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Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in the intensive care unit, resulting in a high burden of illness, mortality and increased cost. The literature around the cost-effectiveness of probiotics in prevention of health-care associated infections has not been previously well-described, and a definitive health economic evaluation alongside a well-designed randomized control trial assessing probiotic prophylaxis has not been previously performed. This thesis consists of 3 separate manuscripts (with 2 published in peer-reviewed journals and 1 pending). The theme of this thesis was to: (1) describe the literature about the cost-effectiveness of probiotics in hospitalized patients in preventing healthcare-associated infections; (2) design a protocol for an economic evaluation alongside a randomized control trial (RCT) examining probiotic prophylaxis of VAP; and then (3) perform and analyze the health economic evaluation presented in the protocol. The first component of this thesis is a systematic review of probiotic prophylaxis of healthcare-associated infections in hospitalized patients. We performed an extensive search including multiple databases which found 7 studies. Probiotics demonstrated favourable cost-effectiveness in 6 of 7 (86%) economic evaluations, with 3 studies being manufacturer-supported, all suggesting cost-effectiveness. Certainty of cost-effectiveness evidence was very low due to risk of bias, imprecision and inconsistency using the GRADE approach. Hence further RCTs with economic evaluations were stated as a solution. The second component of this thesis is a study protocol for an economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT), which assessed the efficacy of probiotic prophylaxis in the prevention of healthcare-associated infections (specifically VAP). The third component of this thesis is the cost-effectiveness analysis performed utilizing the individual patient data from PROSPECT to produce the economic evaluation (E-PROSPECT). As of the date of thesis submission, PROSPECT is still pending publication, and hence E-PROSPECT is also pending analysis and publication. However, I have prepared a draft manuscript (along with figures and tables) that will be produced at the conclusion of E-PROSPECT for thesis committee review. / Thesis / Master of Health Sciences (MSc) / Ventilator-associated pneumonia (VAP) is the most common healthcare-associated infection in the intensive care unit, resulting in a high burden of illness, mortality and increased cost. The literature around the cost-effectiveness of probiotics in prevention of health-care associated infections has not been previously well-described, and a definitive health economic evaluation alongside a well-designed randomized control trial assessing probiotic prophylaxis has not been previously performed. This thesis consists of 3 separate manuscripts (with 2 published in peer-reviewed journals and 1 pending). The theme of this thesis was to: (1) describe the literature about the cost-effectiveness of probiotics in hospitalized patients in preventing healthcare-associated infections; (2) design a protocol for an economic evaluation alongside a randomized control trial (RCT) examining probiotic prophylaxis of VAP; and then (3) perform and analyze the health economic evaluation presented in the protocol. The first component of this thesis is a systematic review of probiotic prophylaxis of healthcare-associated infections in hospitalized patients. We performed an extensive search including multiple databases which found 7 studies. Probiotics demonstrated favourable cost-effectiveness in 6 of 7 (86%) economic evaluations, with 3 studies being manufacturer-supported, all suggesting cost-effectiveness. Certainty of cost-effectiveness evidence was very low due to risk of bias, imprecision and inconsistency using the GRADE approach. Hence further RCTs with economic evaluations were stated as a solution. The second component of this thesis is a study protocol for an economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT), which assessed the efficacy of probiotic prophylaxis in the prevention of healthcare-associated infections (specifically VAP). The third component of this thesis is the cost-effectiveness analysis performed utilizing the individual patient data from PROSPECT to produce the economic evaluation (E-PROSPECT). As of the date of thesis submission, PROSPECT is still pending publication, and hence E-PROSPECT is also pending analysis and publication. However, I have prepared a draft manuscript (along with figures and tables) that will be produced at the conclusion of E-PROSPECT for thesis committee review.

Le pneumothorax spontané (PS) est une pathologie le plus souvent bégnine quand elle survient chez un sujet sain. Le principal risque est la récidive dans environ 30 % des cas. L'évolution des connaissances concernant sa physiopathologie, associée aux résultats des études cliniques évaluant sa prise en charge en ambulatoire, font reconsidérer les stratégies de traitement initial et de prévention des récidives. Nos travaux de recherche sur le PS ont plusieurs axes relatifs aux aspects épidémiologiques, diagnostiques et thérapeutiques de sa prise en charge initiale, en particulier dans les services d'urgence. Cette thèse s'articule autour de 3 volets. Le premier volet correspond à l'identification de facteurs associés à la récurrence du PS. Si le tabac, le sexe ou l'intoxication au cannabis sont des facteurs de risque reconnu d'occurence, leur impact sur la récidive n'est pas consensuel. C'est pourquoi nous avons mené une étude rétrospective multicentrique dans des services d'urgence français. Sur cette série de 1491 PSP, dont respectivement 62 et 38% correspondaient à un premier épisode et à une récidive, aucun facteur de risque clinique n'était lié à la récidive. Malgré des limites méthodologiques liées notamment à son caractère rétrospectif, cette série représente la plus importante quantitativement jamais publiée. Un deuxième axe concerne l'étude de la prise en charge thérapeutique initiale du PS aux urgences. Bien que des études préliminaires aient montré des taux de succès de plus de 70% en cas de prise en charge ambulatoire, en l'absence de consensus au niveau international ni de recommandations françaises, le choix du traitement initial revient au praticien prenant en charge le patient. Très peu de données existent sur cette prise en charge initiale dans la vraie vie, qu'il s'agisse de la décision thérapeutique, du matériel employé ou du spécialiste impliqué. Ainsi, nous avons mené une étude rétrospective à propos de 1849 PS pris en charge dans 14 services d'urgence en France afin de documenter la filière de prise en charge. Cette étude a montré que la prise en charge était pluridisciplinaire, que l'abstention était la stratégie thérapeutique de première intention pour la moitié des patients. et qu'en cas de geste le drainage était choisi dans près de 80% des cas. La stratégie ambulatoire ne concernait que 239 patients, dont 230 PS primitifs et 9 PS secondaires (4%), très majoritairement en cas d'abstention thérapeutique. Le troisième volet concerne l'évaluation médico-économique de deux stratégies de traitement d'un premier PS primitif: drainage thoracique standard versus une stratégie combinée avec exsufflation en première intention (étude EXPRED). L'étude a porté sur une série de 379 patients, randomisés en deux bras. Les résultats de cette étude multicentrique ont montré que les deux stratégies étaient équivalentes en ce qui concerne le succès immédiat, évalué sur le recollement pleural, et le taux de récidive à un an. L'évaluation médico économique, conduite avec une approche de minimisation des coûts et avec l'hypothèse d'une équivalence des deux stratégies, dans la perspective du payeur, a montré que l'exsufflation était une stratégie plus coût efficace que le drainage. Au final, les résultats de ces travaux montrent qu'en pratique, actuellement, dans les services d'urgences en France, l'abstention thérapeutique et le drainage thoracique sont préférentiellement choisis lors de la prise en charge du PS, à l'inverse des stratégies ambulatoires. Les connaissances apportées par l'étude EXPRED et celles sur les facteurs de risque de récidive sont de nature à influencer les recommandations françaises à venir. De futurs travaux de recherche devront s'attacher à identifier les freins à l'implantation de ces recommandations, ainsi que ceux relatifs à l'adhésion à une stratégie ambulatoire de prise en charge / Spontaneous pneumothorax (SP) is usually a benign pathology, when it occurs at a healthy subject. Recurrence is the main risk, in approximately 30% of the cases. Current knowledge concerning physiopathology, associated with the results of clinical trials estimating ambulatory treatment, make reconsider the strategies of initial treatment and prevention of recurrence. Our research on SP have several topics related to epidemiological, diagnostic and therapeutic aspects of initial management in the Emergency Department (ED). This work treats three axis. The first axis corresponds to identification of factors associated with recurrence of primary spontaneous pneumothorax (PSP). If tobacco, gender or use of cannabis are identified as a risk factor of occurrence, their impact on recurrence are not consensual. Then, we conducted a retrospective multicenter study in 14 french ED. In this population of 1491 PSP, among whom respectively 62 and 38% corresponded to a first episod and to a recurrence, no clinical risk factor of recurrence was highl ighted. In spite of methodological limits, in particular in line with its retrospective design, this series represents the most larger never published. The second axis concerns the study of initial treatrnent of PS in 14 ED. Although preliminary studies showed rates of success of more than 70% in case of ambulatory management, in the absence of international consensus and French recommandations, the choice of initial treatment depends on physicians decision. Few data exist on this initial management in real life condition, concerning therapeutic action, material devices used, or speciality of physicians implied. Again, we conducted a second retrospective study with 1849 PS in 14 french ED in France to precise healthcare pathways. The study showed that the management was multidisciplinary, abstention was the frst therapeutic strategy for half of patients and in case of intervention, chest tube was chosen in about 80% of cases. Ambulatory strategy concerned only 239 patients (14%), among whom 230 PSP and 9 secondary PS, mostly in case of abstention. The third axis concerns medical economic evaluation of two treatments strategies of first primary PS : chest tube drainage versus aspiration as first therapeutic action (EXPRED study).The study concerned a serie of 379 patients, randomized in Iwo arms. The results of this multicenter study showed that both strategies are equivalent concerning immediat success estimated on pneumothorax resolution and the rate of recurrence at one year. The medicoeconomic evaluation as a minimization of the costs and with the hypothesis of an equivalence of both strategies with the prospect of the payer, showed that aspiration was a strategy more cost effective than chest tube. Finally, results of these works showed that actually in practice, abstention and chest tube drainage are preferentially chosen for the management of PS in ED in France, compare to ambulatory strategy. Results of EXPRED study and knowledge about risk factors of recurrence can influence future french recommandations. Future research are necessary to identify barriers to implementation of these recommandations, as well asthose relative to adhesion of ambulatory management.

Estudo comparativo entre os custos dos tratamentos clínico, cirúrgico ou percutâneo em portadores de doença multiarterial coronária estável - 5 anos de seguimento [tese]. São Paulo: Faculdade de Medicina, Universidade de São Paulo, 2013. INTRODUÇÃO: As principais opções terapêuticas para a doença multiarterial coronária incluem cirurgia de revascularização miocárdica (CRM), intervenção coronária percutânea (ICP) e tratamento clínico (TC). Essas três estratégias terapêuticas apresentam eficácia similar em determinados subgrupos de pacientes. No presente momento, estudos direcionados à análise econômica são escassos, e contemplam, principalmente, os custos comparativos entre as intervenções cirúrgica e percutânea. OBJETIVOS: Analisar, prospectivamente, o custo comparativo das três formas terapêuticas da doença multiarterial coronária estável, durante cinco anos de seguimento. MÉTODOS: Foi computado o custo terapêutico global de 611 pacientes do ensaio clínico The Second Medicine, Angioplasty, or Surgery Study (MASS II), baseado na remuneração provida pelo sistema de saúde suplementar do Instituto do Coração do HC/FMUSP, tomando-se os valores em moeda nacional corrente. Realizou-se, posteriormente, análise de custo-efetividade para o tempo livre de eventos clínicos e o tempo livre de eventos acrescido de tempo livre de angina. RESULTADOS: O TC apresentou 3.79 e 2.07 QALY (quality-adjusted lifeyears); o ICP apresentou 3.59 e 2.77 QALY; e o CRM apresentou 4.4 e 2.81 QALY, respectivamente, para sobrevida livre de eventos e sobrevida livre de eventos e angina. Os custos para sobrevida livre de eventos foram R$ 16.327,80 para TC, R$ 35.940,60 para ICP e R$ 32.873,40 para CRM. A análise pareada dos custos para sobrevida livre de eventos mostrou que houve diferença significante favorecendo TC contra ICP (P < 0,01), e em comparação com CRM (P < 0,01); e CRM versus ICP (P = 0,01). Os custos para sobrevida livre de eventos e angina foram R$ 29.795,40, R$ 46.495,80 e R$ 44.305,20, respectivamente. A comparação pareada dos custos livres de eventos mais livres de angina demonstrou que houve diferença significante favorecendo TC contra ICP (P = 0,04), e em comparação com CRM (P < 0,001). Não houve diferença entre CRM e ICP (P > 0,05). CONCLUSÃO: A análise comparativa entre as diferentes opções terapêuticas desta amostra revelou que TC foi mais custo-efetivo que CRM, e esta, por sua vez, mais custo-efetivo que ICP / BACKGROUND: The therapeutic options for multivessel coronary artery disease are coronary artery bypass graft surgery (CABG), percutaneous coronary intervention (PCI), or medical treatment alone (MT). These three therapeutic strategies present similar efficacy for specific subgroups. At the present moment, economic outcome trials are scant, and contemplate comparative cost between surgical or percutaneous intervention. OBJECTIVE: To analyze, prospectively, the comparative cost from three therapeutic strategies in multivessel coronary artery disease, at 5-year of follow-up. METHODS: We analyzed cumulative costs of 611 patients from clinical trial The Second Medicine, Angioplasty, or Surgery Study (MASS II). The economic analysis is based on remuneration provided by the supplementary health system of the Heart Institute of the Clinical Hospital of FMUSP, expressing these values in Brazilian currency. It was compared to the cumulative costs of each therapeutic strategy in the 5-year follow-up period. A cost-effectiveness analysis was then conducted for event-free survival and event plus angina-free survival. Cost-effectiveness analysis was performed by quality-adjusted life- year (QALY) analysis. RESULTS: Respectively, for event-free survival and event plus angina-free survival, MT presented 3.79 quality-adjusted life-years (QALY) and 2.07 QALY; PCI presented 3.59 and 2.77 QALY; and CABG demonstrated 4.4 and 2.81 QALY. The event-free costs were R$ 16327.80 for MT; R$ 35940.60 for PCI; and R$ 32873.40 for CABG. The paired comparison of the event-free costs showed that there was a significant difference favoring MT versus PCI (P < 0.01) and versus CABG (P < 0.01) and CABG versus PCI (P =0.01). The event-free plus angina-free costs were R$ 29795.40, R$ 46495.80 e R$ 44305.20, respectively. The paired comparison of the event-free plus angina-free costs showed that there was a significant difference favoring MT versus PCI (P =0.04), and versus CABG (P < 0.001); there was no difference between CABG and PCI (P > 0.05). CONCLUSION: The comparative analysis among the different therapeutic strategies demonstrated that MT was more cost-effective than CABG, and this than PCI

INTRODUÇÃO: Infecções causadas por Streptococcus pneumoniae são uma das maiores causas de morbidade e mortalidade no mundo, particularmente em países em desenvolvimento, gerando um impacto clínico e econômico significante. Crianças com menos de dois anos de idade, adultos com mais de 60 anos e pessoas com condições crônicas são as populações mais afetadas. Devido ao aumento da resistência a antibióticos e do impacto crescente das consequências da doença, vem sendo discutida a prevenção primária por meio das vacinas antipneumocócicas como uma das estratégias de saúde pública mais eficaz na redução da carga da doença. OBJETIVO: Revisar sistematicamente e avaliar a qualidade do relato dos estudos de avaliação econômica da vacina pneumocócica polissacarídea 23-valente em idosos, com o intuito de comparar as diferentes estratégias metodológicas adotadas pelos estudos publicados e discutir os parâmetros e premissas que possam ter influenciado os resultados dos modelos econômicos. MÉTODOS: Pesquisou-se nas bases de dados eletrônicas Medical Literature Analysis and Retrieval System Online (via PubMed), Excerpta Medica database, Cochrane reviews, Centre for Reviews and Dissemination Database, Web of Science, Scopus Citation Index e Literatura LatinoAmericana e do Caribe em Ciências da Saúde por avaliações econômicas completas da vacina pneumocócica polissacarídea 23-valente, publicadas até março de 2016. Dois revisores independentes selecionaram artigos relevantes de acordo com critérios de inclusão e exclusão e extraíram seus dados. As principais características dos estudos e métodos (dados clínicos e econômicos, custo e relação de custo-efetividade incremental) foram extraídas e comparadas. Custos foram atualizados para dólar internacional de 2016. RESULTADOS: Vinte e sete avaliações econômicas publicadas entre 1980 e 2016 foram incluídas na revisão sistemática, grande parte publicada nos Estados Unidos e na Europa. Apenas três estudos foram conduzidos na América Latina (dois no Brasil, um na Colômbia). Soma-se a esse cenário de comparação entre a vacinação e a não vacinação com a vacina pneumocócica polissacarídea 23-valente, três estudos que também cotejaram a vacina pneumocócica polissacarídea 23valente com a conjugada 13-valente. Todos os estudos utilizaram modelos estáticos. A maioria considerou horizonte temporal para toda a vida (44,4%) ou de cinco a seis anos de horizonte (33,3%). Apenas três estudos consideraram a proteção indireta causada pela imunização da vacina pneumocócica conjugada 13-valente em crianças no modelo. Apesar da diversidade de síndromes clínicas incluídas, das diferentes definições de cada síndrome clínica, da variação nas estimativas de eficácia e de coberturas vacinais e dos custos hospitalares e ambulatoriais das doenças pneumocócicas, a maioria dos estudos incluídos apresentou relações de custo-efetividade incremental favoráveis (menos de US$ 50.000,00 por ano de vida ganho ou por ano de vida ajustado pela qualidade, Quality Adjusted Life Year) e algumas vezes econômicas. Nos estudos, a relação de custo-efetividade incremental variou de costsaving a US$ 84.636,00 por ano de vida ajustado pela qualidade (Quality Adjusted Life Year). As estimativas de impacto da doença, a eficácia/efetividade da vacina pneumocócica polissacarídea 23valente e os efeitos da proteção indireta pela imunização em crianças foram os parâmetros que mais influenciaram os resultados do modelo. Em relação à qualidade do relato dos estudos, as principais limitações foram: descrição clara e completa do resumo, declaração do financiamento do estudo e declaração dos conflitos de interesse. CONCLUSÃO: Esta revisão sistemática revelou que os resultados de custo-efetividade foram variados, de cost-saving a não custo-efetivo. Estudos de custo-efetividade bem estruturados da vacina pneumocócica polissacarídea 23-valente que representam a epidemiologia atual e reduzem a incerteza de parâmetros chave, como a eficácia/efetividade da vacina, são extremamente importantes para auxiliar no processo de decisão / INTRODUCTION: Infections caused by Streptococcus pneumoniae are one of the main causes of morbidity and mortality in the world, particularly in developing countries, generating a significant clinical and economic impact. Children under 2 years old, adults ³60 years old and populations with cronic conditions are the most affected populations. Due to the increase in antibiotic resistance and the increase of the disease\'s consequences, primary prevention of the disease is being discussed with antipneumococcal vaccination as one of the most effective public health strategies in reducing the burden of the disease. OBJECTIVE: To systematically review and evaluate the quality of the reported economic evaluation studies of the 23-valent pneumococcal polysaccharide vaccine in the elderly immunization with the aim to compare the different methodological strategies adopted by the published studies and discuss the parameters and premises that may have influenced the results of economic models. METHODS: It was searched in the electronic databases Medical Literature Analysis and Retrieval System Online (PubMed), Excerpta Medica database, Cochrane reviews, Centre for Reviews and Dissemination Database, Web of Science, Scopus Citation Index and Latin-American and Caribbean Health Sciences Literature for full economic evaluations of 23-valent pneumococcal polysaccharide vaccine published up to March 2016. Two independent reviewers screened articles according to inclusion and exclusion criterias and extracted the data. Main studies characteristics and methods (clinical and economic data, cost and incremental cost-effectiveness ratio) were extracted and compared. Costs were updated to 2016 International Dollar. RESULTS: Twenty seven evaluations published between 1980 and 2016 were included in the systematic review, most of them being published in the United States and Europe. Only three studies were conducted in Latin America (two in Brazil, one in Colombia). In addition to the scenario comparing 23-valent pneumococcal polysaccharide vaccine vaccination to non-vaccination, three studies also compared 23-valent pneumococcal polysaccharide vaccine to 13-valent pneumococcal conjugate vaccine. All studies used static models. The majority considered a lifetime time horizon (44.4%) or from 5 to 6 years of time horizon (33.3%). Only three studies considered the indirect protection from 13-valent pneumococcal conjugate vaccine immunization in children in the model. Despite the diversity of clinical syndromes included, from the different definitions of each clinical syndrome, the variation in vaccine efficacy and inpatient and outpatient costs for the pneumococcal disease, most of the included studies showed and favorable incremental cost-effectiveness ratio (less than US$ 50,000.00 per year of life or Quality Adjusted Life Year) and sometimes cost-saving. In the evaluations, incremental cost-effectiveness ratio ranged from cost-saving to US$ 84,636.00/Quality Adjusted Life Year. The estimates of disease burden, the efficacy/effectiveness of 23-valent pneumococcal polysaccharide vaccine, and the effects of herd protection from childhood immunization had most influence on the results. Regarding the study quality, the main limitations were: clear and complete summary description, statement of the study founding source and declaration of conflicts of interest. CONCLUSIONS: This systematic review revealed that the cost-effectiveness results have conflicting results, from cost-saving to not cost-effective at all. Welldesigned cost-effectiveness studies of 23-valent pneumococcal polysaccharide vaccine that represent the current epidemiological scenario and reduce uncertainty related to efficacy/effectiveness are extremely relevant to informing the decision-making process

Face aux problématiques d’accès, de désertification médicale et de qualité des soins, la loi « Hôpital, Patients, Santé, Territoires » (HPST), votée en 2009, représente un socle pour la réorganisation des soins primaires en France. L’accent est mis sur la collaboration entre les professionnels de santé et l’optimisation des compétences de chacun. Le pharmacien d’officine se trouve au coeur de cette loi. Grâce à son accessibilité, sa formation et sa proximité avec les patients sains comme malades, il voit l’opportunité d’étendre ses pratiques au-delà de la simple dispensation des médicaments en fournissant directement des soins au patient. Cette proposition n’est pas une exception française mais s’inspire des expériences internationales et du concept de « soins pharmaceutiques ». Le pharmacien écossais peut désormais être payé à la capitation pour délivrer des consultations pharmaceutiques lors du renouvellement d’ordonnance au patient atteint de maladie chronique; le pharmacien anglais peut prescrire des médicaments dans le cadre d’un plan de gestion clinique et recevoir un honoraire de dispensation; le pharmacien suisse peut organiser des réunions de discussion avec les médecins; et le pharmacien portugais peut vacciner son patient au sein de l’officine. Les illustrations de la diversification des pratiques du pharmacien d’officine sont donc variées et se replacent dans leur contexte national. L’enjeu est aujourd’hui de comprendre les conditions et les effets d’un ensemble d’innovations techniques, organisationnelles et sociales qui pourraient être en faveur du développement des soins pharmaceutiques en France. Ce travail de thèse a pour objectif de nourrir les débats autour de cette problématique. Un état des lieux de la profession en France et une enquête d’opinion auprès des futurs pharmaciens montrent que le contexte sanitaire, professionnel, économique est propice au développement des pratiques du pharmacien et que l’avenir des soins pharmaceutiques trouve un écho favorable auprès des pharmaciens de demain. Cependant, nombreux sont les facteurs qui peuvent constituer des obstacles à leur diffusion (Chapitres 1 et 2). D’un point de vue économique, d’après une revue de littérature systématique sur l’efficience des soins pharmaceutiques en Europe, les services de surveillance médicamenteuse, de médication officinale, de collaboration entre les professionnels de santé et de promotion de la santé pourraient être, dans certaines conditions, des interventions coût-efficaces d’un point de vue collectif (Chapitre 3). Mais qu’en est-il en France ? On ne dispose pas de travaux sur le sujet. Deux travaux originaux - une étude de cohorte (exposés/non exposés) et une analyse coût-efficacité -, que nous avons menés, se focalisant sur l’implication du pharmacien d’officine dans le dépistage d’une maladie chronique (le syndrome d’apnées du sommeil) montrent que les coûts engendrés par la mise en place d’une telle intervention sont sous certaines conditions compensés par les gains générés, et les résultats sont en faveur de l’implantation du service en pratique de routine (Chapitre 4). / Facing the issues of access, quality and proximity, the "Hospital, Patients, Health and Territories" (HPST) law, passed in 2009, constitutes a basis for the reorganization of primary care in France. The healthcare reform emphasizes on the collaboration between healthcare professionals and the optimization of their skills. The community pharmacist is on the forefront of this reform. Through its accessibility, its training and its proximity with healthy and sick patients, community pharmacists have the opportunity to broaden the scope of their practices beyond the merely dispensing of medication by delivering patient care. This proposal is not a French exception but takes inspiration from international experiences and the concept of "pharmaceutical care." The Scottish pharmacist can now be paid by capitation to renew a prescription for a patient with chronic illness; the English pharmacist can prescribe medication as part of a clinical management plan and receive a dispensing fee, the Swiss pharmacist can organize meetings with general practitioners and in Portugal, pharmacists can vaccinate a patient in the pharmacy. Pharmaceutical care practices are diversified and depend on national context. The challenge today is to understand the conditions and consequences of technical, organizational and social innovations that could be in favor of the development of pharmaceutical care in France. The objective of the thesis is to feed into the debates around this problematic. An overview of profession in France and an original opinion survey of future pharmacists show that the healthcare, professional and economic contexts are suitable to develop pharmaceutical care and future pharmacists are in favor of it. However, there are many barriers to their spread in routine practice (Chapters 1 and 2). From an economical perspective, a systematic review of the literature on the efficiency of pharmaceutical care in Europe show that drug monitoring services, prescription for minor ailments, collaboration between health professionals and health promotion interventions could be cost-effective from a collective point of view under certain conditions (Chapter 3). What about France? There is no study on this topic. We conducted two original studies - a cohort study (exposed / unexposed), and a cost-effectiveness analysis which focused on the involvement of the pharmacist in screening for chronic disease (sleep apnea syndrome). We show that the costs of implementing such an intervention are offset by the gains under certain conditions, and the results are in favor of the implementation of the service in routine practice (Chapter 4).

The aims of this thesis were to evaluate caries-preventive measures from a societal perspective, to demonstrate the use of resources in preventive dentistry, to develop and discuss techniques suitable for evaluating dental care costs and outcomes, and to test costs and consequences within a health economic decision model adapted to preventive dental care. The thesis is based on three separate studies with three separate cohorts. In the first study, performed at a single dental clinic, analysis was made of data on dental caries progression over four years in 92 adolescents, along with the use of resources for preventive treatment. In the second study, data from the intervention study “Evaluation of caries-preventive measures” (performed between 1995 and 1999 at 26 dental health clinics throughout Sweden) were used for economic evaluation. Three different approaches to calculating unit cost were discussed, each of which reflect the differences in treatment costs as influenced by the practitioner’s level of skill and competence (salary) and by methods of handling overhead cost allocation. These methods seem useful for evaluating costs in cost-effectiveness analysis (CEA) and cost-benefit analysis (CBA). The CEA showed an incremental cost-effectiveness over four years of SEK 2 043* per averted decayed (D) enamel (e) and dentine caries, missing (M) and filled (F) surface (S) (DeMFS). In the third study, 82 19-year-old individuals agreed to participate in a pilot exploratory case-control study. Individuals with high caries experience formed the test group while the control group consisted of individuals with no caries experience. To explore whether any differences existed between these two groups in perceived oral health-related quality of life (OHRQOL), two OHRQOL measures were used. Additionally, the willingness of these individuals to pay (WTP) for a preventive strategy was elicited using the contingent valuation method (CVM) within a cost-benefit approach. Using these WTP values, the cost-benefit analyses showed positive net social benefit (NSB) values for both study groups, meaning that the benefits of prevention exceeded the costs. A new outcome measure, Value of Statistical Oral Health (VOSOH), was also presented. Consideration was also made, within the economic framework fundamental to this thesis, of the trend away from a strictly bio-medical paradigm towards a biopsychosocial perspective. The health economic decision model encompasses a number of different techniques for comparing costs with consequences, each with its own advantages and disadvantages and each with its own field of application. These techniques should be seen as complementary rather than competing. Preventive dentistry plays a central role in Swedish dental health care, and it is important that resources are used properly. Accurate evaluation methods are necessary in order to improve the basis for public decision-making; the methods proposed in this thesis seem to be of potential use in this endeavour. *SEK8.54 = US$1 (December 1999).

Aims: To assess effectiveness and economic benefit of the psychological treatment of anxiety disorders in order to compare them with the consumed resources of the treatment. Methods: Assessment of specific and non-specific symptoms and impairments in N=493 anxiety patients (DSM-IV) receiving cognitive behavior therapy pre, post, and one year after treatment with various measures. Additional analyses of costs of the treatment and the benefits due to reduced work disability and health care utilization after therapy (including a pilot study using a willingness-to-pay approach). The treatment setting can be characterised as clinically typical for everyday practice. Core results: a) effectiveness: Effect sizes ranged from 0.9 to 1.9. All improvements were significant and lasted until 1-year-follow-up. Rates of clinically significant therapy success ranged from 63% to 79% depending on outcome measure and success criteria. b) cost-effectiveness analysis: Cost-effectiveness-indices ranged from DM 8338.- to DM 10456.- for one successful treatment (average costs taking also the costs of unsuccessful treatments into account). c) cost-benefit-analysis: Cost reduction in the year after therapy was remarkable (inpatient costs about 25%, other cost factors 87%-100%), resulting in a benefit of DM 3026.- per patient and a cost-benefit-ratio of 1:0.58 in the first year after treatment. Assuming that the improvements are stable, the cost-benefit-ratio after five years would be estimated as 1:2.63. Discussion: The present study shows exemplarily for CBT of anxiety disorders that modern psychotherapy can produce remarkable results at reasonable costs. Furthermore, clinical-psychological treatment methods show an additional economic benefit. Clinical Psychology can benefit from focusing not only the promising developments in classification, etiology, and treatment but also taking over the cost perspective (which is relatively new in scientific evaluation of psychotherapy). (Appendix: Cost-Benefit-Calculator.htm; 8,97 KB -- Usage: Referat Informationsvermittlung/ SLUB) / Fragestellungen: Ermittlung von Effektivität und monetärem Nutzen psychologischer Behandlung von Angststörungen, die dann den für die Therapie aufgewendeten Ressourcen gegenübergestellt werden. Methoden: N=493 Patienten mit Angststörungen (DSM-IV), die eine ambulante störungsspezifische kognitive Verhaltenstherapie absolviert haben, wurden prä, post und zur 1-Jahres-Katamnese untersucht. Das Spektrum der Erhebungen umfasste störungsspezifische und störungsübergreifende Symptombelastung und Beeinträchtigungen in verschiedenen Lebensbereichen, sowie eine globale Therapieerfolgseinschätzung von Patienten und Therapeuten. In einer zweiten Studie wurden zusätzlich an einer Teilstichprobe Kosten-Nutzen-Aspekte untersucht (Einsparungen durch Reduktion von Gesundheitsleistungen und Arbeitsunfähigkeit; außerdem Pilotstudie zu willingness-to-pay-Ansatz). Das Behandlungssetting der Studie ist charakterisiert durch klinisch relevante Rahmenbedingungen und Praxisnähe. Zentrale Ergebnisse: a) Effektivität: Die Effektstärken reichten in Abhängigkeit von der Meßmethode von 0.9 bis 1.9. Die Verbesserungen waren durchgängig signifikant und blieben bis zur 1-Jahres-Katamnese stabil. Die Raten klinisch bedeutsamer Besserungen betrugen 63% - 79% in Abhängigkeit von Mess- und Auswertungsmethode. b) Kosten-Effektivitäts-Analyse: Die Kosten-Effektivitätivitäts-Indices betrugen DM 8338.- bis DM 10456.- (dieser Index gibt an, was eine erfolgreiche Behandlung durchschnittlich kostet, also unter Einbezug der nicht erfolgreichen Behandlungen in die Gesamtkosten). c) Kosten-Nutzen-Analyse: Im Jahr nach Therapie reduzierten sich die Kostenfaktoren der Störungen vor Therapie beträchtlich (stationäre Kosten um 25%, restliche Kostenfaktoren 87% - 100%). Die dadurch erzielten Einsparungen betrugen durchschnittlich DM 3026.- (Kosten-Nutzen-Verhältnis im ersten Jahr: 1 : 0.58). Unter der Annahme, dass die Auswirkungen der Therapie auch über die 1-Jahres-Katamnese hinaus stabil bleiben, kann man abschätzen, dass sich die Therapie innerhalb des zweiten Jahres amortisiert und das Kosten-Nutzen-Verhältnis nach fünf Jahren (diskontiert) 1 : 2.63 beträgt. Diskussion: Wie in dieser Arbeit anhand der kognitiven Verhaltenstherapie für Angststörungen gezeigt wird, kann moderne Psychotherapie bei vertretbarem Aufwand beachtliche Erfolge verbuchen. Klinisch-psychologische Behandlungsmethoden sind darüber hinaus auch wirtschaftlich, derart, dass sie über den reinen Behandlungserfolg hinaus zu Kosteneinsparungen beitragen könnten. Es ist erstaunlich, dass die Kosten-Perspektive der wissenschaftlichen Bewertung von Psychotherapie noch recht neu ist. Die Klinische Psychologie kann davon profitieren, diese Dimension (neben den beachtlichen Erkenntnisfortschritten in bezug auf Klassifikation, Ätiologie, Verlaufsforschung und Behandlungsverfahren) mehr herauszustellen. (Anlage: Cost-Benefit-Calculator.htm; 8,97 KB -- Nutzung: Referat Informationsvermittlung der SLUB)

Background: In the ‘Arimidex’, Tamoxifen Alone or in Combination (ATAC) trial, the aromatase inhibitor (AI) anastrozole had a ignificantly better efficacy and safety profile than tamoxifen as initial adjuvant therapy for hormone receptor-positive (HR+) early breast cancer (EBC) in postmenopausal patients. To compare the combined long-term clinical and economic benefits, we carried out a cost-effectiveness analysis (CEA) of anastrozole versus tamoxifen based on the data of the 100- month analysis of the ATAC trial from the perspective of the German public health insurance. Patients and Methods: A Markov model with a 25-year time horizon was developed using the 100-month analysis of the ATAC trial as well as data obtained from published literature and expert opinion. Results: Adjuvant treatment of EBC with anastrozole achieved an additional 0.32 quality-adjusted life-years (QALYs) gained per patient compared with tamoxifen, at an additional cost of D 6819 per patient. Thus, the incremental cost effectiveness of anastrozole versus tamoxifen at 25 years was D 21,069 ($ 30,717) per QALY gained. Conclusions: This is the first CEA of an AI that is based on extended follow-up data, taking into account the carryover effect of anastrozole, which maintains the efficacy benefits beyond therapy completion after 5 years. Adjuvant treatment with anastrozole for postmenopausal women with HR+ EBC is a cost-effective alternative to tamoxifen. / Hintergrund: Bei der adjuvanten Therapie von postmenopausalen Patientinnen mit Hormonrezeptor-positivem (HR+) Mammakarzinom belegen die ATAC-100-Monatsdaten (ATAC-Studie: ‘Arimidex’, Tamoxifen Alone or in Combination) einen signifikanten Vorteil von Anastrozol gegenüber Tamoxifen in Bezug auf Rezidivrisiko und Verträglichkeit. Es wurde eine Kosten-Nutzwert-Analyse von Anastrozol im Vergleich zu Tamoxifen aus der Sicht des deutschen Gesundheitssystems durchgeführt. Material und Methoden: Als Berechnungsbasis wurde ein Markov- Modell zur Abschätzung der Kosteneffektivität entwickelt. Der Modellierungszeitraum umfasste 25 Jahre. Die Daten wurden anhand der ATAC-100-Monatsdaten, vorliegender Literatur und durch ein interdisziplinäres Expertenteam ermittelt. Ergebnisse: Eine adjuvante Therapie mit Anastrozol erzielte 0,32 quality-adjusted life-years (QALYs) pro Patientin mehr, verglichen mit einer adjuvanten Tamoxifentherapie. Die zusätzlichen Kosten der Therapie mit Anastrozol lagen bei 6819 D pro Patientin. Im Vergleich mit Tamoxifen erzielte Anastrozol einen ICER (Incremental Cost-Effectiveness Ratio) von 21 069 D (30 717 $)/QALY über den gesamten Modellierungszeitraum. Schlussfolgerung: Diese Kosten- Nutzwert-Analyse eines Aromatasehemmers basiert erstmals auf einer Datenanalyse, die auch das Follow-Up und den sogenannten Carryover- Effekt nach einer abgeschlossenen 5-Jahres-Therapie beinhaltet. Anastrozol ist auch nach dieser Analyse aus der Sicht des deutschen Gesundheitssystems eine kosteneffektive Therapieoption für postmenopausale Patientinnen mit einem HR+ frühen Mammakarzinom. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Radiative forcing by increased atmospheric levels of greenhouse gases (GHGs) produced by human activities could lead to strongly undesirable effects on oceans and their dependent human systems in the coming centuries. Such dangerous anthropogenic interference with the climate system is a possibility the UN Framework Convention on Climate Change (UNFCCC) calls on nations to avoid. Unacceptable consequences of such interference could include inundation of coastal areas and low-lying islands by rising sea level, the rate of which could exceed natural and human ability to adapt, and ocean acidification contributing to widespread disruption of marine and human food systems. Such consequences pose daunting socioeconomic costs, for developing nations in particular. Drawing on existing literature, we define example levels of acceptable global marine change in terms of global mean temperature rise, sea level rise and ocean acidification. A global-mean climate model (ACC2), is implemented in an optimizing environment, GAMS, and coupled to an economic model (DICE). Using cost-effectiveness analysis and the tolerable windows approach (TWA) allows for the computation of both economically optimal carbon dioxide emissions pathways as well as a range in carbon dioxide emissions (the so-called ``emissions corridor'') which respect the predetermined ceilings and take into account the socio-economically acceptable pace of emissions reductions. The German Advisory Council on Global Change (WBGU) has issued several guardrails focused on marine changes, of which we find the rate and absolute rise in global mean temperature to be the most restrictive (0.2 degrees Celsius per decade, 2 degrees Celsius total). Respecting these guardrails will require large reductions in both carbon and non-carbon GHGs over the next century, regardless of equilibrium climate sensitivity. WBGU sea level rise and rate of rise guardrails (1 meter absolute, 5 cm per decade) are substantially less restrictive, and respecting them does not require deviation from a business-as-usual path in the next couple hundred of years, provided common assumptions of Antarctic ice mass balance sensitivity are correct. The ocean acidification guardrail (0.2 unit decline relative to the pre-industrial value) is less restrictive than those for temperature, but does require emissions reductions into the coming century.