Yes / Background: Mycobacterium tuberculosis rapid diagnostic tests (RDTs) are widely employed in routine laboratories and national surveys for detection of rifampicinresistant (RR)-TB. However, as next-generation sequencing technologies have become more commonplace in research and surveillance programs, RDTs are being increasingly complemented by whole genome sequencing (WGS). While comparison between RDTs is difficult, all RDT results can be derived from WGS data. This can facilitate continuous analysis of RR-TB burden regardless of the data generation technology employed. By converting WGS to RDT results, we enable comparison of data with different formats and sources particularly for low- and middle-income high TB-burden countries that employ different diagnostic algorithms for drug resistance surveys. This allows national TB control programs (NTPs) and epidemiologists to utilize all available data in the setting for improved RR-TB surveillance. Methods: We developed the Python-based MycTB Genome to Test (MTBGT) tool that transforms WGS-derived data into laboratory-validated results of the primary RDTs—Xpert MTB/RIF, XpertMTB/RIF Ultra, GenoType MDRTBplus v2.0, and GenoscholarNTM+MDRTB II. The tool was validated through RDT results of RR-TB strains with diverse resistance patterns and geographic origins and applied on routine-derived WGS data. Results: The MTBGT tool correctly transformed the single nucleotide polymorphism (SNP) data into the RDT results and generated tabulated frequencies of the RDT probes as well as rifampicin-susceptible cases. The tool supplemented the RDT probe reactions output with the RR-conferring mutation based on identified SNPs. The MTBGT tool facilitated continuous analysis of RR-TB and Xpert probe reactions from different platforms and collection periods in Rwanda. Conclusion: Overall, the MTBGT tool allows low- and middle-income countries to make sense of the increasingly generated WGS in light of the readily available RDT. / Erasmus Mundus Joint Doctorate Fellowship grant 2016- 1346.

Situated on the north-eastern coast of Morocco, the Spanish enclave of Melilla is a paradigmatic case of an unusual yet increasingly common kind of community. These are small, rather isolated communities with no industry or natural resources of their own, which rely heavily on capital and labour drawn from outside. Together with Ceuta, Melilla is one of the two only land borders between Europe and Africa. The enclave’s economic and political set up reflects its geopolitical importance. Across the border from Melilla lies the Moroccan province of Nador, home to one of the largest communities of Moroccan emigrants in Europe and a steady source of unskilled labour on which the Spanish enclave relies. Connections across the border are strong, including kinship links, employment networks and a wide range of both legal and illegal commercial transactions. Based on twelve months of fieldwork conducted on both sides of the border, this thesis departs from prevailing images of the borderland as either an abstract space of ‘creolisation’ and ‘hybridity’ or a locus of resistance to state power, and suggests, instead, that we carefully consider the large-scale political and economic processes through which places like Melilla and Nador are produced, and analyse the ways in which such global structures shape local reality. A fundamental aim of the thesis, therefore, is to elucidate the nature of the relations between space, place and capital at the Spanish-Moroccan frontier, and understand how such relations affect the lives of those who inhabit the region. This involves thinking about the language of a ‘community’ and the discourses and practices of morality that sustain it; analysing discourses of ‘us’ vs. ‘them’ in contexts of institutionalised economic inequality; and understanding local conceptions of identity, morality and legitimacy, and how the three interact.

The research presented within this dissertation focused on two major areas of research: monitoring the response to single-dose radiotherapy in a RIF-1 tumor model and the role of cortical spreading depression in the evolution of ischemic stroke. For the research in the first half of this dissertation, quantitative MRI was performed to investigate the spatial correlation between the apparent diffusion coefficient (ADC), spin-spin relaxation times (T2), and proton density (M0) in murine radiation-induced fibrosarcoma (RIF-1) tumors following single-dose (1000cGy) radiotherapy using the k-means (KM) algorithm. An in-depth comparison between KM-derived volume estimates and conventional histology via the hematoxylin-eosin (H&E) staining procedure (for identification of viable tumor versus necrosis), as well as via hypoxic-inducible factor-1alpha (HIF-1alpha) immunohistochemistry (for identification of regions of hypoxia versus well-oxygenated tissue) was performed. The results of this study demonstrated that multispectral (MS) analysis provides: (1) an improved tissue segmentation method over results obtained from conventional single-parameter approaches, (2) subdivision based on the degree of necrosis, as well as delineation between well-oxygenated and hypoxic viable tissue, (3) good correlation with both H&E staining and HIF-1alpha immunohistochemistry, and (4) a method for monitoring the range of tissue viability as a function of time post-treatment, with the potential for predicting therapeutic efficacy. For the research in the second half of this dissertation, manganese-enhanced MRI (MEMRI) was employed for the characterization of both experimental and pathological cortical spreading depression (CSD). In order to determine the utility of manganese ions (Mn2+) as a marker for spreading depression (SD), experimental SD was elicited by chemical stimulation (KCl application to exposed rat cortex) and compared with control conditions. This study demonstrated that (1) Mn2+ is a more accurate marker for SD than DWI or T2* methods, (2) cortical restriction of MEMRI enhancement supports the contention that apical dendrites are necessary for SD propagation. (3) subcortical enhancement was a result of cortical-subcortical neuronal connectivity. Based on these results, preliminary experiments involving the study of SD in ischemia using Mn2+ were performed. Initial results indicate: (1) MEMRI may provide a method for estimating the likelihood of progression to infarction at acute timepoints post onset of stroke. These studies provide a foundation for further investigation into the role of SD in stroke, and the application of Mn2+ towards the design of therapeutic strategies targeting SD inhibition.

Zugl.: Münster, Univ., Diss., 2003

Texte remanié de: Th. univ.--Théol.--Leyde, 1995. / En appendice, choix de documents. Bibliogr. p. 271-278. Glossaire. Index.

Introdução: O teste Xpert MTB / RIF está sendo cada vez mais utilizado em muitos países como diagnóstico inicial para a tuberculose (TB). Poucos estudos avaliaram o impacto do Xpert no diagnóstico em rotinas de programas de controle de TB no Brasil. O objetivo do presente estudo foi avaliar o impacto da introdução do Xpert MTB / RIF no diagnóstico de TB em uma cidade com alta incidência de TB no Brasil. Métodos: Incluímos pacientes avaliados com testes diagnósticos convencionais durante um ano antes da introdução do Xpert (grupo pré-Xpert) e pacientes avaliados usando Xpert durante um ano após a introdução do teste (grupo pós-Xpert). Resultados: 620 pacientes preencheram os critérios de inclusão (208 no grupo pré-Xpert e 412 no grupo pós-Xpert) e foram incluídos na análise. O tempo até o diagnóstico de TB foi menor no grupo pós-Xpert (0,7 dias, IQR: 0,5-1,0 dias) do que no grupo pré-Xpert (2,0 dias, IQR: 2,0-2,0 dias) (p <0,0001). Características atípicas da doença, como menor perda de peso, febre, dispneia, sudorese noturna e hemoptise; baciloscopia de escarro negativa; cultura negativa e radiografia de tórax atípica de TB foram mais comuns no grupo pós-Xpert do que no grupo pré-Xpert (p <0,0001 para todos). Conclusões: Observamos que a implementação do ensaio Xpert MTB / RIF, em rotinas de programas de controle de TB, melhora e facilita o diagnóstico de tuberculose, especialmente nos casos com manifestações da doença atípica. Esses resultados podem provavelmente ser generalizados para locais com incidência de TB similar. / Introduction: The receptor for advanced glycation end products (RAGE) is expressed in normal lungs and is upregulated during inflammation and infection. The interaction between AGEs and RAGE on the plasma membrane causes oxidative stress and apoptosis in lung cells. The objective of this study is to evaluate plasma levels of AGEs and its soluble receptor (sRAGE) in patients with active TB and healthy controls, and to investigate their relationship with food intake and nutritional status. Methods: Case-control study. AGE (carboxymethil lysine, CML) and RAGE were measured by Elisa. Nutritional assessment was performed by body mass index, triceps skin-fold thickness, mid-arm circumference, mid-arm muscle circumference, bioelectrical impedance analysis, and food frequency questionnaire. Results: 35 TB patients and 35 controls were included in the study. The mean S-RAGE levels were higher in TB patients than in controls (68.5 ± 28.1 vs 57.5 ± 24.0, p=0.046). Among cases that were current smokers, lower S-RAGE levels were associated with mortality (S-RAGE levels= 58.0 ± 36.5 [non-survivors] vs 71.3 ± 25.6 [survivors], p=0.006), and with weight loss (S-RAGE levels= 65.6 ± 27.4 [weight loss] vs 98.6 ± 16.7 [no weight loss], p=0.034). There was no statistically significant difference in CML levels and diet CML content between cases and controls. Malnutrition was more frequent in cases than in controls, but there was no correlation between nutritional parameters and CML or S-RAGE levels. Conclusions: TB patients had higher S-RAGE levels than controls. S-RAGE may play a role in disease manifestations and outcomes, being associated with weight loss and mortality.

Introdução: O teste Xpert MTB / RIF está sendo cada vez mais utilizado em muitos países como diagnóstico inicial para a tuberculose (TB). Poucos estudos avaliaram o impacto do Xpert no diagnóstico em rotinas de programas de controle de TB no Brasil. O objetivo do presente estudo foi avaliar o impacto da introdução do Xpert MTB / RIF no diagnóstico de TB em uma cidade com alta incidência de TB no Brasil. Métodos: Incluímos pacientes avaliados com testes diagnósticos convencionais durante um ano antes da introdução do Xpert (grupo pré-Xpert) e pacientes avaliados usando Xpert durante um ano após a introdução do teste (grupo pós-Xpert). Resultados: 620 pacientes preencheram os critérios de inclusão (208 no grupo pré-Xpert e 412 no grupo pós-Xpert) e foram incluídos na análise. O tempo até o diagnóstico de TB foi menor no grupo pós-Xpert (0,7 dias, IQR: 0,5-1,0 dias) do que no grupo pré-Xpert (2,0 dias, IQR: 2,0-2,0 dias) (p <0,0001). Características atípicas da doença, como menor perda de peso, febre, dispneia, sudorese noturna e hemoptise; baciloscopia de escarro negativa; cultura negativa e radiografia de tórax atípica de TB foram mais comuns no grupo pós-Xpert do que no grupo pré-Xpert (p <0,0001 para todos). Conclusões: Observamos que a implementação do ensaio Xpert MTB / RIF, em rotinas de programas de controle de TB, melhora e facilita o diagnóstico de tuberculose, especialmente nos casos com manifestações da doença atípica. Esses resultados podem provavelmente ser generalizados para locais com incidência de TB similar. / Introduction: The receptor for advanced glycation end products (RAGE) is expressed in normal lungs and is upregulated during inflammation and infection. The interaction between AGEs and RAGE on the plasma membrane causes oxidative stress and apoptosis in lung cells. The objective of this study is to evaluate plasma levels of AGEs and its soluble receptor (sRAGE) in patients with active TB and healthy controls, and to investigate their relationship with food intake and nutritional status. Methods: Case-control study. AGE (carboxymethil lysine, CML) and RAGE were measured by Elisa. Nutritional assessment was performed by body mass index, triceps skin-fold thickness, mid-arm circumference, mid-arm muscle circumference, bioelectrical impedance analysis, and food frequency questionnaire. Results: 35 TB patients and 35 controls were included in the study. The mean S-RAGE levels were higher in TB patients than in controls (68.5 ± 28.1 vs 57.5 ± 24.0, p=0.046). Among cases that were current smokers, lower S-RAGE levels were associated with mortality (S-RAGE levels= 58.0 ± 36.5 [non-survivors] vs 71.3 ± 25.6 [survivors], p=0.006), and with weight loss (S-RAGE levels= 65.6 ± 27.4 [weight loss] vs 98.6 ± 16.7 [no weight loss], p=0.034). There was no statistically significant difference in CML levels and diet CML content between cases and controls. Malnutrition was more frequent in cases than in controls, but there was no correlation between nutritional parameters and CML or S-RAGE levels. Conclusions: TB patients had higher S-RAGE levels than controls. S-RAGE may play a role in disease manifestations and outcomes, being associated with weight loss and mortality.

Ce travail de thèse porte sur l’étude de la photoluminescence de microcristaux en vue de concevoir une sonde hybride permettant des mesures de la température et de la conductivité thermique d’un échantillon aux micro/nano-échelles. Pour cela, une sonde thermorésistive en Wollaston, utilisée en microscopie thermique (SThM), a été couplée à un microcristal de Cd0.7Sr0.3F2 (4% Er3+) dopé Erbium dont le spectre d’émission est sensible à la température. Dans un premier temps, les propriétés optiques du cristal massif ont été étudiées en vue de son application en thermométrie. Nous avons travaillé à l’interprétation de son spectre de luminescence obtenu par up-conversion avec une diode laser centrée à 655 nm de 4mW. Nous avons alors proposé trois méthodes de détermination des intensités de fluorescence pour accéder à cette température via la technique RIF (Rapport des Intensités de Fluorescence). Nous avons montré qu’il était possible de déterminer sa température en utilisant les intensités des émissions des sous-niveaux Stark des niveaux thermalisés. Nous avons, ensuite, étudié le comportement en température de microcristaux fixés individuellement à l’extrémité de sondes thermorésistives. Les résultats expérimentaux ont permis d’en déduire la taille optimale du microcristal et la méthode de détermination des intensités la plus adaptée à la nano/microthermométrie.Après avoir validé notre approche de la température aux microcristaux, nous nous sommes intéressés au principe d’imagerie en température à partir des spectres de photoluminescence. Nous présentons une application sur un microsystème composé de fils conducteurs de 350nm de diamètre recouverts par un film mince de SiO2. / This PhD work focuses on the study of microcrystals photoluminescence in order to design a hybrid probe allowing micro/nano-scales measurements of a sample’s temperature and the thermal conductivity. Thus, a Wollaston thermoresistive probe used in thermal microscopy (SThM), was coupled to an Erbium doped microcrystal of Cd0.7Sr0.3F2 (4% Er3+), whose emission spectrum is sensitive to the temperature.At first, for its applications in thermometry, the optical properties of the bulk crystal have been studied. We worked on the interpretation of its luminescence spectrum obtained by up-conversion using a laser diode centered at 655 nm and 4mW. Then, we proposed three methods to determine the fluorescence intensities to access this temperature via the RIF (Fluorescence Intensity Ratio) technique. We have shown that it is possible to determine its temperature using the Stark sub-levels of the thermalized levels emissions intensities.Furthermore, we studied the temperature behavior of the microcrystals individually fixed at the end of thermoresistive probes. The experimental results made it possible to deduce the optimal size of the microcrystal and the most adapted intensity determination method for nano/microthermometry.After validating our microcrystal temperature approach, we focused on the principle of temperature imaging from photoluminescence spectra. We present an application on a microsystem composed of wires with a diameter of 350nm covered by a SiO2 thin film.

Introdução: O teste Xpert MTB / RIF está sendo cada vez mais utilizado em muitos países como diagnóstico inicial para a tuberculose (TB). Poucos estudos avaliaram o impacto do Xpert no diagnóstico em rotinas de programas de controle de TB no Brasil. O objetivo do presente estudo foi avaliar o impacto da introdução do Xpert MTB / RIF no diagnóstico de TB em uma cidade com alta incidência de TB no Brasil. Métodos: Incluímos pacientes avaliados com testes diagnósticos convencionais durante um ano antes da introdução do Xpert (grupo pré-Xpert) e pacientes avaliados usando Xpert durante um ano após a introdução do teste (grupo pós-Xpert). Resultados: 620 pacientes preencheram os critérios de inclusão (208 no grupo pré-Xpert e 412 no grupo pós-Xpert) e foram incluídos na análise. O tempo até o diagnóstico de TB foi menor no grupo pós-Xpert (0,7 dias, IQR: 0,5-1,0 dias) do que no grupo pré-Xpert (2,0 dias, IQR: 2,0-2,0 dias) (p <0,0001). Características atípicas da doença, como menor perda de peso, febre, dispneia, sudorese noturna e hemoptise; baciloscopia de escarro negativa; cultura negativa e radiografia de tórax atípica de TB foram mais comuns no grupo pós-Xpert do que no grupo pré-Xpert (p <0,0001 para todos). Conclusões: Observamos que a implementação do ensaio Xpert MTB / RIF, em rotinas de programas de controle de TB, melhora e facilita o diagnóstico de tuberculose, especialmente nos casos com manifestações da doença atípica. Esses resultados podem provavelmente ser generalizados para locais com incidência de TB similar. / Introduction: The receptor for advanced glycation end products (RAGE) is expressed in normal lungs and is upregulated during inflammation and infection. The interaction between AGEs and RAGE on the plasma membrane causes oxidative stress and apoptosis in lung cells. The objective of this study is to evaluate plasma levels of AGEs and its soluble receptor (sRAGE) in patients with active TB and healthy controls, and to investigate their relationship with food intake and nutritional status. Methods: Case-control study. AGE (carboxymethil lysine, CML) and RAGE were measured by Elisa. Nutritional assessment was performed by body mass index, triceps skin-fold thickness, mid-arm circumference, mid-arm muscle circumference, bioelectrical impedance analysis, and food frequency questionnaire. Results: 35 TB patients and 35 controls were included in the study. The mean S-RAGE levels were higher in TB patients than in controls (68.5 ± 28.1 vs 57.5 ± 24.0, p=0.046). Among cases that were current smokers, lower S-RAGE levels were associated with mortality (S-RAGE levels= 58.0 ± 36.5 [non-survivors] vs 71.3 ± 25.6 [survivors], p=0.006), and with weight loss (S-RAGE levels= 65.6 ± 27.4 [weight loss] vs 98.6 ± 16.7 [no weight loss], p=0.034). There was no statistically significant difference in CML levels and diet CML content between cases and controls. Malnutrition was more frequent in cases than in controls, but there was no correlation between nutritional parameters and CML or S-RAGE levels. Conclusions: TB patients had higher S-RAGE levels than controls. S-RAGE may play a role in disease manifestations and outcomes, being associated with weight loss and mortality.

Wage dispersion is one of the social and economic issues arousing public concern in Hong Kong. There are many studies exploring the possible causes and changes in wage dispersion. They often focus on the study of summary measures such as Gini and Theil indexes, or adopt OLS-based regression approach. In foreign studies on wage dispersion, Oaxaca-Blinder decomposition, originated from Oaxaca (1974) and Blinder (1973), is a common method of decomposing changes or differences in mean wages between two groups into wage structure effect and composition effect, and then further decomposing the two effects into contributions of each control variable. Nevertheless, focusing on summary measures or decomposing mean wages can just give people an insight into the causes and changes in general wage dispersion but not the entire wage distribution. As pointed out by Chi, Li and Yu (2007), the estimation of the entire wage distribution and decomposition of the distributional changes in wage dispersion has been attracting the attention of labour economists. This thesis adopts a distributional approach proposed by Firpo, Fortin and Lemieux (2007) to study the changes in wage dispersion of Hong Kong since 1980s. The FFL approach comprises a two-stage procedure. Firstly, changes in dispersion are divided into wage structure effect and composition effect without directly estimating a wage-setting model. This is done by doing a proper reweighting to obtain counterfactual wage vectors. Kernel density estimation is used for visualizing the wage distribution in different years and the counterfactuals; secondly, novel recentered influence function (RIF) regressions across quantiles are performed to further decompose the two effects into contributions of each control variable. The findings are outlined as follows: first, there was an increase in wage dispersion over the whole wage distribution from 1980s but a decrease from 2001 to 2006; second, the composition effect dominates the wage structure effect over years; third, changes in the distribution of characteristics and the returns to these characteristics are highly responsive to each other, suggesting that our labour market is highly responsive to structural changes; fourth, The common wage-determining factors may not be able to explain the earnings-profile of low wage earners well. In brief, the development of the economy since 1980s increased the wage dispersion over years. Nevertheless, the economic downturn due to external shocks and internal unfavourable events and general skill-upgrading in labour-intensive industries decreased the wage dispersion since 2000s.