur le travail pour aider le salarié à faire les liens entre le travail et la santé. Ils mobilisent la parole des salariés issue de la consultation dans les espaces d'échanges publics de l'entreprise, tout en respectant le secret médical, afin de modifier la représentation des acteurs sur les liens travail-santé. Autrement dit, il est impossible dans l'activité de prévention du médecin de délier l'approche individuelle et collective car celles-ci sont sans arrêt articuler et combiner. Cela conduit à s'interroger sur l'évolution de la loi et à comparer les pratiques avec d'autres systèmes de prévention, comme celui du Québec.

International audience; Background: Large data sets with many variables provide particular challenges when constructing analytic models. Lasso-related methods provide a useful tool, although one that remains unfamiliar to most epidemiologists. Methods: We illustrate the application of lasso methods in an analysis of the impact of prescribed drugs on the risk of a road traffic crash, using a large French nationwide database (PLoS Med 2010; 7:e1000366). In the original case-control study, the authors analyzed each exposure separately. We use the lasso method, which can simultaneously perform estimation and variable selection in a single model. We compare point estimates and confidence intervals using (1) a separate logistic regression model for each drug with a Bonferroni correction and (2) lasso shrinkage logistic regression analysis. Results: Shrinkage regression had little effect on (bias corrected) point estimates, but led to less conservative results, noticeably for drugs with moderate levels of exposure. Carbamates, carboxamide derivative and fatty acid derivative antiepileptics, drugs used in opioid dependence, and mineral supplements of potassium showed stronger associations. Conclusion: Lasso is a relevant method in the analysis of databases with large number of exposures and can be recommended as an alternative to conventional strategies.

The benchmarking, a managerial process of best practices implementation at the best cost, is a recent concept in the health system. The objectives of this paper were to define the concept and its evolution in the healthcare sector, to suggest an operational definition and to describe French and international ways of implementing benchmarking in healthcare. A non-exhaustive literature review was carried out in the industrial and service sectors to answer the first two objectives and in the healthcare sector the latter one. Benchmarking is most often used for the comparison of indicators. It is yet not perceived as a tool based on a voluntary and active cooperation among several organizations to build emulation and implement best practices. The main characteristic of a real benchmarking approach in indeed to participate in a global and participative continuous improvement. Among the key factors of success, are an appropriate and thorough preparation of the project, a monitoring based on relevant indicators, frontline staff involvement and interhealthcare organisation visits. Compared to methods previously implemented in France (Breakthough series and Collaboratives), benchmarking includes specificities which enable this approach to be considered as innovative in healthcare. Specifically, its implementation by healthcare or social organisations will be perceived as new because the principle of visits inter-institutions do not belong to the local culture. An evaluation of its feasibility and acceptability is therefore necessary before generalisation., Le benchmarking, démarche managériale de mise en œuvre des meilleures pratiques au meilleur coût, est un concept récent dans le système de santé. Les objectifs de cet article sont de mieux comprendre ce concept et son évolution dans le secteur de la santé, de proposer une définition opérationnelle et de décrire quelques expériences françaises et internationales dans le secteur de la santé. À cette fin, nous avons réalisé une revue de la littérature explorant le contexte d'émergence d'une telle approche dans le milieu industriel, son évolution, ses champs d'application et des exemples d'application de cette méthode dans le secteur de la santé. Le benchmarking est souvent considéré comme la comparaison d'indicateurs et n'est pas perçu dans son entièreté, à savoir comme un outil fondé sur une collaboration volontaire et active entre plusieurs organisations en vue de créer une émulation et de mettre en application les meilleures pratiques. La principale caractéristique du benchmarking est son inscription dans une politique globale et participative d'amélioration continue de la qualité. Les conditions de réussite s'axent essentiellement sur la bonne préparation de la démarche, le suivi d'indicateurs pertinents, l'implication du personnel et la conduite de visites entre structures. Par rapport à des méthodes antérieurement mises en oeuvre en France (programme d'amélioration continue [PAC] et projets collaboratifs), le benchmarking comporte des spécificités permettant de considérer cette approche comme innovante en santé. Elle le sera tout particulièrement pour les établissements de santé ou médicosociaux car le principe des visites interétablissements n'est pas inscrit dans leurs cultures. Une évaluation de sa faisabilité et de son acceptabilité est donc nécessaire avant toute promotion de cette démarche.

International audience; Pulmonary circulation could be one of the primary vascular targets of finest particles that can deeply penetrate into the lungs after inhalation. We investigated the effects of engineered nanoparticles on vasomotor responses of small intrapulmonary arteries using isometric tension measurements. Acute in vitro exposure to carbon nanoparticles (CNP) decreased, and in some case abolished, the vasomotor responses induced by several vasoactive agents, whereas acute exposure to titanium dioxide nanoparticles (TiO(2)NP) did not. This could be attributed to a decrease in the activity of those vasoactive agents (including PGF(2)(alpha), serotonin, endothelin-1 and acetylcholine), as suggested when they were exposed to CNP before being applied to arteries. Also, CNP decreased the contraction induced by 30 mM KCl, without decreasing its activity. After endoplasmic reticulum calcium stores depletion (by caffeine and thapsigargin), CaCl(2) addition induced a contraction, dependent on Store-Operated Calcium Channels that was not modified by acute CNP exposure. Further addition of 30 mM KCl elicited a contraction, originating from activation of Voltage-Operated Calcium Channels that was diminished by CNP. Contractile responses to PGF(2)(alpha) or KCl, and relaxation to acetylcholine were modified neither in pulmonary arteries exposed in vitro for prolonged time to CNP or TiO(2)NP, nor in those removed from rats intratracheally instilled with CNP or TiO(2)NP. In conclusion, prolonged in vitro or in vivo exposure to CNP or TiO(2)NP does not affect vasomotor responses of pulmonary arteries. However, acute exposure to CNP decreases contraction mediated by activation of Voltage-Operated, but not Store-Operated, Calcium Channels. Moreover, interaction of some vasoactive agents with CNP decreases their biological activity that might lead to misinterpretation of experimental data.

International audience; The evolution of pleural cancers and malignant pleural mesothelioma incidence in France between 1980 and 2005 was analysed using data derived from the French network of cancer registries (FRANCIM) and the French National Mesothelioma Surveillance Program (PNSM). Mesothelioma proportions in pleural cancers were calculated by diagnosis year in the 1980-2000 period. Our results suggest that the incidences of pleural cancer and mesothelioma levelled off in French men since 2000 and continued to increase in French women. A decrease of the annual pleural cancer incidence average in men was noticed (-3.4% of annual rate of change) between 2000 and 2005. The proportion of pleural cancers that were mesothelioma was unchanged between 1980 and 2003 with an average of 86%. The age standardised incidence rate of pleural mesothelioma remained relatively stable between 1998 and 2005 with a slight falling trend. For women, the age standardised incidence rate of pleural cancers and mesothelioma increased during the period 1998-2005. Additionally, the proportion of pleural cancers that were mesothelioma increased during the same period of time. Finally, the increased trend observed in the incidence of pleural mesothelioma and cancers in women is credibly due to their under diagnosis in the 1980-1997 period. The comparison between the French incidence and the American and British ones shows that the decreasing trend in incidence of mesothelioma and pleural cancers in French men since 2000 is potentially associated with a lower amphibole consumption and by the implementation of safety regulations at work from 1977. (c) 2009 UICC.

International audience; Nanotechnology, defined as techniques aimed to design, characterize and produce materials on a nanometer scale, is a fast-growing field today. Nanomaterials are made of nanoobjects (nanoparticles, nanofibers, nanotubes...). The nanoscale confers on these materials their novel, hitherto unknown, chemical and physical properties by the laws of quantum physics which are essentially expressed on this scale. Nanotechnology applications are numerous (e.g., cosmetics, industry and medicine) and they keep growing. We can safely predict that the production and utilization of nanomaterials will increase greatly in the years to come. Nonetheless, the same properties that make these nanomaterials very attractive are a source of concern: there are questions about their potential toxicity, their long-term side effects, and their biodegradability. These questions are based on knowledge of the toxic effects of micrometric particles in air pollution and the fear that these effects will be amplified because of the nanometric size of the new materials. We present in this article a global but not exhaustive summary of current knowledge. We begin by defining lung penetration, deposition, translocation and elimination of nanoparticles. Finally, we consider the respiratory effects of metallic nanoparticles, titanium dioxide nanoparticles in particular, and carbon nanotubes. In vivo and in vitro experimental studies currently available highlight the existence of biological effects of nanoparticles on the respiratory system with generation of oxidative stress, pro-inflammatory and pro-thrombotic effects and the possible development of fibrosis and pulmonary emphysema or DNA damage. A better understanding of the potential biological effects of nanoparticles is required to implement appropriate preventive measures in the workplace and/or in the general population, if this should be necessary.

International audience; Nanotechnology, defined as techniques aimed to design, characterize and produce materials on a nanometer scale, is a fast-growing field today. Nanomaterials are made of nanoobjects (nanoparticles, nanofibers, nanotubes...). The nanoscale confers on these materials their novel, hitherto unknown, chemical and physical properties by the laws of quantum physics which are essentially expressed on this scale. Nanotechnology applications are numerous (e.g., cosmetics, industry and medicine) and they keep growing. We can safely predict that the production and utilization of nanomaterials will increase greatly in the years to come. Nonetheless, the same properties that make these nanomaterials very attractive are a source of concern: there are questions about their potential toxicity, their long-term side effects, and their biodegradability. These questions are based on knowledge of the toxic effects of micrometric particles in air pollution and the fear that these effects will be amplified because of the nanometric size of the new materials. We present in this article a global but not exhaustive summary of current knowledge. We begin by defining lung penetration, deposition, translocation and elimination of nanoparticles. Finally, we consider the respiratory effects of metallic nanoparticles, titanium dioxide nanoparticles in particular, and carbon nanotubes. In vivo and in vitro experimental studies currently available highlight the existence of biological effects of nanoparticles on the respiratory system with generation of oxidative stress, pro-inflammatory and pro-thrombotic effects and the possible development of fibrosis and pulmonary emphysema or DNA damage. A better understanding of the potential biological effects of nanoparticles is required to implement appropriate preventive measures in the workplace and/or in the general population, if this should be necessary.

International audience; Nanotechnology, defined as techniques aimed to design, characterize and produce materials on a nanometer scale, is a fast-growing field today. Nanomaterials are made of nanoobjects (nanoparticles, nanofibers, nanotubes...). The nanoscale confers on these materials their novel, hitherto unknown, chemical and physical properties by the laws of quantum physics which are essentially expressed on this scale. Nanotechnology applications are numerous (e.g., cosmetics, industry and medicine) and they keep growing. We can safely predict that the production and utilization of nanomaterials will increase greatly in the years to come. Nonetheless, the same properties that make these nanomaterials very attractive are a source of concern: there are questions about their potential toxicity, their long-term side effects, and their biodegradability. These questions are based on knowledge of the toxic effects of micrometric particles in air pollution and the fear that these effects will be amplified because of the nanometric size of the new materials. We present in this article a global but not exhaustive summary of current knowledge. We begin by defining lung penetration, deposition, translocation and elimination of nanoparticles. Finally, we consider the respiratory effects of metallic nanoparticles, titanium dioxide nanoparticles in particular, and carbon nanotubes. In vivo and in vitro experimental studies currently available highlight the existence of biological effects of nanoparticles on the respiratory system with generation of oxidative stress, pro-inflammatory and pro-thrombotic effects and the possible development of fibrosis and pulmonary emphysema or DNA damage. A better understanding of the potential biological effects of nanoparticles is required to implement appropriate preventive measures in the workplace and/or in the general population, if this should be necessary.

International audience; BACKGROUND: Consensus-based studies are increasingly used as decision making methods, for they have lower production cost than other methods (observation, experimentation, modelling) and provide results more rapidly. The objective of this paper is to describe the principles and methods of the four main methods, Delphi, nominal group, consensus development conference and RAND/UCLA, their use as it appears in peer-reviewed publications and validation studies published in the healthcare literature. METHODS: A bibliographic search was performed in PubMed/Medline, Banque de donn? sant?ublique (BDSP), The Cochrane Library, Pascal and Francis. Keywords, headings and qualifiers corresponding to a list of terms and expressions related to the consensus methods were searched in the thesauri, and used in the literature search. A search with the same terms and expressions was performed on Internet using the website Google Scholar. RESULTS: All methods, precisely described in the literature, are based on common basic principles such as definition of subject, selection of experts, and direct or remote interaction processes. They sometimes use quantitative assessment for ranking items. Numerous variants of these methods have been described. Few validation studies have been implemented. Not implementing these basic principles and failing to describe the methods used to reach the consensus were both frequent reasons contributing to raise suspicion regarding the validity of consensus methods. CONCLUSION: When it is applied to a new domain with important consequences in terms of decision making, a consensus method should be first validated.

International audience; Pharmacovigilance aims at detecting adverse effects of marketed drugs. It is generally based on a Spontaneous Reporting System (SRS) that consists of the spontaneous reporting, by health professionals, of events that are supposed to be adverse effects of marketed drugs. SRS supply huge databases, the human-based exploitation of which cannot be exhaustive. Automated signal generation methods have been proposed in the literature but no consensus exists concerning their efficiency and applicability due to the difficulties in evaluating the methods on real data.The objective is to propose SRS modelling in order to simulate realistic data sets that would permit completion of the methods’ evaluation and comparison. In fact, as the status of the drug-event relationships is known in the simulated data sets, generated signals can be labelled as “true” or “false.”The spontaneous reporting is viewed as a Poisson process depending on: the drug’s exposure frequency, the delay from the drug’s launch, the adverse events’ background incidence and seriousness, and the reporting probability. This reporting probability, quantitatively unknown, is derived from the qualitative knowledge found in the literature and expressed by experts. This knowledge is represented and exploited by means of a set of fuzzy rules.Then, we show that the SRS modelling permits to evaluate the automatic signal generation methods proposed within pharmacovigilance and contribute to generate a consensus on drugs’ postmarketing surveillance strategies.

International audience; Pharmacovigilance aims at detecting the adverse effects of marketed drugs. It is generally based on the spontaneous reporting of events thought to be the adverse effects of drugs. Spontaneous Reporting Systems (SRSs) supply huge databases that pharmacovigilance experts cannot exhaustively exploit without data mining tools. Data mining methods; i.e., statistical association measures in conjunction with signal generation criteria, have been proposed in the literature but there is no consensus regarding their applicability and efficiency, especially since such methods are difficult to evaluate on the basis of actual data. The objective of this paper is to evaluate association measures on simulated datasets obtained with SRS modeling. We compared association measures using the percentage of false positive signals among a given number of the most highly ranked drug-event combinations according to the values of the association measures. By considering 150 drugs and 100 adverse events, these percentages of false positives, among the 500 most highly ranked drug-event couples, vary from 1.1% to 53.4% (averages over 1000 simulated datasets). As the measures led to very different results, we could identify which measures appeared to be the most relevant for pharmacovigilance.

International audience; BACKGROUND: The French pharmacovigilance system is based on a network of 31 regional centres located in teaching hospitals and coordinated by the French Medicines Agency ("Agence Française de Sécurité Sanitaire des Produits de Santé" [Afssaps]). Since 1984, they have shared a common database of adverse drug reactions (ADRs) that are spontaneously reported by healthcare professionals. The objective of this study is to describe the characteristics of the reports and the reporting trends in the French pharmacovigilance spontaneous reporting database from 1986 to 2001. METHODS: All the reports from January 1986 to December 2001 were included. Drugs and ADRs were translated to anatomical therapeutic chemical (ATC) codes and MedDRA classifications, respectively. RESULTS: The total number of reports was 197 580 over the 16-year period, with linearly increase over time. The median (interquartile range [IQR]) age of the patients was 53 (34-70) and the male/female ratio was 0.82. The median (IQR) time between the date of occurrence of the ADR and the date of report was 73 days (34-166). The reporter was a specialist in 74% of the reports and a general practitioner in 17%. The annual rate of reporting according to medical demography strongly increased for the specialists, especially since 1994. At least one ADR was considered as serious in 44.8% of the reports. The ADRs were most frequently related to nervous system drugs (23%), followed by cardiovascular drugs (19%) and systemic anti-infectives (17%). The latter class had the fastest progression mostly due to antiretroviral therapy since 1996. According to the Medical Dictionary for Regulatory Activities (MedDRA) coding, the system organ most often reported was skin and subcutaneous tissue disorders (29%), followed by nervous system disorders (19%), gastrointestinal disorders (12%), blood and lymphatic system disorders (12%), vascular disorders (12%) and general disorders and administration site conditions (12%). DISCUSSION: All spontaneous reporting systems are affected by under-reporting. One of their goals is to generate early signals, which might be more affected by reporting bias than by under-reporting. Some improvements should be made in the design of the French database, but data collected since 1986 constitute an essential tool for the routine work of the 31 pharmacovigilance centres. CONCLUSION: This first description of the data of the French pharmacovigilance database involving all drugs and ADRs shows an increasing tendency to reporting over time, especially in specialists and for systemic anti-infective drugs. The database that uses hierarchical international classifications for drugs and adverse reactions may be used for further studies and could be the basis for an automatic signal generation system.

Environ 170 millions de personnes sont infectées par le virus de l’hépatite C(VHC) à travers le monde, dont 500 000 à 650 000 en France. La gravité del’infection par le VHC tient à la très haute fréquence de développement d’uneinfection chronique (55 à 90 % des patients), susceptible d’évoluer vers unecirrhose et éventuellement un cancer primitif du foie. Cela explique quel’hépatite C est devenue, en France comme en Europe, l’une des toutespremières causes de maladie chronique du foie et une indication majeure detransplantation.Le virus de l’hépatite C a été identifié en 1989. Des techniques de détectionsensibles ont été mises au point et ont en particulier permis la quasiéliminationdes hépatites post-transfusionnelles, qui étaient très majoritairementdues au VHC. La transmission du virus de l’hépatite C est en effetessentiellement due à une contamination par le sang. Après la transmissiontransfusionnelle, aujourd’hui maîtrisée, la transmission parmi les usagers dedrogue reste un souci majeur. Par ailleurs, pour environ 10 à 30 % despersonnes infectées, l’origine précise de la contamination ne peut être identi-fiée ; il est probable que pour une forte proportion d’entre elles, des pratiquesde soins mal contrôlées sont responsables de la contamination. Cette situationest d’autant plus préoccupante qu’il n’existe pas, malgré des pistes prometteuses,de vaccin disponible.Un progrès majeur de ces dernières années a été l’obtention de guérisons del’hépatite chronique C. Ce succès thérapeutique se traduit par un arrêt défi-nitif de la réplication virale, associé à la régression des lésions hépatiques.Globalement, environ 50 % des personnes chroniquement infectées par levirus de l’hépatite C peuvent être guéries par la combinaison interféronpégylé-ribavirine. Le taux de guérison dépend du génotype du VHC : il atteint80 % chez les patients infectés par le génotype 2 ou 3, mais est seulement de40 % chez ceux infectés par le génotype 1. Aujourd’hui encore, 50 % despersonnes traitées restent donc en situation d’impasse thérapeutique. Dans cecontexte, les enjeux de la recherche de nouvelles cibles thérapeutiques,comme le développement d’anti-enzymes spécifiques, sont majeurs.En 1999, le ministère de la Santé a lancé un programme national de luttecontre l’hépatite C : un effort considérable a été entrepris pour améliorer laprise en charge des malades atteints d’hépatite C au sein des hôpitaux etl’accès au dépistage a été renforcé. S’agissant de la recherche, des moyensimportants ont été mis en œuvre. L’Agence nationale de la recherche sur lesida (ANRS) a vu ses missions s’élargir à tous les domaines de recherche sur leshépatites C puis B. Récemment, l’Inserm a mis en place une action thématique concertée pourrenforcer le potentiel de recherche sur l’hépatite C en favorisant la coordinationentre toutes les équipes travaillant dans le domaine. Un programme,établi en concertation avec l’ANRS et le ministère de la Recherche assureainsi le continuum entre recherche fondamentale, recherche clinique etthérapeutique et recherche en santé publique. De même, l’Inserm a développéplusieurs actions (programme Avenir, accueil de médecins, contrats d’interface,réseaux de recherche clinique{) pour assurer un rapprochement permanententre la recherche fondamentale menée dans ses laboratoires et lesacteurs des services hospitaliers impliqués dans la recherche clinique. J’aisouhaité en outre impliquer étroitement l’ensemble de nos partenaires – académiques,médicaux et industriels – dans les programmes de recherche del’Institut.L’expertise collective présentée dans ce rapport répond pour la première fois àde nombreuses questions sur des aspects encore peu connus aujourd’hui del’infection par le virus de l’hépatite C. Dans une première partie, elle rendcompte des données les plus récentes sur les différents modes de contaminationpar le VHC et sur leur importance respective, notamment pour lescontaminations nosocomiales, sujet toujours très préoccupant pour les médecins,les décideurs et le public. Pour cette raison, la Direction générale de lasanté (DGS), demandeur de l’expertise, a souhaité un point des connaissancessur ces questions. Les experts ont souligné la nécessité du respect des règlesd’hygiène universelles, ainsi que d’une évaluation de l’application de cesrègles, seule mesure susceptible de faire chuter l’incidence des contaminationsrésiduelles en milieu de soins.Le devenir des personnes infectées par le VHC et les perspectives d’évolutionde l’infection constituent le sujet de la deuxième partie de l’expertise. Lesmodélisations présentées montrent que, malgré une probable diminution del’incidence de l’infection, les contaminations passées auront pour conséquencedans les vingt prochaines années une augmentation de la complicationla plus sérieuse de l’infection, le carcinome hépatocellulaire. L’effet destraitements récents, plus efficaces, pourrait toutefois limiter cette tendance.L’évaluation économique des stratégies de dépistage et de traitement qui estprésentée dans ce rapport est un élément d’éclairage pour les décisions ensanté publique. Enfin, les experts insistent sur l’intérêt de la prise en charge despatients en fonction du stade de leur maladie, du pronostic, mais aussi de leurqualité de vie, dimension encore trop peu présente dans la pratique médicale.Je remercie les scientifiques qui ont contribué à cet important travail, quidevrait être très utile, tant aux praticiens qu’aux décideurs des politiques desanté.