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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of drugs have mostly been studied considering drug prescription patterns for the therapeutic alternatives of the withdrawn drugs.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 This could relate to a higher occurrence of AEs in new users of alternatives who switched from the withdrawn medicines or to an increased awareness of possible AEs.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; 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.

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

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; 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 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.

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.