Cette mémoire vise à développer une méthode de pondération par l’inverse de le probabilité de traitement (Augmented Inverse Probability of Treatment Weighting; AIPTW) et estimation par maximum de vraisemblance ciblée (Targeted Maximum Likelihood Estimation; TMLE) dans le contexte d'une méta-analyse en réseau avec données individuelles (Individual Patient Data Network Meta-Analysis; IPD-NMA) avec données observationnelles. Nous proposons également des méthodes pour estimer le score de propension généralisé (Generalized Propensity Score; GPS) pour finalement estimer l'effet causal d'une combinaison donnée de traitements (un régime) interprété à partir de d’une population globale. Cette recherche a été motivée par une mise à jour récente des données de patients atteints de la tuberculose multirésistante (Multidrug-Resistant Tuberculosis ; MDR-TB), une maladie infectieuse respiratoire causée par le bacillus mycobactérie avec un taux de mortalité élevé. Une compléxité notable de notre scénario est que toutes les régimes de traitements n'ont pas été observés dans toutes les études. L’inférence causale est définie comme l'étude de l'effet des traitements sur un résultat. Bien que les études cliniques randomisées sont l'étalon-or pour l'investigation des causes et effets, en raison de certaines limitations, leur utilisation n'est pas toujours faisable. Ainsi, l’analyse de données observationnelles est proposée. Donc, il est important de développer des méthodes qui nous permettent d'utiliser les informations provenant des données observationnelles. L'utilisation des informations provenant de plusieurs études individuelles nous permet d'évaluer les associations entre les traitements et les résultats qui sont spécifiques aux sous-populations. Aussi, une méta-analyse en réseau nous permet comparer plusieurs régimes au lieu de seulement deux. Nous estimons le taux de succès d’un régime donné à partir d'un ensemble d'études dans lesquelles le régime était disponible, puis le généralisons à l'ensemble de la population source. La théorie et les résultats d’une étude de simulation démontre que les méthodes développées sont doublement robustes. Cependant, TMLE démontre plus de robustesse, en particulier lorsqu’une méthode nouvellement proposée pour estimer le GPS est utilisée. Le résultat de l'application donne des estimations d’un taux de succès de traitement généralisé entre 50 à 61 % pour le régime {Pyrazinamide,Kanamycin,Ofloxacin,Ethionamide,Cyloserine} tandis que le taux observé de l’ensemble des données était de 59 %. / This thesis aims for developing Augmented Inverse Probability of Treatment Weighting (AIPTW) and Targeted Maximum Likelihood Estimation (TMLE) in the setting of Individual Patient Data Network Meta-Analysis (IPD-NMA) of observational data and propose a method to estimate the Generalized Propensity Score (GPS) to eventually estimate the causal effect of a given combination of treatments (a regimen) and generalize it to a global population. This research was motivated by a recent update on IPD_NMA of Multidrug-Resistant Tuberculosis (MDR-TB) - a respiratory infectious disease caused by bacillus mycobacterium with a high rate of mortality - where not all the regimens observed in all the studies. Although Randomized Controlled Trials (RCTs) are known to be the gold standard in investigating cause-and-effect including in causal inference (defined as the study of the effect of treatments on an outcome), but because of some known limitations using them is not always feasible. Thus, observational data are being proposed. Therefore, developing methods that enable us to use the information from observational data is important. In addition, using the information coming from individual studies allows us to evaluate associations between treatments and outcome which are specific to subpopulations. Also, a network meta-analysis allows us to study the effect of multiple treatments instead of two. We estimate the rate of treatment success for a given regimen from a set of studies where the regimen was available, and then generalize it to the whole network. The simulation result shows that the developed methods are doubly robust, however TMLE shows more robustness specially when the new proposed approach to estimate the GPS is being used. The application result shows a range of 50-61% for the generalized success rate of regimen {Pyrazinamide,Kanamycin,Ofloxacin,Ethionamide,Cyloserine} while the observed rate was 59% from multiple regimens.

A family of novel large cage Tb-based TNT-EMFs Tb₃N@C_2n (40 ≤ n ≤ 44), and a family of novel dimetallic endohedral metalloazafullerenes with the molecular formula of M₂@C₇₉N (M=Y, Tb, and La), were for the first time systematically synthesized, isolated, and structurally characterized. The protocol developed in this thesis provides an effective and systematic method for the synthesis, purification, and characterization of TNT-EMFs and other novel EMFs. Structural information about this family of Tb-based TNT-EMFs strongly supports the TNT formation mechanism of TNT-EMFs. It also demonstrates for the first time that EMFs do not necessarily choose an IPR-obeying cage even if the IPR cages are available. At room temperature and in a non-polar organic solvent, the fluorescence of the hydrogenated product of Tb₃N@C₈₀ was for the first time successfully obtained based on the proposed idea: de-shielding the screen effect of the fullerene cage on the metal ions or clusters inside the fullerene cage. The structural characterization of Tb₂@C₇₉N using single crystal X-ray diffraction crystallography demonstrated that the fullerene cage of M₂@C₇₉N is an I_h eighty-atom cage. The presence of the N atom in the molecule was further confirmed by mass spectra of the ¹⁵N labeled samples. ESR data demonstrated that there is a single-electron bond between the two Y atoms in Y₂@C₇₉N molecules. Theoretical calculations showed for the first time that the single-electron bond is low-lying at the HOMO-2 orbital and thereby resulting in a large HOMO-LUMO gap. It is, in fact, this large HOMO-LUMO gap and the low-lying single-electron orbital (hidden at HOMO-2) that are jointly responsible for the stability of M2@C79N. The single-electron bonds are the longest metal-metal bond reported so far. The chromatographic retention behavior of TNT-EMFs was also systematically studied on 5PBB and 5PYE columns. Both experimental and theoretical data demonstrated that the 5PBB column is sensitive to a fullerene's predicted cage size but indifferent to its cage symmetry, while the 5PYE column is more sensitive to the density and distribution of Ï electrons in a fullerene cage. Therefore, the 5PYE column is more suitable for separating structural isomers. The combination of the 5PBB column in the first stage and the 5PYE column in the second provides a highly effective way for isolating specific isomers. / Ph. D.

No / BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is considered to be less transmissible due to the fitness cost associated with drug resistance-conferring mutations in essential genes. OBJECTIVE: To test the hypothesis that TB drug resistance-conferring mutations with fitness cost are more frequent among human immunodeficiency virus (HIV) positive than among HIV-negative patients. DESIGN: We analysed all strains from the two TB drug resistance surveys conducted in Uganda between 2008 and 2011. Strains phenotypically susceptible to rifampicin and/or isoniazid were assumed to be wild-type; in all other cases, we performed whole-genome sequencing. Mutations at the rpoB531 and katG315 codons were considered without fitness loss, whereas other rpoB codons and non-katG were considered with fitness loss. RESULTS: Of the 897 TB patients, 286 (32.1%) were HIV-positive. Mutations with fitness loss in HIV-positive and HIV-negative patients were respectively as follows: non-531 rpoB: 1.03% (n = 3), 0.71% (n = 4) (OR 1.46, 95%CI 0.58-3.68); non-katG: 0.40% (n = 1), 1.0% (n = 6) (OR 0.40, 95%CI 0.07-2.20); rpoB531: 1.49% (n = 4), 0.69% (n = 4) (OR 2.29, 95%CI 0.83-5.77); katG315: 3.86% (n = 11), 2.55% (n = 15) (OR 1.54, 95%CI 0.81-2.90). The odds of mutations with and without fitness cost were higher for patients with a history of previous anti-tuberculosis treatment. CONCLUSIONS: Our data do not support the hypothesis that resistance-conferring mutations with fitness cost are likely to be often present in HIV-positive individuals.

Yes / Background: Tracking recent transmission is a vital part of controlling widespread pathogens such as Mycobacterium tuberculosis. Multiple methods with specific performance characteristics exist for detecting recent transmission chains, usually by clustering strains based on genotype similarities. With such a large variety of methods available, informed selection of an appropriate approach for determining transmissions within a given setting/time period is difficult. Methods: This study combines whole genome sequence (WGS) data derived from 324 isolates collected 2005–2010 in Kinshasa, Democratic Republic of Congo (DRC), a high endemic setting, with phylodynamics to unveil the timing of transmission events posited by a variety of standard genotyping methods. Clustering data based on Spoligotyping, 24-loci MIRU-VNTR typing, WGS based SNP (Single Nucleotide Polymorphism) and core genome multi locus sequence typing (cgMLST) typing were evaluated. Findings: Our results suggest that clusters based on Spoligotyping could encompass transmission events that occurred almost 200 years prior to sampling while 24-loci-MIRU-VNTR often represented three decades of transmission. Instead, WGS based genotyping applying low SNP or cgMLST allele thresholds allows for determination of recent transmission events, e.g. in timespans of up to 10 years for a 5 SNP/allele cut-off. Interpretation: With the rapid uptake of WGS methods in surveillance and outbreak tracking, the findings obtained in this study can guide the selection of appropriate clustering methods for uncovering relevant transmission chains within a given time-period. For high resolution cluster analyses, WGS-SNP and cgMLST based analyses have similar clustering/timing characteristics even for data obtained from a high incidence setting. / ERC grant [INTERRUPTB; no. 311725] to BdJ, FG and CJM; an ERC grant to TS [PhyPD; no. 335529]; an FWO PhD fellowship to PM [grant number 1141217N]; the Leibniz Science Campus EvolLUNG for MM and SN; the German Centre for Infection Research (DZIF) for TAK, MM, CU, PB and SN; a SNF SystemsX grant (TBX) to JP and TS and a Marie Heim-Vögtlin fellowship granted to DK by the Swiss National Science Foundation. The computational resources and services used in this work were provided by the VSC (Flemish Supercomputer Center), funded by the Research Foundation - Flanders (FWO) and the Flemish Government – department EWI.

Yes / We investigated whether companion drug resistance was associated with adverse outcome of the shorter MDR-TB regimen in Bangladesh, after adjusting for fluoroquinolone resistance. MDR/RR-TB patients registered for treatment with a standardized gatifloxacin-based shorter MDR-TB regimen were selected for the study. Drug resistance was determined using the proportion method, gatifloxacin and isoniazid minimum inhibitory concentration testing for selected isolates, and whole genome sequencing. Low-level and high-level fluoroquinolone resistance were the most important predictors of adverse outcomes, with pyrazinamide resistance having a significant yet lower impact. In patients with fluoroquinolone-/second-line injectable-susceptible TB, non-eligibility to the shorter MDR-TB regimen (initial resistance to either pyrazinamide, ethionamide, or ethambutol) was not associated with adverse outcome (aOR 1.01; 95%CI 0.4-2.8). Kanamycin resistance was uncommon (1.3%). Increasing levels of resistance to isoniazid predicted treatment failure, also in a subgroup of patients with high-level fluoroquinolone-resistant TB. Our results suggest that resistance to companion drugs of the shorter MDR-TB regimen, except kanamycin resistance, is of no clinical importance as long as fluoroquinolone susceptibility is preserved. Hence, contrary to current WHO guidelines, exclusions to the standard regimen are justified only in the case of fluoroquinolone, and possibly kanamycin resistance. / Damien Foundation Belgium for its financial and logistic support to run the project including its research activities. European Research Council (Starting Grant INTERRUPTB 311725).

BACKGROUND: The prevalence of tuberculosis (TB) has been rapidly on the ascendency in the recent years globally due to its co-infection with HIV/AIDS. TB case finding is one of the technical pillars of the Directly Observed Treatment Short course (DOTS) TB strategy and there has been advocacy for early TB case detection to be the new focus of TB control efforts. PURPOSE: The purpose of this non-experimental study was to assess the determinants of TB case finding among pulmonary TB patients registered for treatment in Makana Municipality METHOD: A quantitative, non-experimental, cross sectional descriptive study among PTB patients registered for treatment at the primary health care clinics in Makana Municipality was done. Data collection was by self-administered questionnaires while sampling was by systematic sampling of PTB patients at five systematically selected clinics. RESULTS: Patient–related delay contributed more to total delay, in this study sample, than health system-related delay. Health system delay was found to be significantly associated with poorer finances, passive smoking history, seeking care from multiple health providers, initially visiting a non- NTCP health provider, TB stigma , overcrowding in the household and having difficulty with breathing as an initial symptom (p<0.05). CONCLUSION: There was a significant delay in TB case finding among PTB patients in this local municipality and patient related determinants contributed more than health system related determinants to this delay. There is need for the municipal TB programme to embark on an aggressive health education programme to furnish the populace with accurate information about TB, improve their health seeking behaviour and help address the issue of stigma associated with TB. / Health Studies

Giant magnetostrictive RFe2 type (R represents rare earths) intermetallics form an important class of magnetic materials keeping in view of their potential applications as sensors and/ or actuators. In this thesis, one such mixed rare earth compound (Tb,Dy)Fe2 has been chosen for investigations. Being a technologically important material system, several investigations concerning physical and magnetic properties of the material and effect of processing parameters on magnetic properties have been reported in the available literature. However, existing literature does not provide a clear insight into some important aspects such as phase equilibria, evolution of texture and microstructure of directionally solidified Tb-Dy-Fe alloys. Therefore, the present work was undertaken to bring out tangible process-structure-property correlations with an emphasis to clarify the grey areas in the available literature. The investigation on the nature of ternary phase equilibria of Tb-Dy-Fe was taken up with an aim to understand the effect of Tb/Dy ratio on phase equilibria and magnetic properties of TbxDy1-xFe1.95 (x=0-1) alloys. Microstructural and micro-chemical analysis along with study of lattice parameter has been used to predict the nature of phase equilibria and the deviation from the assumed pseudo-binary behaviour. Further, from the microstructural investigations and study of lattice parameter and Curie temperature, a schematic sketch of a section of the ternary diagram, where (Tb,Dy) / Fe =1.95, was formulated and presented. Directional solidification technique is the most widely adopted method for processing the (Tb,Dy)Fe2, to impart grain orientation for practical applications. Therefore, it was aimed in the present study to understand the evolution of texture and microstructure in directionally solidified Tb0.3Dy0.7Fe1.95 alloy by modified Bridgman and zone melting techniques. The alloy was directionally solidified by modified Bridgman technique with a series of growth rates 5 - 100 cm/h, at a constant temperature gradient of 150oC/ cm. Microstructural investigation revealed formation of island banding at lower growth rate and peritectic coupled growth at higher growth rates. The texture study indicated a transition of growth texture from <113> to <110> and finally to <112> with increase of growth rate. A mechanism based on atomic attachment kinetics is proposed to explain the orientation selection with growth rate. The texture and microstructure have been correlated with magnetostriction and static strain co-efficient (dλ/dH) of the Bridgman solidified alloys. The solidification morphology observed in Bridgman solidified samples was found to be mostly plane front. Therefore, in order to understand the microstructure and texture evolution in cellular/ dendritic regime, directional solidification of Tb0.3Dy0.7Fe1.95 was attempted by zone melting technique with a lesser temperature gradient of 100oC/cm. A detailed texture study indicated a transition in preferred growth direction from <110> to <112> with increase of growth rate. In this case of cellular/ dendritic growth regime, a mechanism based on atomic attachment kinetics has been proposed and the preferred morphologies of the solid-liquid interface for <110> and <112> growth have been modelled. The modelled interfaces have been correlated to the shape of cell/ dendrite cross-section observed for the growth rates adopted in this study. Apart from the investigation carried out on the (Tb,Dy)Fe2 alloys, attempts have been made to understand the role of microstructure, especially the ordered phases on the magnetostriction of an emerging magnetostrictive material Fe-Ga. A series of alloy compositions of Fe-x at % Ga (x=17, 20, 23 and 25) were prepared and subjected to different thermal treatments and characterized for microstructural features and magnetostriction. Microstructure investigation of slow cooled, quenched and quenched + aged alloys reveals formation of ordered DO3 phase from disordered A2 phase by first order transformation in 17 and 20 at% Ga alloys, whereas for 23 and 25 at% alloys, the transformation takes place by continuous ordering. It could be observed that large magnetostriction arises owing to the presence of disordered A2 phase or ordered DO3 phase alone. The magnetostriction however decreases substantially when these two phases are co-existing.

On étudie dans cette thèse les théorèmes Tb locaux pour les opérateurs d’intégrale singulière, dans le cadre des espaces de type homogène. On donne une preuve directe du théorème Tb local avec hypothèses d’intégrabilité L^2 sur le système pseudo-accrétif. Notre argument repose sur l’algorithme Beylkin-Coifman-Rokhlin, appliqué dans des bases d’ondelettes de Haar adaptées, et sur des résultats de temps d’arrêt. Motivés par une question posée par S. Hofmann, on étend notre résultat au cas où les conditions d’intégrabilité sont inférieures à 2, avec une hypothèse supplémentaire de type faible bornitude, qui incorpore des inégalités de type Hardy. On étudie la possibilité d’affaiblir les conditions de support du système pseudo-accrétif en l’autorisant à être défini sur un petit élargissement des cubes dyadiques. On donne également un résultat dans le cas où, pour des raisons pratiques, les hypothèses sur le système pseudo-accrétif sont faites sur les boules au lieu des cubes dyadiques. Enfin, on s’intéresse au cas des opérateurs parfaitement dyadiques pour lesquels la démonstration est grandement simplifiée. Notre argument nous donne l’opportunité de nous intéresser aux inégalités de type Hardy. Ces estimations sont bien connues des spécialistes dans le cadre Euclidien, mais elles ne semblent pas avoir été étudiées dans les espaces de type homogène. On montre qu’elles sont vérifiées sans restriction dans le cadre dyadique. Dans le cas plus général d’une boule B et de sa couronne 2B\B, elles peuvent être déduites de certaines conditions géométriques de distribution des points dans l’espace de type homogène. Par exemple, on prouve qu’une condition de petite couche relative est suffisante. On montre aussi que cette propriété est impliquée par la propriété de monotonie géodésique de Tessera. Enfin, on présente quelques exemples et contre-exemples explicites dans le plan complexe, afin d’illustrer le lien entre la géométrie de l’espace de type homogène et la validité des inégalités de type Hardy. / In this thesis, we study local Tb theorems for singular integral operators in the setting of spaces of homogeneous type. We give a direct proof of the local Tb theorem with L^2 integrability on the pseudo- accretive system. Our argument relies on the Beylkin-Coifman-Rokhlin algorithm applied in adapted Haar wavelet basis and some stopping time results. Motivated by questions of S. Hofmann, we extend it to the case when the integrability conditions are lower than 2, with an additional weak boundedness type hypothesis, which incorporates some Hardy type inequalities. We study the possibility of relaxing the support conditions on the pseudo-accretive system to a slight enlargement of the dyadic cubes. We also give a result in the case when, for practical reasons, hypotheses on the pseudo-accretive system are made on balls rather than dyadic cubes. Finally we study the particular case of perfect dyadic operators for which the proof gets much simpler. Our argument gives us the opportunity to study Hardy type inequalities. The latter are well known in the Euclidean setting, but seem to have been overlooked in spaces of homogeneous type. We prove that they hold without restriction in the dyadic setting. In the more general case of a ball B and its corona 2B\B, they can be obtained from some geometric conditions relative to the distribution of points in the homogeneous space. For example, we prove that some relative layer decay property suffices. We also prove that this property is implied by the monotone geodesic property of Tessera. Finally, we give some explicit examples and counterexamples in the complex plane to illustrate the relationship between the geometry of the homogeneous space and the validity of the Hardy type inequalities.

Ao mesmo tempo em que produções transmídia se tornam cada vez mais comuns, estão ocorrendo mudanças no Brasil que favorecem o aumento do uso de interatividade no dia a dia. Uma das mudanças fundamentais foi a adoção de um sistema de televisão digital terrestre que, em comparação ao sistema analógico, proporciona mais do que recepção de sons e imagens de melhor qualidade em televisores fixos: torna possível receber os sinais de televisão também em dispositivos móveis e portáteis, além de possibilitar a interatividade. Dada a importância da televisão como plataforma de mídia no país (a televisão está presente em 96,9% dos domicílios brasileiros), foi feito um estudo da Qualidade de Experiência (QoE) percebida, com base na avaliação da qualidade do vídeo obtido ao utilizar uma aplicação interativa transmídia de televisão digital terrestre. Foi desenvolvida uma aplicação interativa em linguagem NCL, linguagem declarativa padrão do Sistema Brasileiro de TV Digital Terrestre (ISDB-TB), onde um vídeo secundário é carregado via Internet em banda larga (por streaming) ao mesmo tempo em que o vídeo principal é recebido via radiodifusão. Criou-se um cenário de teste onde foi introduzida, de forma controlada, perda de pacotes IP enquanto o vídeo secundário era carregado, simulando o que poderia ocorrer na Internet. A qualidade dos vídeos obtidos em cada situação de perda de pacotes foi analisada segundo métricas objetivas e os dados encontrados permitiram inferir qual seria a QoE percebida em cada caso. / At the same time that transmedia productions are becoming more common, legal changes are occurring in Brazil that bring an increase on daily interactivity use. One of that was the adoption of a terrestrial digital television system that, when compared to legacy analog broadcast systems, yields more than sounds and images of better quality, but also makes it possible to receive TV signals on portable devices and mobile television receivers besides enabling interactivity. Owing to the importance of television as a media platform in Brazil (it is present in 96,9% households) a analysis of Quality of Experience (QoE) was made, measuring the user perception with an interactive application of terrestrial digital television. Such an application was developed using NCL language, which is the standard declarative language of Brazilian digital television system (ISDB-TB). In that application a secondary video is loaded through a broadband Internet access simultaneously with the main video being received thru broadcasting. A test platform was created where IP packet losses was introduced in a controlled way affecting the secondary video, as it is expected to occur in a real network. Video quality was assessed for each loss level with objective metrics in order to compare QoE in each situation.

Ao mesmo tempo em que produções transmídia se tornam cada vez mais comuns, estão ocorrendo mudanças no Brasil que favorecem o aumento do uso de interatividade no dia a dia. Uma das mudanças fundamentais foi a adoção de um sistema de televisão digital terrestre que, em comparação ao sistema analógico, proporciona mais do que recepção de sons e imagens de melhor qualidade em televisores fixos: torna possível receber os sinais de televisão também em dispositivos móveis e portáteis, além de possibilitar a interatividade. Dada a importância da televisão como plataforma de mídia no país (a televisão está presente em 96,9% dos domicílios brasileiros), foi feito um estudo da Qualidade de Experiência (QoE) percebida, com base na avaliação da qualidade do vídeo obtido ao utilizar uma aplicação interativa transmídia de televisão digital terrestre. Foi desenvolvida uma aplicação interativa em linguagem NCL, linguagem declarativa padrão do Sistema Brasileiro de TV Digital Terrestre (ISDB-TB), onde um vídeo secundário é carregado via Internet em banda larga (por streaming) ao mesmo tempo em que o vídeo principal é recebido via radiodifusão. Criou-se um cenário de teste onde foi introduzida, de forma controlada, perda de pacotes IP enquanto o vídeo secundário era carregado, simulando o que poderia ocorrer na Internet. A qualidade dos vídeos obtidos em cada situação de perda de pacotes foi analisada segundo métricas objetivas e os dados encontrados permitiram inferir qual seria a QoE percebida em cada caso. / At the same time that transmedia productions are becoming more common, legal changes are occurring in Brazil that bring an increase on daily interactivity use. One of that was the adoption of a terrestrial digital television system that, when compared to legacy analog broadcast systems, yields more than sounds and images of better quality, but also makes it possible to receive TV signals on portable devices and mobile television receivers besides enabling interactivity. Owing to the importance of television as a media platform in Brazil (it is present in 96,9% households) a analysis of Quality of Experience (QoE) was made, measuring the user perception with an interactive application of terrestrial digital television. Such an application was developed using NCL language, which is the standard declarative language of Brazilian digital television system (ISDB-TB). In that application a secondary video is loaded through a broadband Internet access simultaneously with the main video being received thru broadcasting. A test platform was created where IP packet losses was introduced in a controlled way affecting the secondary video, as it is expected to occur in a real network. Video quality was assessed for each loss level with objective metrics in order to compare QoE in each situation.