INTRODUÇÃO: Dengue é uma doença viral prevalente e potencialmente fatal associada à alteração da permeabilidade capilar e coagulopatia. Entretanto, não há estudos concernentes aos achados tromboelastométricos nesta doença. Realizamos o presente estudo para analisar pacientes com dengue e plaquetopenia por meio de um exame rápido, efetivo e a beira leito comparando com os exames convencionais de coagulação. MÉTODOS: Trata-se de um estudo observacional e transversal conduzido entre os dias 6 de abril a 5 de maio de 2015, em São Paulo, Brasil, durante epidemia de dengue. Foi realizado tromboelastometria ROTEM® em 53 pacientes com dengue e trombocitopenia em associação com exames convencionais de coagulação: tempo de protrombina (TP), international normalized ratio (INR), tempo de tromboplastina parcial ativado (TTPa), tempo de trombina (TT), contagem de plaquetas, fibrinogênio e d-dímero. Um grupo controle de pacientes foi estabelecido para comparação do status tromboelastométrico. RESULTADOS: Um total de 38 pacientes de 53 (71,7%) apresentaram anormalidades no INTEM e 29/53 (57,4%) no EXTEM. Em contrapartida, alterações no FIBTEM foram encontradas apenas em 3/53 (5,7%). Houve significância estatística em pacientes correlacionando alterações tromboelastométricas no EXTEM e INTEM e contagem de plaquetas (p=0,052) e (p=0,005), respectivamente; assim como os valores de fibrinogênio (p=0,006) e (p=0,021), respectivamente. O grupo controle (GC) apresentou status tromboelastométrico normal em 10/10 (100%) na análise do INTEM, EXTEM, FIBTEM. Avaliação do EXTEM demonstrou significância estatística entre o GC e o grupo Dengue: CT (p=0,044); CFT (p<0,001); MCF (p < 0,001) e Alpha (p < 0,001). Foram observados níveis normais de fibrinogênio (mediana: 290) e altos níveis de d-dímero (mediana: 1330) com IQR (800-1840). Todos os pacientes (53/53) apresentavam trombocitopenia abaixo de 100 x 109/L (mediana 77 x 109/L) IQR (63-88). Exames convencionais de coagulação revelaram-se completamente normais: TP (mediana: 100%) IQR (90-100); INR (mediana: 1,0) IQR (1,0-1,1); TTPa (mediana: 28,9 segundos) IQR (26,0-32,5) e TT (mediana: 18,2 segundos) IQR (17,0-19,5). Apenas (7/49) 14,3% pacientes apresentaram sangramento e (3/52) 5,8% necessitou de hospitalização. Não houve associação entre alterações tromboelastométricas com sangramento ou hospitalização. CONCLUSÕES: Dengue representa um processo inflamatório intenso, mantendo níveis normais de fibrinogênio. Portanto, FIBTEM mantém-se normal promovendo boa formação do coágulo sem risco imediato de sangramento. Não houve correlação entre os achados tromboelastométricos com os exames convencionais de coagulação, sugerindo que testes viscoelásticos são exames mais sensíveis para análise de coagulopatia precoce nessa população / INTRODUCTION: Dengue is a prevalent and potentially fatal viral disease associated with plasma leakage and coagulopathy, though no information is available on thromboelastometric profile. We performed this study to analyze dengue fever patients with thrombocytopenia clot changes through point-ofcare thromboelastometry tests and standard coagulation tests. METHODS: This was an observational, transversal and cross sectional study conducted between April 6th and May 5th 2015 in São Paulo, Brazil, during a dengue outbreak. Thromboelastometry ROTEM® was performed in 53 patients with dengue and thrombocytopenia, in association with conventional coagulation tests: prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time (TT); platelet count, fibrinogen level, and d-dimer. A control group of 10 patients was established to compare thromboelastometry profiles. RESULTS: A total of 38 patients in 53 (71,7%) had abnormalities in INTEM, 29 in 53 (57,4%) in EXTEM. Conversely, FIBTEM was abnormal in 3/53 (5,7%). Statistical analysis revealed significant relation in those patients with impairment EXTEM and INTEM with lowered platelet (p=0,052) and (p=0,005) respectively and lowered fibrinogen levels (p=0,006) and (p=0,021) respectively. Control group (CG) had normal status in 10/10 (100%) of INTEM, EXTEM, FIBTEM analysis. EXTEM analysis demonstrated statistical differences between CG and dengue group: CT (p=0,044); CFT (p < 0,001); MCF (p < 0,001) and Alpha (p < 0,001). Normal levels of fibrinogen (median: 290) and high levels of ddimer (median: 1330) IQR (800-1840) were found. All patients (53/53) had platelet under 100 x 109/L (median 77 x 109/L) IQR (63-88). Standard coagulation tests were completely normal: PT (median: 100%) IQR (90-100); INR (median: 1,0) IQR (1,0-1,1); aPTT (median: 28,9 seconds) IQR (26.0- 32,5) and TT (median: 18,2 seconds) IQR (17,0-19.5). Only (7/49) 14,3% patients had bleeding manifestations and (3/52) 5,8% needed hospitalization. There was no association between altered thromboelastometry with bleeding manifestations or hospitalization. CONCLUSIONS: Dengue represents an intense inflammatory process, maintaining normal levels of fibrinogen. FIBTEM remains normal providing good clot strength without immediate bleeding risk. There were no correlation between thromboelastometry findings and standard coagulation exams, suggesting that viscoelastic tests are more sensible method to analyze early coagulation impairments in this population

Introdução: As avaliações econômicas completas do tipo custo-utilidade, suportadas por dados de efetividade do mundo real, permitem uma perspectiva diferenciada da avaliação de tecnologia em saúde. Objetivo: Realizar uma análise de custo-utilidade do uso de estatinas para a prevenção secundária de eventos cardiovasculares em portadores de doença cardiovascular isquêmica, e avaliar a variabilidade da efetividade e da razão de custo-efetividade incremental com diferentes classificações de usuários de estatina (incidentes e prevalentes). Método: Um modelo de microssimulação de Markov com 5 estados, ciclos anuais e horizonte temporal de 20 anos, com taxas de desconto de 5% foi desenvolvido. As probabilidades de transição para mortalidade por todas as causas foram extraídas após pareamento por escore de propensão dos dados e tratamento de dados ausentes de uma base secundária de registro assistencial com linkage determinístico com a base de mortalidade do Ministério da Saúde. As probabilidades dos desfechos não-fatais foram obtidas na literatura. As medidas de efetividade (QALY) foram calculadas com dados publicados dos domínios do SF-36 de um estudo realizado com a população do mesmo hospital, no mesmo período e com as mesmas condições clínicas e transformados em medidas de utilidade por modelo validado. Somente custos diretos na perspectiva do reembolso do SUS foram considerados. Resultados: 3.150 pacientes foram pareados após o escore de propensão, 1.050 não usuários de estatina, 1.050 usuários de estatinas classificados como prevalentes e 1.050 usuários de estatinas classificados como incidentes, com diagnóstico de doença cardiovascular isquêmica prévia, com seguimento médio de 5,1 anos. A efetividade das estatinas quando considerados todos os usuários em relação aos não usuários resultou em um HR para mortalidade de 0,992 (IC 95% 0,85; 0,96) e de 0,90 (IC 95% 0,85; 0,96) para os usuários incidentes. A RCEI comparando todos os usuários de estatinas versus não usuários foi de R$5.846,10/QALY e de R$7.275,61/QALY para os usuários incidentes. Conclusão: As estatinas diminuíram a mortalidade por todas as causas, e a análise incluindo usuários prevalentes diminui o tamanho do efeito. O tratamento possui custo-efetividade favorável dentro do limiar de disponibilidade a pagar definido, sendo modificado pela forma de extração do dado de efetividade / Background: The complete economic evaluations, such as cost-utility analysis, supported by real world data of effectiveness lead to a more realistic perspective of a health technology assessment. Objective: Perform a cost-utility analysis of statins for secondary prevention in ischemic cardiovascular disease patients based on effectiveness from real world data and evaluate the variability of effectiveness and incremental cost-effectiveness ratio (ICER) considering prevalent and incident users. Methods: A Markov microssimulation model with five states, annual cycle and time horizon (TH) of 20 years, with discount rate of 5% was developed. Transition probabilities for all cause mortality was derived from a secondary database of a teaching hospital after record linkage with national registry of mortality database and an analysis of propensity score matching and multiple imputation analysis for missing data. Non-fatal endpoints were derived from a published meta-analysis. Utility measures was calculated with a validated model to derive values from published domains of SF-36 QoL questionnaire, domains was measured for a published RCT in the same teaching hospital, over the same period, with similar age and diagnostic characteristics. Only direct costs were analyzed from the Brazilian public health reimbursement perspective. Results: 3150 patients were matched, 1050 non-statins users (CG), 1050 prevalent statins users (PSU) and 1050 incident statins users (ISU) with previous cardiovascular disease, with mean follow-up of 5,1 years. Treatment effects on the treatment group considering all statins users for all cause mortality had a hazard ratio of HR:0,992 (IC 95% 0,85 - 0,96) and HR: 0,90 (IC 95% 0,85 - 0,96) only for ISU. The ICER comparing all users with non-users was R$5.846,10 per QALY and for ISU was R$7.275,61 per QALY. Conclusion: Real world evidence demonstrated that statins are an effective treatment to reduce all cause mortality in secondary prevention and are a cost-effective strategy considering the willingness to pay established, but the prevalent users resulted in less effectiveness of the drug when included in the analysis and influenced the ICER

Introdução: Câncer de mama é o mais comum em mulheres. Embora sua incidência ainda esteja em ascensão, as taxas de recorrência e mortalidade têm diminuído, em especial nos países desenvolvidos. Assim o câncer pode ser considerado um choque transitório que não impede que os sobreviventes retomem a normalidade em suas vidas, incluindo atividades laborais. Na América do Norte e Europa, as taxas de RT entre as pacientes com câncer de mama variam de 24-66% após 6 meses e 53-82% após 36 meses de diagnóstico. Os fatores mais associados ao RT são: idade, quimioterapia, sequelas da terapia do câncer e apoio do empregador e colegas de trabalho. Esses achados, no entanto, variam sugerindo que outros fatores e até aspectos de diferentes legislações podem interferir no RT. Na América Latina há escassez de dados sobre RT após o diagnóstico de câncer de mama. Objetivos: Avaliar as taxas de retorno ao trabalho nos meses 12 e 24 após o diagnóstico de câncer de mama e verificar a correlação de fatores à retomada ao trabalho aos 24 meses. Métodos: Estudo prospectivo observacional avaliando taxas de RT em mulheres com câncer de mama tratadas no Instituto do Câncer do estado de São Paulo, com idade > 18 e < 57 anos e que trabalhavam de forma remunerada por pelo menos 03 meses ao diagnóstico. Pacientes com doença inoperável ou metastática foram excluídas. Nos meses 06, 12 e 24 do seguimento responderam à questionários do estudo e de qualidade de vida (FACT-B), por telefone. Resultados: Entre julho/2012 e setembro/2014, 125 pacientes assinaram o TCLE. Quatro foram excluídas da análise (02 óbitos e 02 sem contato por telefone). A idade média foi de 45.1 anos (± 8,1). A maioria (94%) gostava do trabalho, 73% receberam apoio do empregador, mas apenas 29% relataram ter recebido oferta de ajuste no trabalho. Metade apresentava doença no estádio II e 93% fizeram quimioterapia como parte de seu tratamento. As taxas de RT foram 21,5%, 30,3% e 60,4% aos 06, 12 e 24 meses, após o diagnóstico de câncer de mama. Na análise multivariada os fatores que afetaram de forma positiva as taxas de RT foram: renda familiar mensal >= 02 salários mínimos (OR 17,76, IC95% 3,33-94,75, p 0,001), cirurgia conservadora da mama (OR 9,77, IC 95% 2,03-47,05, p 0,004) e oferta de ajuste no trabalho pelo empregador (OR 37,62, IC95% 2,03-47,05, p 0,004). Fatores que se associaram de forma negativa ao RT foram: terapia endócrina (OR 0,11, IC95%0,02-0,74, p 0,023) e diagnóstico de depressão após o câncer (OR 0,07, IC95% 0,01-0,63, p 0,017). Conclusões: As taxas de RT aos 12 e 24 meses após diagnóstico de câncer de mama são inferiores a maioria dos estudos conduzidos na América do Norte e Europa. Oferta de ajuste no trabalho, maior renda familiar, cirurgia conservadora da mama, terapia endócrina adjuvante e diagnóstico de depressão após o câncer de mama desempenharam importante papel no RT / Background: Breast cancer is the most common cancer in women. While its incidence has been increasing, recurrence and mortality rates have been decreasing, mainly because of better treatment options. Because of that cancer can be regarded as a transient shock that does not prevent survivors resume normality in their lives including return to their workplace. In North America and Europe return to work (RTW) rates vary among breast cancer patients from 24- 66% after 06 months and 53-82% after 36 months of diagnosis. Factors most associated with the decision to return to work are: age, chemotherapy, sequelae related to cancer therapy and support from the employer and coworkers. However, these findings vary among the different populations evaluated, suggesting that other factors and even variations in countries laws may interfere with the decision to return to work. So far there is a lack of data on RTW after breast cancer diagnosis in Latin America. Endpoints: To evaluate return to work rates on months 12 and 24 after breast cancer diagnosis, and check the correlation of some factors with the decision to return to work at 24 months. Methods: A prospective, observational study evaluating RTW rates in patients with breast cancer diagnosis, > 18 and < 57 years old and a paid work for at least 03 months at the time of dianosis. Patients with inoperable or metastatic disease were excluded. On months 6, 12 and 24 they answered a telephone interview and the quality of life questionnaire (FACT-B). Results: Between july/2012 and september/2014, 125 patients were enrolled. Two of them died and two other could not be reached by telephone, and were excluded from the analysis. Mean age was 45,1 years (± 8,1). Most of them reported that they liked their job (94%) and received support from employer (73%), but only 29,1% reported having been offered work adjustment. Half of patients had stage II disease and 93% received chemotherapy as part of their treatment. Overall, 21,5%, 30,3% and 60,4% of patients returned to work 06, 12 and 24 months after breast cancer diagnosis, respectively. In the multivariate analysis, factors associated with positive RTW outcomes included higher income (OR: 17,76, CI95% 3,33-94,75; p = 0,001), breast conserving surgery (OR: 9,77, CI95% 2,03-47,05; p = 0,004) and work adjustment (OR: 37,62, CI95% 2,03-47,05; p= 0,004). Factors associated with negative RTW outcomes included adjuvant endocrine therapy (OR: 0,11, IC95% 0,02-0,74; p = 0,023) and depression diagnosis after breast cancer diagnosis (OR: 0,07, IC95% 0,01-0,63; p = 0,017). Conclusion: RTW rates after 12 and 24 months of breast cancer diagnosis are lower than reported in North America (with exception for low income americans) and Europe. Workplace adjustments, higher income, breast conserving surgery, endocrine therapy and depression after breast cancer played an important role in the RTW decision

Vers la fin des années 1990, l’utilisation des supernovae de type Ia (SNe Ia) comme indicateurs de distance a permis de mettre en évidence l’expansion accélérée de l’univers. Depuis lors, des campagnes d’observations de grandes envergures ont permis d’augmenter de façon significative le nombre de SNe Ia observées, mais les incertitudes systématiques liées à la qualité des échantillons de SNe Ia proches restent un facteur limitant sur la précision des mesures actuelles. C’est dans le but de réduire ces incertitudes que le projet the Nearby Supernova Factory (SNfactory), à l’aide d’un instrument spectro-photométrique dédié à l’observation des SNe Ia (the Supernova Integral Field Spectrograph), a collecté depuis 2004 plus de 3000 spectres de près de 200 SNe Ia proches. Une des limitations actuelles de leur utilisation, outre les aspects liés aux problèmes d’inter-calibration entre les différentes expériences, est celle du mélange des différentes composantes de leurs variabilités lors de la standardisation empirique de leur module de distance. Une meilleure séparation de ces composantes, ainsi que la découverte de nouveaux indicateurs de distance, font partie des améliorations que peut apporter un échantillon spectral de SNe Ia proches tel que celui de la collaboration SNfactory. Cette thèse de doctorat, effectuée à l’Institut de Physique Nucléaire de Lyon et au Lawrence Berkeley National Laboratory, s’inscrit directement dans cette problématique, en se concentrant sur la mesure d’indicateurs spectraux sur l’échantillon spectral de la collaboration Snfactory. Le plan de cette thèse est le suivant : La première partie présente le contexte scientifique ainsi que l’échantillon de SNe Ia de la collaboration SNfactory utilisé dans les analyses. La deuxième partie se concentre sur la méthode de mesure d’indicateurs spectraux appliquée à l’échantillon spectrale présenté, ainsi que sur une étude de leur sensibilité à l’extinction par le milieu interstellaire. La troisième partie est une étude des corrélations des indicateurs spectraux et de leur utilisation pour la standardisation des Sne Ia. Dans la dernière partie, une utilisation de ces indicateurs spectraux pour la détermination d’une loi d’extinction moyenne est présentée / One of the current limitations of type Ia supernovae used as distance indicators is themixing of their different sources of variabilitiy during the empirical standardization of their distance modulus. Using the nearby SNe Ia spectral sample observed by the Nearby Supernovae Collaboration with the instrument SNIFS (Supernovae Intergral Field Sperctrograph), this thesis mainly focuses on this problematic using spectral indicators measurements. The first part of the thesis presents the scientific context as well as the sample used in the analysis. The second part focus on the spectral indicators measurement and their properties in the presence of interstellar dust extinction. The third part is a study of spectral indicators correlations and their use as standardization parameters. In the last part, we use these spectral indicators to construct a mean extinction law for type Ia supernovae

Des travaux antérieurs de l’équipe ont démontré l’impact majeur de la lymphopénie (<1Giga/L), détectée avant tout traitement, sur la survie globale des patients atteints d’un cancer solide en phase métastatique, soulignant ainsi l’importance du système immunitaire dans le contrôle de la progression tumorale. Au cours de mon projet de thèse, j’ai analysé l’apport de la diversité combinatoire de la chaine β du TCR, autre indicateur de la qualité du système immunitaire, en tant que marqueur pronostique chez des patientes atteintes de cancer du sein en phase métastatique. J’ai pu montrer qu’un score combinant la diversité des TCR et le nombre de lymphocytes (score NDL) est un facteur indépendant de mauvais pronostic en analyse multivariée. Ce score permet l’identification d’une sous population de patientes à risque qui présente à la fois une lymphopénie et une faible diversité (< 33%) combinatoire du TCR et pour laquelle une très forte réduction de la médiane de survie est observée. Nous avons également réalisé une étude plus approfondie de l’impact des sous-populations de lymphocytes et des cytokines plasmatiques produites. En parallèle, j’ai été amené à développer des tests de biologie moléculaire pour améliorer l’étude de la diversité du répertoire des TCR au niveau génomique. Ces travaux nous ouvrent la voie vers de nouvelles stratégies thérapeutiques qui intégreraient les perturbations du système immunitaire. En effet, suite à ces résultats, un essai clinique basé sur l’administration d’IL-7, cytokine permettant l’expansion des cellules T avant ou pendant la chimiothérapie vient d’être activé au Centre Léon Bérard / Previous work of the team demonstrated the major impact of lymphopenia (<1Giga/L), detected before treatment, on overall survival of patients with solid metastatic cancer, highlighting the importance of immune system in controlling tumor progression. During my thesis project, I analyzed the contribution of the combinatorial diversity of the TCR β chain, another indicator of the quality of the immune system, as a prognostic marker in patients with metastatic breast cancer. I was able to show that a score combining the diversity of TCR and the number of lymphocytes (score NDL) is an independent factor of poor prognostic in multivariate analysis. This score allows identification of a subpopulation of patients at risk who has both a lymphopenia and a low combinatorial diversity (<33%) of TCR and for which a reduction in the median survival was observed. We also made further study of the impact of subpopulations of lymphocytes and plasma cytokines. In parallel, I developed molecular tests to improve the study of TCR repertoire diversity at the genomic level. This work opens the door to new therapeutic strategies that would consider immune system dysfunctions. Indeed, following these results, a clinical trial based on the administration of IL-7 cytokine for the expansion of T cells before or during chemotherapy has been activated at the Centre Léon Bérard

L’imitation volontaire est établie comme l’un des modes principaux d’acquisition des habiletés motrices. Il existe également une autre forme d’imitation, automatique et involontaire, étudiée initialement en psychologie sociale du fait de son interaction étroite avec les comportements pro-sociaux. Récemment, et sous l’influence de travaux des années 1990 mettant en lumière des substrats neuronaux communs à l’observation et à l’exécution du mouvement, les recherches scientifiques se sont concentrées sur cette notion d’imitation automatique et ont investigué, via différents paradigmes expérimentaux, les effets de facilitation et d’interférence entre mouvements observés et exécutés. Le travail réalisé dans le cadre de cette thèse vise à améliorer notre compréhension des mécanismes de contagion motrice et à identifier leurs applications possibles au réentraînement moteur. Dans une première étude, nous avons évalué l’impact de l’observation de mouvements de déséquilibre sur le balancement postural d’observateurs jeunes (24,5 ± 5 ans), sans troubles posturaux. Le contrôle de l’équilibre orthostatique fait principalement intervenir des structures sous-corticales pour le maintien du tonus postural et l’intégration multisensorielle. Ces substrats neuronaux seraient, de la même manière que les fonctions végétatives indépendantes du contrôle volontaire, plus facilement contaminés par les mouvements observés. Cependant, l’observation d’un déséquilibre sollicite également des mécanismes de régulation posturale, qui restreignent le balancement de l’observateur et se surajoutent à des processus inhibiteurs prévenant l’imitation compulsive des mouvements observés. Par conséquent, ce paradigme expérimental nous a permis de tester les limites des effets de contagion à partir d’une situation où les processus inhibiteurs et régulateurs de la posture étaient fortement sollicités. Cette étude nous a conduits à mettre en évidence une contamination du balancement postural des sujets par le déséquilibre observé, ce qui a confirmé l’importance et la prédominance des processus d’imitation. Ce résultat soulève des questions importantes en termes d’applications au réentraînement moteur chez les patients souffrant de troubles posturaux, en particulier chez les personnes âgées qui présentent une altération de leurs fonctions de stabilisation. En effet, si l’observation d’un déséquilibre conduit à une réaction de contagion motrice, il est vraisemblable qu’elle sollicite également des fonctions inhibitrices et régulatrices permettant la stabilisation de l’observateur. La visualisation répétée d’un déséquilibre peut-elle alors conduire à une amélioration de la stabilisation chez les personnes à risque ? Pour étudier cette question, il serait nécessaire de répéter ce protocole chez le public cible - les réponses pouvant être modulées par l’âge et les aptitudes motrices des personnes. Notre seconde étude visait à évaluer l’impact du répertoire moteur sur les réactions de contagion motrice. S’il est admis que le système moteur (contraintes biomécaniques, niveau d’expertise) affecte les processus perceptifs, son effet sur les réactions d’imitation automatique a été peu étudié. Nous avons analysé les réactions posturales d’observateurs jeunes (24,2 ± 3,7 ans), sains, face à des séquences de déséquilibre antéro-postérieur et médio-latéral. Les stratégies d’équilibration posturale sont associées à des contraintes différentes selon ces deux axes, avec une symétrie médio-latérale et une asymétrie antéropostérieure – asymétrie résultant d’une position du centre de masse en avant de l’articulation de la cheville, qui induit une sollicitation accrue des muscles du plan postérieur pour la stabilisation posturale. Un impact du système moteur sur le processus de contagion serait donc susceptible de se traduire par des réactions posturales différentes dans nos deux conditions d’observation. etc / Voluntary imitation is known as a major means of acquisition of motor skills. Besides, another form of imitation, automatic and involuntary, was initially more extensively studied in social psychology, perhaps because of its close interaction with prosocial behaviors. Recently, there was a renewal of interest in automatic imitation, following research works of the 1990s that highlighted common neural substrates for movement observation and execution. In this context, scientific studies started, through various experimental paradigms, to investigate facilitation and interference effects between observed and executed movements. Research work presented in this thesis aims to improve our understanding of the mechanisms involved in motor contagion and to identify their possible application to motor retraining. For this purpose, we evaluated, in our first study, the impact of observation of postural imbalance on body sway of young (24.5 ± 5 years), healthy observers. Postural control mainly relies on subcortical structures for maintaining postural tonus and ensuring multisensory integration. Similarly to vegetative functions that are independent of voluntary control, these neural substrates would be more easily contaminated by observed movements. However in response to observed imbalance, postural regulation mechanisms, superimposed to inhibitory processes that prevent compulsive imitation, restrain observers’ disequilibrium. Therefore, this experimental paradigm enabled us to test the limits of contagion mechanisms in a situation highly soliciting inhibitory and regulation processes. Our results led us to highlight a contagion effect of observed imbalance on subjects’ postural sway, which confirmed the importance of imitation processes. These results raise an important question in terms of applications for movement retraining in patients with postural disorders, more specifically in elderly patients with impaired stabilization functions. In effect, if observation of postural imbalance leads to a motor contagion response, it is also likely to solicit regulatory and inhibitory functions for observers’ postural stabilization. Thus, could repeated observation of such disequilibrium movements lead to an improvement of stabilization functions for subjects with postural deficits? To investigate this question, it will be necessary to repeat this protocol with the target population, since observers’ response is likely to vary with age and motor competences. To complete this work, we conducted a second study to assess the impact of the motor repertoire on motor contagion responses. Although it is widely accepted that the motor system (biomechanical constraints, level of expertise) affects perceptual processes, its effect on imitative responses has been little studied. We analyzed postural reactions of young (24.2 ± 3.7 years), healthy observers when presented with sequences of anteroposterior and medio-lateral imbalance. Postural equilibration strategies are associated with different constraints along these two axes, with a medio-lateral symmetry and an anteroposterior asymmetry – this latter asymmetry results from a location of the center of mass ahead of the ankle joint, which induces an increased solicitation of muscles from the posterior plane for stabilization. An impact of the motor system on the contagion process could therefore appear in the form of different postural responses in our two observation conditions. Our results indicated a greater contagion effect during observation of anteroposterior compared to medio-lateral imbalance. Postural contagion is therefore conditioned by observers’ equilibration strategy. In our third study, we considered using this contagion effect for perceptual training aimed at the maintenance and improvement of elderly subjects’ motor performances. The issue of an observational training device is especially relevant when considering people for whom physical exercise is limited due to fatigue or pain.etc

The aim of the study was to investigate classroom discourse among high school natural science students in Swaziland. The research problem was: Can student interactions tell us something about the negotiation of understanding during natural science teaching? A qualitative approach was used, specifically, the observational case study style. The population comprised three Form 4 students and their natural science teacher, purposely selected. Data was collected using the non-participant observation and the standardised open-ended interview methods. The collected data was analysed using the discourse analysis approach. The analysed data indicated that prevailing discourse patterns were teacher and student talk, as well as written work. A conclusion was that student classroom discourse in the natural sciences should be encouraged among all students for improved understanding and meaning making. / Science and Technology Education / M. Ed. (Natural Science Education)

Les rhumatismes inflammatoires juvéniles sont des maladies chroniques débutant avant l’âge de 16 ans. Comprennent des pathologies classées dans un continuum, allant de la dérégulation de l’immunité innée à la dérégulation de l‘immunité adaptative. L’arthrite juvénile idiopathique (AJI) reste la plus fréquemment diagnostiqué. Les options thérapeutiques se sont élargies à partir des années 2000 avec le développement des thérapies ciblées, les biothérapies, associés aux traitements standard utilisés en rhumatologie pédiatrique (ex : anti-inflammatoires non stéroïdiens, corticostéroïdes, méthotrexate, et autres immunosuppresseurs). L’objectif de ce travail de thèse était d’estimer la relation bénéfice-risque des biothérapies utilisés dans les rhumatismes inflammatoires juvéniles à partir des essais cliniques randomisés (ECR) et d’explorer la tolérance à long cours à partir des essais observationnels. Premièrement, en utilisant une approche méta-analitique, les données des ECR en double aveugle contre placebo ou en ouvert dans l’AJI ont été analysées pour modéliser la relation bénéfice-risque des biothérapies avec le bénéfice net. Pour cela, l’efficacité clinique, mesuré par un score composite clinique et biologique (ACRped30), a été confronté à la tolérance clinique pendant la phase randomisée des ECR. Le critère de tolérance était la survenue d’un évènement indésirable (EI) grave (EIG). La balance bénéfice-risque reste favorable pour les biothérapies. Cependant, ces résultats sont limités par le suivi de faible durée, qui peut sous-estimer l’incidence des EI. Deuxièmement, nous avons conduit une étude observationnelle pour étudier la tolérance à moyen et long-terme des biothérapies utilisant les EI et les EIG décrits dans une base de données multicentrique rétrospective. La sécurité globale des biothérapies a été acceptable chez les enfants atteints de rhumatismes inflammatoires. Nous avons observé une variation des EIG au cours du temps et que la prescription concomitante des immunosuppresseurs a représenté un risque indépendant pour la survenue des EI. Afin d’explorer ces éléments et connaître la tolérance au long-terme, une méta-analyse des études observationnelles a été fait. Nous avons utilisé les EIG pour étudier précisément la tolérance à court et à long terme / Juvenile inflammatory rheumatism is a chronic disease that begins before the age of 16. Includes conditions classified along a continuum, ranging from the deregulation of innate immunity to the deregulation of adaptive immunity. Juvenile idiopathic arthritis (JIA) remains the most frequently diagnosed disease. Therapeutic options have expanded since the 2000s with the development of targeted therapies: biological agents (BAs). They can be combined with standard treatments used in paediatric rheumatology (e.g. non-steroidal anti-inflammatory drugs, corticosteroids, methotrexate, and other immunosuppressive drugs). The objective of the work of this thesis was to model the benefit-risk balance of BAs used in JIA from randomized clinical trials (RCTs) and to explore long-term tolerance from observational trials. First, using a meta-analytical approach, the data from double-blind, placebo-controlled or open RCTs in JIA were analysed for modelling the benefit-risk balance of BAs. For this purpose, the efficacy measured by a composite clinical and biological score (ACRped30), was compared with clinical safety during the randomized phase of RCTs. Safety criterion was the occurrence of adverse events (AEs). The risk-benefit balance remains favourable for biotherapies. However, these results are limited by the short follow-up period, which may underestimate the incidence of AEs. Second, we conducted an observational study to investigate the medium- and long-term safety of biotherapies using AEs and serious AEs described in a retrospective multicentre database. The overall safety of biotherapies has been acceptable in children with inflammatory rheumatic diseases. We observed a variation in the SAEs over time and that the concomitant prescription of immunosuppressants represented an independent risk for the occurrence of AEs. In order to explore these elements and long-term safety, a meta-analysis of observational studies was conducted. We used the SAEs to study precisely the short and long-term tolerance

Background: Community acquired pneumonia (CAP) is a high incidence disease resulting in about 260,000 hospital admissions per year in Germany, more than myocardial infarction or stroke. Worldwide, CAP is the most frequent infectious disease with high lethality ranging from 1.2 % in those 20–29 years old to over 10 % in patients older than 70 years, even in industrial nations. CAP poses numerous medical challenges, which the PROGRESS (Pneumonia Research Network on Genetic Resistance and Susceptibility for the Evolution of Severe Sepsis) network aims to tackle: Operationalization of disease severity throughout the course of disease, outcome prediction for hospitalized patients and prediction of transitions from uncomplicated CAP to severe CAP, and finally, to CAP with sepsis and organ failure as a life-threatening condition. It is a major aim of PROGRESS to understand and predict patient heterogeneity regarding outcome in the hospital and to develop novel treatment concepts. Methods: PROGRESS was designed as a clinical, observational, multi-center study of patients with CAP requiring hospitalization. More than 1600 patients selected for low burden of co-morbidities have been enrolled, aiming at a total of 3000. Course of disease, along with therapy, was closely monitored by daily assessments and long-term follow-up. Daily blood samples allow in depth molecular-genetic characterization of patients. We established a well-organized workflow for sample logistics and a comprehensive data management system to collect and manage data from more than 50 study centers in Germany and Austria. Samples are stored in a central biobank and clinical data are stored in a central data base which also integrates all data from molecular assessments. Discussion: With the PROGRESS study, we established a comprehensive data base of high quality clinical and molecular data allowing investigation of pressing research questions regarding CAP. In-depth molecular characterization will contribute to the discovery of disease mechanisms and establishment of diagnostic and predictive biomarkers. A strength of PROGRESS is the focus on younger patients with low burden of co-morbidities, allowing a more direct look at host biology with less confounding. As a resulting limitation, insights from PROGRESS will require validation in representative patient cohorts to assess clinical utility. Trial registration: The PROGRESS study was retrospectively registered on May 24th, 2016 with ClinicalTrials.gov: NCT02782013

There is a paramount need for online university education to effectively contribute in the development of students' ability to construct and create new knowledge. Online learning should thus go beyond the production of knowledge for knowledge's sake, but should result in relevant and meaningful learning on the part of the online learner. In addition, online learning ought to result in the application of knowledge to practice. While gains made by constructivism and observational learning are well documented, research addressing online media blends that best encourage constructivist and observational learning in open and distance and e-learning (ODeL) contexts is limited. In addition, guidelines that can be used by online learning facilitators and policy makers regarding media for constructivist and observational learning were lacking when this research was conducted. The research was deemed significant in contributing to the development of an online learning framework that could be used to guide policy formulation and practice in the area of online course implementation in ODeL institutions. Using an explorative qualitative approach, this study explored online media blends for constructivist and observational learning. The study comprised three phases. The first phase was a meta-ethnography study whose objective was to synthesise previous research theses in order to gain an understanding of lecturers' and students' experiences of online media, constructivism and observational learning. The second phase consisted of a phenomenological study conducted at the University of South Africa, to explore lecturers' experiences of online media in the facilitation of constructivism and observational learning. The final phase of the research was the development of a framework based on constructivism and observational learning to guide online teaching and learning. The findings of this research study revealed that lecturers did not use media blends to a large extent in their interaction with students. The study indicated that some cognitive processes need to be exercised on the part of the facilitators when online learning is offered. It is concluded that during the curriculum planning phase, lecturers should decide on methods and media to arouse the students' attention during online courses. This also implies a more reasonable lecturer­ student ratio because large numbers of students per lecturer is not feasible in online learning. / Curriculum and Instructional Studies / D. Ed. (Curriculum Studies)