Background: The causes of childhood brain tumors (CBT) are essentially unknown. Exposure to extremely low frequency magnetic fields (ELF-MF) (3-3000Hz) is an ubiquitous part of modern life. However, very few studies have investigated the possible effect of maternal occupational ELF-MF exposure on CBT and the available findings are inconsistent across studies. / Methods: We examined the role of maternal occupational exposure to ELF-MF shortly before and during pregnancy on the incidence of childhood brain tumors. A total of 548 incident cases and 760 healthy controls recruited between 1980 and 2002 from two Canadian provinces (Quebec and Ontario) were included and their mothers were interviewed. Tumors were classified as astroglial tumors, primitive neuroectodermal tumors (PNET), and other gliomas. Quantitative occupational ELF-MF exposure in microtesla units was estimated using individual exposure estimations or a job exposure matrix. We used three metrics to analyze exposure: cumulative, average, and maximum level attained. / Results: Using the average exposure metric measured before conception, an increased risk was observed for astroglial tumors (OR=1.5, and 95% CI=1.0-2.4). During the entire pregnancy period, a significantly increased risk was observed for astroglial tumors as well as for all childhood brain tumors with the average metric (OR=1.6, 95% CI=1.1-2.5 and OR=1.5; 95% CI=1.1-2.2, respectively). Based on job titles, a two-fold risk increase was observed for astroglial tumors (OR=2.3, 95% CI=0.8-6.3) and for all childhood brain tumors (OR=2.3, 95% CI=1.0-5.4) among sewing machine operators. / Conclusion: Results are suggestive of a possible association between maternal occupational ELF-MF exposure and certain brain tumors in their offspring. / Keywords: brain tumors, occupational exposures, maternal exposures, magnetic fields, childhood cancer, job exposure matrix

Background: Drug interactions resulting in adverse drug reactions (ADRs) represent a major health problem both for individuals and society in general. Post-marketing pharmacovigilance reporting databases with compiled individual case safety reports (ICSRs) have been shown to be particularly useful in the detection of novel drug - ADR combinations, though these reports have not been fully used to detect adverse drug interactions. Aim: To explore the potential to identify drug interactions using ICSRs and to develop a method to facilitate the detection of adverse drug interaction signals in the WHO Global ICSR Database, VigiBase. Methods: All six studies included in this thesis are based on ICSRs available in VigiBase. Two studies aimed to characterise drug interactions reported in VigiBase. In the first study we examined if contraindicated drug combinations (given in a reference source of drug interactions) were reported on the individual reports in the database, and in the second study we examined the scientific literature for interaction mechanisms for drug combinations most frequently co-reported as interacting in VigiBase. Two studies were case series analyses where the individual reports were manually reviewed. The two remaining studies aimed to develop a method to facilitate detection of novel adverse drug interactions in VigiBase. One examined what information (referred to as indicators) was reported on ICSRs in VigiBase before the interactions became listed in the literature. In the second methodological study, logistic regression was used to set the relative weights of the indicators to form triage algorithms. Three algorithms (one completely data driven, one semi-automated and one based on clinical knowledge) based on pharmacological and reported clinical information and the relative reporting rate of an ADR with a drug combination were developed. The algorithms were then evaluated against a set of 100 randomly selected case series with potential adverse drug interactions. The algorithm’s performances were then evaluated among DDAs with high coefficients. Results: Drug interactions classified as contraindicated are reported on the individual reports in VigiBase, although they are not necessarily recognised as interactions when reported. The majority (113/123) of drug combinations suspected for being responsible for an ADR were established drug interactions in the literature. Of the 113 drug interactions 46 (41%) were identified as purely pharmacodynamic; 28 (25%) as pharmacokinetic; 18 (16%) were a mix of both types and for 21 (19%) the mechanism have not yet been identified. Suspicions of a drug interaction explicitly noted by the reporter are much more common for known adverse drug interactions than for drugs not known to interact. The clinical evaluation of the triage algorithms showed that 20 were already known in the literature, 30 were classified as signals and 50 as not signals. The performance of the semi-automated and the clinical algorithm were comparable. In the end the clinical algorithm was chosen. At a relevant level, 38% were of the adverse drug interactions were already known in the literature and of the remaining 80% were classified as signals for this algorithm. Conclusions: This thesis demonstrated that drug interactions can be identified in large post-marketing pharmacovigilance reporting databases. As both pharmacokinetic and pharmacodynamic interactions were reported on ICSRs the surveillance system should aim to detect both. The proposed triage algorithm had a high performance in comparison to the disproportionality measure alone.

Thesis (M.S.)--University of South Florida, 2007. / Title from PDF of title page. Document formatted into pages; contains 80 pages. Includes bibliographical references.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / nÃo hà / A Flutamida à um medicamento anti-androgÃnico nÃo esterÃide aprovado para o tratamento do cÃncer de prÃstata. Seu efeito hepatotÃxico foi conhecido desde o inÃcio do perÃodo de comercializaÃÃo, hà mais de 10 anos. Em marÃo e junho de 2002, a Unidade de FarmacovigilÃncia da ANVISA recebeu as primeiras comunicaÃÃes de Ãbitos por hepatite fulminante associados ao uso da substÃncia (medicamento manipulado) em jovens do sexo feminino. A literatura mundial nunca registrara caso semelhante. O objetivo deste trabalho foi revisar e acrescentar informaÃÃes a respeito da seguranÃa da Flutamida quando utilizadas por pacientes do sexo feminino para o tratamento de hirsutismo, acne e alopecia androgenÃtica. Foram realizadas pesquisas para conhecer a indicaÃÃo aprovada em outros paÃses e as notificaÃÃes de reaÃÃes adversas graves em mulheres no banco de dados da OMS. AlÃm disso, por meio de busca ativa, tentou-se identificar outros casos no Brasil; rever as informaÃÃes das bulas de todos os medicamentos comercializados e analisar se as informaÃÃes obrigatÃrias e relevantes para diminuir o risco de reaÃÃes hepÃticas graves estavam presentes. Por fim, foi realizada pesquisa com os prescritores, por meio de questionÃrio eletrÃnico, para conhecer as informaÃÃes de que dispunham sobre a utilizaÃÃo do medicamento em mulheres e comparar estas informaÃÃes com uma revisÃo crÃtica da literatura no que tange à seguranÃa e eficÃcia. Os resultados de todas estas estratÃgias mostraram que a substÃncia tambÃm à utilizada off label em mulheres em outros paÃses, e tambÃm causou reaÃÃes adversas graves, mas nenhum Ãbito no sexo feminino fora relatado. Durante o trabalho, outros casos de Ãbito no Brasil foram identificados. Todas as bulas comercializadas no Brasil mencionavam que a substÃncia nÃo devia ser utilizada por mulheres, assim como mencionavam as reaÃÃes hepÃticas graves. As respostas dos prescritores ao questionÃrio permitem afirmar que a Flutamida se constitui em importante arsenal terapÃutico, e que o risco de seu uso vem sendo subestimado. O trabalho permite concluir que a Flutamida mostra-se eficaz para as condiÃÃes em que vem sendo utilizada em mulheres. Entretanto, os riscos evidenciam uma relaÃÃo benefÃcio/risco inaceitÃvel para as condiÃÃes estÃticas em que vem sendo empregada. / Flutamide is a non steroid anti-androgenic drug used to treat prostate cancer patients. When it became commercialized, more than 10 years ago, the hepatotoxic effect of flutamide was already recognized. In March and July 2002, the first cases of deaths in young females caused by fulminant hepatitis associated to off label use of this substance (magistral drug) was reported to the Pharmacovigilance Office/ANVISA. Up to now, similar cases were not described in the international literature. This work aimed to review and add information about the adequate use of flutamide by female patients to treat hirsutism, acne and androgenetic alopecia. To identify the standard prescriptions and the reported serious reactions in females worldwide, an extensive research through data provided by OMS was conducted. Moreover, using active search we looked for new local cases and review the information from package insert of all commercialized drugs in Brazil to analyze if the required and relevant information warning patients against the serious hepatic risks were provided. Finally, a survey with the prescribers was carried on through the web to identify the available information about the use of this drug in females and to make comparisons with data from the literature about the safety and efficacy of the use of this substance. The results showed that this substance is also used off label by women from other countries, who also presented serious adverse reactions. However, it was not reported any case of female death. Over the study, new cases of obituary occurred in Brazil, despite all analyzed package insert explain that this substance should not be used by females and mention serious hepatic reactions. The answers of the prescribers to the survey indicated that flutamide is an important therapeutic arsenal and that the risk of the use of this substance seem to have been underestimated. We concluded that flutamide is effective for the women treatment which it has been used. However, the threats of this drug point to the unacceptable use of this drug when applied for the esthetic finality.

No description available.

Nous prenons l’approche d’annonce des salaires avec la recherche d’emploi à étudier trois problèmes dans le marché du travail. Le premier problème concerne l’arrêt de travail prématuré des travailleurs. Tel arrêt de travail prématuré crée des risques de chiffre d’affaires pour les entreprises, donc les entreprises veulent proposer des profils de salaire pour minimiser ces risques. Dans ce problème, l’asymétrie de l’information joue un rôle important. Nous adoptons une approche du mécanisme design et considérons les différents timings auxquels l’information privée est réalisée. Dans un papier de suivi, nous proposons une politique d’Age spécifique par laquelle cette inefficacité peut être atténuée, et étudions son implication sur le bien-être et la production globale. Dans le deuxième problème, nous revisitons l’analyse du bien-être de l’impact de la discrimination sur le choix des compétences sous une norme d’embauche multidimensionnelle le long des caractéristiques qui sont soit liées à la productivité soit indépendantes de la productivité. Nous montrons comment l’investissement de compétences stratégique entre le groupe favorise et discrimine se pose. Nous comparons également deux mécanismes de détermination des salaires (salaire annoncé et négocié) pour vérifier la robustesse de résultats. Dans le troisième problème, nous considérons dans quelle mesure l’allocation de chômage et le salaire minimum peuvent corriger les répartitions inefficaces découlant du pouvoir de marche des firmes. Notre contexte concerne les petits marchés ou le ratio travailleurs/firmes ne soit pas grand. L’imperfection de marche vient du fait qu’au marché du travail à petite échelle les firmes paient un niveau de salaire moins que le niveau compétitif. Nous procédons à partir d’un point de vue d’organisation industrielle, et proposons en se concentrant sur la mauvaise répartition d’emploi et de surplus lors de l’analyse de l’efficacité de l’instrument de la politique. / We take the wage posting approach with search friction to study three issues in labor market. The first issue concerns the premature quitting of workers. Our framework is suitable for contexts such as disability shock, retirement, maternity leaves etc. Such premature quitting creates turnover risks for firms, hence the firms propose wage profiles to minimize or avoid it. In this issue, the asymmetric information plays an important role. We adopt an approach of mechanism design and consider different timings at which the private information is realized. In a follow-up paper, we propose an age-directed policy by which this inefficiency can be alleviated and study its implication on welfare and aggregate output. In the second issue, we revisit welfare analysis of impact of discrimination on skill choice under a multi-dimensional hiring norm along both productivity-related and -unrelated characteristics. We show how strategic skill investment between favored and discriminated group arise. We compare also two wage determination mechanisms (posted and bargained wage). In the third issue, we consider to which extent can the roles of unemployment benefit and minimum wage correct inefficient allocations arising from firms’ market power. Our context concerns small markets where the workers/firms ratio is not large. The market imperfection comes from the fact that in such a small market firms pay less than competitive level of wages. We proceed from an industrial organizational perspective and suggest focusing on both misallocation of labor and surplus when analyzing the effectiveness of the policy instrument.

The U.S. Food and Drug Administration (FDA) uses the FDA Adverse Event Reporting System (FAERS) to monitor adverse events resulting from pharmaceutical drug use. However, this system has limitations such as not allowing real-time data collection. To address these limitations, the FDA launched the Sentinel Initiative in 2008. This comparative case study was conducted to describe perceptions of investigating the efficacy of the Sentinel Initiative compared with the FAERS. The study was based on the theory of preemption as it emphasized the need for efficient means for providing unquestionable proof that consumers suffered adverse drug effects. The sample included interivews of 20 individuals, who worked closely with the FAERS program and were familiar with the Sentinel Initiative. In-depth key-informant interviews had been conducted to determine the perceptions of the participants regarding the challenges and benefits of the Sentinel Initiative compared with FAERS. To analyze data, content analysis was used. The study concluded that the FAERS and Sentinel Initiative provided a systematic database, which included health data, that could be used to improve public health. Due to the FAERS and Sentinel Initiative, adverse effects of drugs will be recognized and the safety of the patients and the public will be prioritized. The findings of this study have potential social impact for positive change at the societal level, organizational level, and individual level in terms of overall safety of the drugs. Sentinel initiative at its present state complements the existing FAERS and leverage its benefits by connecting at a grass roots level patients to an organization level as well as stakeholders to make an impact in providing safer drugs on the market.

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No description available.

Introduction :Les anticoagulants oraux soulèvent des problématiques majeures en termes de risque hémorragique et de bon usage. L’informatisation du dossier médical offre la possibilité d’accéder à de grandes bases de données que l’on peut exploiter de manière automatisée. L’objectif de ce travail est de montrer comment la réutilisation de données peut permettre d’étudier des problématiques liées aux anticoagulants et accompagner une démarche d’assurance de la qualité des soins. MéthodesCe travail a été réalisé sur les données informatisées (97 355 séjours) d’un centre hospitalier général. Pour chaque séjour nous disposons des données diagnostiques, biologiques, médicamenteuses, administratives et des courriers de sortie. Ce travail est organisé autour de 3 axes :Axe I. L’objectif est d’évaluer la qualité de la détection des facteurs pouvant majorer l’effet anticoagulant des antivitamines K (AVK), à l’aide de règles développées au cours de du projet européen PSIP (convention de subvention n° 216130). Une revue des cas sur une année a permis de calculer la valeur prédictive positive et la sensibilité des règles. Axe II. Nous avons réalisé une étude de cohorte historique sur les données de 2007 à 2012 pour déterminer les éléments majeurs impliqués dans l’élévation du risque hémorragique sous AVK dans la réalité clinique. Les cas étaient les séjours présentant une élévation de l’INR au-delà de 5, les témoins n’en présentaient pas. Axe III. Nous avons mis la réutilisation de données au service de l’étude de la qualité des prescriptions. D’une part nous avons évalué le suivi des recommandations de traitement du risque thromboembolique dans la fibrillation atriale (FA) chez la personne âgée, d’autre part nous avons étudié les modalités de prescription des anticoagulants oraux directs (AOD).Résultats : Axe I : La valeur prédictive positive des règles de détection des facteurs favorisant l’élévation de l’INR sous AVK est de 22,4%, leur sensibilité est de 84,6%. Les règles les plus contributives sont les règles de détection d’un syndrome infectieux et de l’administration d’amiodarone. Axe II : Les facteurs majeurs d’élévation du risque hémorragique sous AVK mis en évidence par l’étude de cohorte sont le syndrome infectieux, le cancer, l’hyprotidémie et l’insuffisance hépatique. Axe III : Le taux de suivi des recommandations dans la fibrillation atriale chez le sujet âgé est de 47.8%. Seuls 45% des patients reçoivent des anticoagulants oraux, 22,9% ne reçoivent aucun traitement antithrombotique et 32,1% reçoivent des antiagrégants plaquettaires. Les AOD sont quant à eux prescrits à des posologies inadaptées chez 15 à 31,4% des patients, respectivement pour le dabigatran et le rivaroxaban. Ces erreurs sont principalement des sous-dosages en AOD dans la FA de la personne âgée (82.6%). Discussion : L’informatisation des dossiers médicaux a permis la constitution de grandes bases de données médico-administratives, qui peuvent être utilisées à des fins variées comme nous le montrons dans ce travail. Dans le premier axe nous avons montré que des systèmes d’aide à la décision à base de règles permettent de caractériser les facteurs impliqués dans les surdosages en AVK avec une bonne sensibilité mais avec une faible valeur prédictive positive. Le second axe a montré que l’on pouvait utiliser ces données à des fins exploratoires pour identifier les facteurs liés à l’élévation de l’INR chez les patients recevant des AVK en pratique réelle. Le troisième axe montre que les systèmes à base de règles peuvent aussi être utilisés pour identifier des prescriptions inappropriées à des fins d’amélioration de la qualité des soins. Dans le domaine de l’anticoagulation ce travail ouvre des perspectives innovantes en vue de l’amélioration de la qualité des soins. / Introduction :Oral anticoagulants raise major issues in terms of bleeding risk and appropriate use. The computerization of medical records offers the ability to access large databases that can be explored automatically. The objective of this work is to show how routinely collected data can be reused to study issues related to anticoagulants in a supportive approach to quality of care.MethodsThis work was carried out on the electronic data (97,355 records) of a community hospital. For each inpatient stay we have diagnostic, biological, drug and administrative data, and the discharge letters. This work is organized around three axes:Axis I. The objective is to evaluate the accuracy of the detection of factors that may increase the anticoagulant effect of vitamin K antagonists (VKA), using rules developed in the PSIP european project (grant agreement N° 216130). A case review on one year enabled the calculation of the positive predictive value and sensitivity of the rules. Axis II. We conducted a cohort study on data from 2007 to 2012 to determine the major elements involved in raising the risk of bleeding related to VKA in clinical reality. Cases were the stays with an elevation of the INR beyond 5, the controls did not have.Axis III. We made data reuse serve a study of the quality of the prescriptions. On the one hand we assessed treatment of the thromboembolic risk recommendations in atrial fibrillation (AF) in the elderly, on the other hand we investigated the prescription of direct oral anticoagulants.Results : Axis I : The positive predictive value of the rules intended to detect the factors favoring the elevation of INR in case of treatment with VKA is 22.4%, the sensitivity is 84.6%. The main contributive rules are the ones intended to detect an infectious syndrome and amiodarone.Axis II : The major factor increasing the INR with VKA treatment highlighted by the cohort study are infectious syndrome, cancer, hepatic insufficiency and hypoprotidemia. The recommendations compliance rate in atrial fibrillation in the elderly is 47.8%. Only 45% of patients receive oral anticoagulants, 22.9% do not receive antithrombotic treatment at all and 32.1% received platelet aggregation inhibitors. Direct oral anticoagulants are prescribed at inadequate dosages in 15 to 31.4% of patients, respectively for dabigatran and rivaroxaban. These errors are mainly underdosages in the elderly with atrial fibrillation (82.6%).Discussion : The computerization of medical records has led to the creation of large medical databases, which can be used for various purposes as we show in this work. In the first work axis we have shown that rule-based decision support systems detect the contributing factors for VKA overdose with a good sensitivity but a low positive predictive value. The second line shows that we could use the data for exploratory purposes to identify factors associated with increased INR in patients receiving VKA in “real life practice”. The third line shows that the rule-based systems can also be used to identify inappropriate prescribing for the purpose of improving the quality of care. In the field of anticoagulation this work opens up innovative perspectives for improving the quality of care.