Health education and preventive chemotherapy are main strategies to control or eliminate neglected tropical diseases (NTDs) such as lymphatic filariasis (LF), trachoma, onchocerciasis, schistosomiasis (SCH), and soil-transmitted helminthiasis (STH). Integrated MDA for LF, onchocerciasis, SCH, STH, and trachoma were organized in the Koza district of Cameroon from July to August 2011. Ivermectin (IVM) and albendazole (ALB) were distributed for LF to the entire population except pregnant or lactating women, children <90 cm in height, and the severely ill. Azithromycin was distributed at least one week after the LF MDA to all persons older than 6 months of age. Praziquantel (PZQ), targeting school age children (SAC), was only distributed in schools. In order to validate reported coverage and assess the knowledge and attitude of the population towards NTDs and MDAs, an independent coverage and Knowledge, Attitudes, and Practice (KAP) survey was administered. The WHO recommended population based 30-cluster coverage survey was implemented. Clusters were selected by Probability Proportional to Estimated Size and in each cluster, 10 houses were selected using the improved expanded program on immunization random walk. Coverage questions were administered by trained interviewers to each person living in selected houses and KAP questions were asked to a randomly selected adult in the house. A total of 1301 persons participated in the coverage survey and 149 adults answered the KAP questions. The survey coverage estimates for IVM /ALB and azithromycin are 76.9% (95% CI 72.0-81.9), 86.8% (95% CI 80.9-92.7), respectively, while the reported coverage is 80.3% and 93%, respectively. The survey coverage estimated for PZQ among SAC is 39.9% (95% CI 30.7-49.1), reported coverage is unknown. There was no significant association between participation in the MDA and age, gender, or knowing the disease. SAC who attended school were 269 times as likely to have taken PZQ and 3 times as likely to have taken LF drugs as SAC not attending school. Less than 50% of respondents had heard of LF and only 31.8% could mention at least one LF symptom. More than 70% of respondents had heard of STH, SCH, and trachoma, but only 52.3%, 40%, 30%, respectively, knew at least one way to prevent or treat STH, SCH, and trachoma. Despite low or incorrect knowledge of LF, SCH, STH, and trachoma, overall, MDA coverage was good except for the PZQ which was only distributed in school.

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Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-10-04T12:34:05Z No. of bitstreams: 1 izabelladeoliveirapinheiro.pdf: 2789735 bytes, checksum: 88fd51d57fe8e1982bbacbad4e1341dc (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-10-04T12:39:56Z (GMT) No. of bitstreams: 1 izabelladeoliveirapinheiro.pdf: 2789735 bytes, checksum: 88fd51d57fe8e1982bbacbad4e1341dc (MD5) / Made available in DSpace on 2016-10-04T12:39:56Z (GMT). No. of bitstreams: 1 izabelladeoliveirapinheiro.pdf: 2789735 bytes, checksum: 88fd51d57fe8e1982bbacbad4e1341dc (MD5) Previous issue date: 2010-07-13 / FAPEMIG - Fundação de Amparo à Pesquisa do Estado de Minas Gerais / Doenças tropicais negligenciadas (DTNs), assim classificadas pela Organização Mundial de Saúde, constituem um grupo de infecções praticamente eliminadas no mundo desenvolvido, mas que persistem em áreas pobres de países de baixa renda. Dentre elas estão a ascaridíase, a tricuríase e a ancilostomíase, cujos agentes etiológicos têm parte de seu ciclo evolutivo passando pelo solo, e são, por isso, denominadas de geohelmintoses. Recentemente, a giardíase também foi incluída como DTN, uma vez que sua forma de transmissão pode ser associada com falta de saneamento. Este estudo transversal de base populacional visou à investigação da ocorrência dessas parasitoses em três municípios do sudeste de Minas Gerais. Para tanto, 2367 indivíduos foram selecionados aleatoriamente. Os dados foram obtidos por meio de um questionário estruturado acerca das condições socioeconômicas, ambientais e culturais da população amostral e do exame de uma única amostra fecal de cada participante, pelo método de sedimentação espontânea (HPJ). Para cada amostra fecal foram examinadas cinco lâminas, e concluiu-se que o exame de três lâminas por amostra expressou a melhor relação custo-benefício para o SUS. A análise dos resultados mostrou que 6,1% (n=145) da população amostral estava infectada com uma ou duas DTNs. Dentre os indivíduos infectados, as prevalências observadas para ancilostomídeos, G. lamblia, T. trichiura e A. lumbricoides foram 47,3%, 27,3%, 16,0% e 9,3%, respectivamente. Na análise bivariada dos dados (p<0,05; IC 95%), o teste do Qui-quadrado de Pearson foi usado para avaliar a força das possíveis associações entre as variáveis independentes e o desfecho. Na análise de regressão logística, quatro variáveis permaneceram estatisticamente significantes, sugerindo serem os possíveis fatores de risco para as DTNs nos municípios: o destino inadequado do esgoto (p<0,001), o hábito de beber água não potável (p<0,001), a falta de instalação sanitária adequada (p=0,015) e pertencer ao sexo masculino (p<0,001). Os resultados encontrados neste estudo nos permitem concluir que DTNs estão presentes mesmo em regiões mais desenvolvidas do Brasil. O número de pessoas parasitadas confirma a área como de baixa endemicidade para geohelmintoses e giardíase em relação a outras regiões do Estado, e justifica estudos que avancem no conhecimento do perfil epidemiológico da região e subsidiem o desenvolvimento de políticas públicas locais. / Neglected tropical diseases (NTDs), so classified by the World Health Organization, are a group of infections that have been eliminated in the developed world, but still persist in poor areas of low-income countries. Among them, ascariasis, trichuriasis, and hookworm infection are soil-transmitted helminthiasis. Recently, and despite its worldwide distribution, giardiasis was also included in the WHO list, due to its way of transmission, which can be associated with lack of sanitation. This population-based cross-sectional survey aimed at investigating the occurrence of such infections in three municipalities of southeastern Minas Gerais state. A total of 2,367 individuals randomly chosen provided one single fecal sample. The baseline data consisted of a questionnaire and parasitological coproscopy using the HPJ method. Five slides were examined from each fecal sample, allowing us to conclude that, regarding this method, the examination of three slides per sample presented a satisfactory sensitivity and the best cost-effectiveness for the SUS. The results showed that 6.1% (n=145) of the population sample was infected with either one or two NTDs, of which the prevalences observed for hookworms, G. lamblia, T. trichiura, and A. lumbricoides were 47.3%, 27.3%, 16.0% e 9.3%, respectively. In the bivariate analysis (p<0.05; CI 95%), Pearson Qui-square tests were used to assess the strength of the associations. Multivariate analysis was run with all significant variables. Four variables remained significant in the logistic regression, as the possible risk factors for the installation and spread of the infections in the municipalities: inadequate sewage discharge (p<0.001), the habit of drinking unsafe water (p<0.001), lack of adequate sanitary infrastructure in the household (p=0.015), and masculine sex of the individual (p<0.001). Our findings allow us to conclude that NTDs occur even in more developed areas of Brazil. Our numbers confirm the study area as low endemic for giardiasis and soil-transmitted helminthiasis, and justify surveys in order to get more information on the epidemiological profile of the Zona da Mata Mineira region, aiming at giving support to the development of local health policies.

Nous avons étudié les aspects biochimiques, enzymologiques et génétiques des voies de la méthylation sur les foies foetaux issus d'abortum pour AFTN et témoins. Nous avons mis en évidence un déficit de la vitamine B12 et de la SAM et une baisse des activités MTR et MTHFR dans les tissus AFTN. Ces résultats permettent d'établir qu'une supplémentation en B12 devrait être associée à la supplémentation en folates réalisée en début de grossesse afin de prévenir la survenue de ces AFTN. Nous avons aussi étudié les interactions entre MTR et MMACHC en utilisant des lignées cellulaires de patients porteurs de déficits en MTR (cblG, variant-cblG) et en MMACHC (cblC). Cette étude suggère un rôle régulateur de la MTR dans le métabolisme intracellulaire de la CNCbl, par l'épissage de MTR de deux transcrits codant pour l'enzyme fonctionnelle de taille attendue et une protéine tronquée non fonctionnelle, respectivement / We studied the methylation pathways in liver tissue from fetal NTDs and controls. We identified a vitamin B12 and SAM deficiency and also decreased activities of MTR and MTHFR in NTDs tissue. These results provide evidence that vitamin B12 supplementation should be associated with folate supplementation in early pregnancy in order to prevent the occurrence of these NTDs. We also studied the interactions of MTR with MMACHC by using cell lines patients with MTR and MMACHC deficiency. This study suggests a regulatory role of MTR in the intracellular CNCbl metabolism by splicing of two MTR transcripts encoding the functional enzyme of the expected size and a truncated non-functional protein, respectively

Every year, through mass drug administration (MDA), hundreds of millions of the world’s poorest people receive a single annual dose of one or more drugs to eliminate certain parasitic worm or bacterial infections. Some of these infections, mostly prevalent in tropical areas, have traditionally been neglected from the public health and research point of view. These conditions, collectively known as the neglected tropical diseases (NTDs), still cause, at the cusp of the second decade of the 21st century, a significant amount of morbidity and mortality. The existing control measures for NTD have an enormous potential, although there are still some challenges that require further investigation. For some diseases, alternative strategies may be needed, including longer duration of MDA programmes or modified drug regimens. For other diseases, such as yaws, the work must start almost from scratch, since little has been achieved in terms of control of this disease in the past 50 years. Although eight NTDs affect the region, two diseases pose a major public health problem in the South Pacific Islands, namely yaws and lymphatic filariasis and are the basis for his thesis. These two infections were selected for a number of reasons. First, they affect the South Pacific region disproportionately. Secondly, little research has been conducted in the past years. And third, but more importantly, several epidemiological, technological and historical factors make these two diseases amenable to elimination. Safe and effective tools and interventions to achieve these targets are available and concerted efforts to scale them up are likely to lead to success. Yaws is one of the most neglected of the NTDs. Yaws was one of the first diseases to be targeted for eradication on a global scale, efforts which almost led to the disease disappearance as a result of a massive treatment program started in the 1950s. After the successful eradication campaigns the primary health care systems were supposed to give the last push towards eradication of yaws. However a combination of various factors including poor political commitment and limited funding resulted in a progressive abandonment of efforts and the resurgence of the disease. Every new case of yaws was the disappointing confirmation that the public health world had missed a great opportunity. Today yaws has resurged in many tropical areas and presents new challenges including its unknown epidemiological situation, the attenuated clinical forms of the disease, a poor awareness and knowledge among health care workers, the lack of knowledge about the effectiveness of classic treatment with penicillin and, an obvious need for research into simplified administration schemes or new antibiotic treatments, particularly oral ones. There is an enormous knowledge gap regarding current reliable epidemiological information about the disease. Certainly we know little about the burden in the three Melanesian countries where the disease is highly endemic, Papua New Guinea, Solomon Islands and, Vanuatu. In Solomon Islands and Vanuatu there are indications that Yaws is widespread and prevalent, but we know that the diagnosis is unreliable. This takes us to the next point, what does a diagnosis of yaws mean? Overall the natural history of the disease in this era, where it is often subject to inadequate antibiotic pressure, is very unclear. Some authors have suggested that yaws appears to be attenuated in both Solomon Islands and Vanuatu. They state that bone involvement in yaws is now rare and implies that yaws is a mild disease not requiring efforts for elimination. However, the first paper of this thesis describes the epidemiology of yaws in Lihir Island (Papua New Guinea, PNG) and shows a high rate of classical primary ulcers (almost 60%) and significant bone and periosteal involvement (more than 15%), suggesting that “attenuation” is not an important issue. When we look at the diagnostic criteria for yaws, signs and symptoms alone are still used often in many areas to diagnose the disease. This reliance on clinical findings was the result of the difficulty of performing serological tests in remote areas. Today, available rapid serological tests are simple, rapid, inexpensive and useful for guiding confirmation of cases, making them adequate tools for the diagnosis and monitoring of the disease. The clinical diagnosis of yaws is complicated because its clinical manifestations may be unspecific. Thus, it is possible that a significant proportion of yaws cases may in fact have been falsely diagnosed. We show, in the first article, that in our experience only 60% of the cases with a clinical suspicion of yaws were finally confirmed by serologic tests. Therefore, a proper diagnosis of yaws requires the interpretation of clinical findings with reference to laboratory results and the epidemiologic history of the patient. Serological testing in yaws is not only important for diagnostic accuracy, but also is very helpful in defining the disease’s evolution and eventual cure after treatment. Rapid plasma regain (RPR) titres should decline within 6-12 months, becoming negative in less than 2 years. The second article of this thesis combines a clinical and serological approach to assess the response after treatment with benzathine benzylpenicillin, and it identifies an overall 20% treatment failure. This could be related to resistance to the antimicrobial drug used or to re-infection caused. The distinction between re-infection and true resistance to antibiotic treatment is difficult to make but these failures are worrisome. This article also proposes a multivariate model performed to identify independent determinants of failure that affected the outcome after treatment. The risk for reinfection caused by repeated contact with infected children seems to be a pivotal predictor of failure. Low baseline titters (<1:32) of RPR are also an important and independent predictor of failure, possibly as a result of the greater difficulty in resolving chronic infections which are usually accompanied by low titters. With yaws re-emerging, the development of new strategies against this infection aimed at simplifying its treatment and potentially re-focussing strategies towards its eradication seems essential. Injectable penicillin is still effective but management with an oral drug that can be easily administered on a large scale should be the preferred method for treatment. To date, there had been no studies that directly compared the efficacy of penicillin with any of the potentially alternative agents shown to work in the treatment of the non-venereal treponematoses. The fourth paper in this thesis has shown that a single-dose of oral azithromycin is non-inferior to benzathine benzylpenicillin for the treatment of yaws in children in PNG. In an open-label randomised trial, at 6-month follow-up, 96% of patients treated with azithromycin were cured, as were 93% in the benzathine benzylpenicillin group. The prospects of eliminating and eventually eradicating yaws may now be enhanced by the use of a single-dose of oral azithromycin in mass drug administration campaigns. Community based mass administration of azithromycin has been widely used in many locations for the control of trachoma, which, like yaws, is a disease of poor rural communities in developing countries, and has been used in a more limited way to control granuloma inguinale and outbreaks of venereal syphilis. Elimination of yaws and lymphatic filariasis in the South-Pacific Islands is now considered biologically feasible and programmatically attainable. The Global Programme to Eliminate Lymphatic Filariasis (GPELF) has expanded quickly to reach the target of elimination by 2020. On the other hand the strategy to eliminate yaws is again at the centre of discussions and given that infected humans are the only source of disease, its eradication could be achieved within a very relatively short time. The fifth article of the thesis comprehensively reviews antimicrobial treatments and elimination strategies against yaws. In order to control yaws and push it towards elimination, we propose to move away from penicillin to azithromycin and use mass treatment campaigns of the entire population in endemic communities irrespective of the prevalence. Also, to make sure all cases are tracked down and treated, strict follow-up measures and selective mass treatment will be required until zero case prevalence is reached. Importantly, we suggest testing the principle of interrupting transmission in pilot implementation studies, including prevalence surveys to assess the impact of the intervention and macrolide resistance monitoring which in our opinion will be essential evaluation tools to guide us towards a sustainable elimination. Lymphatic filariasis (LF), caused by the mosquito-borne nematode Wuchereria Bancrofti, is a major public-health problem in the Melanesian countries. Annual MDA over five years is currently the WHO’s recommended strategy to eliminate lymphatic filariasis. This approach aims to suppress microfilaraemia in infected individuals and bring the infection below a threshold that leads to interruption of transmission. However theoretical work and clinical field experience has highlighted how the ecological diversity between different endemic regions can result in elimination thresholds that vary between local communities. This means that the duration required might be different for different areas. Other variables have also been previously identified as potentially having an influence on the outcome of the program, including baseline prevalence of infection, vector density or the treatment coverage. The last article of this thesis provides data about the impact of a five-year filariasis control program in Papua New Guinea. The findings reported support this strategy for areas with low-to-moderate rates of transmission in regions where anopheline mosquitoes transmit this infectious disease. Additional measures or longer periods of treatment may be necessary in areas with a high rate of transmission. The experience acquired on Lihir Island in MDA programs during the campaigns for the elimination of filariasis, will be very valuable when implementing a pilot strategy for yaws control. Also, in the near future it might be important to link yaws mass treatment with other mass programmes to increase efficiency. The plan for elimination of lymphatic filariasis in PNG was approved as a pilot project in 2005 but the program still needs to be extended to the total of 20 provinces in the country where filariasis is endemic. In this context, an integrated approach to NTD control could represent an important global public health solution in PNG and other South Pacific Islands. Little has been achieved in the past decade in NTDs. We are now in a good position to translate into policies the results of our research projects. A new elimination policy for yaws around the azithromycin pillar has been sketched a WHO consultation meeting held in Morges, Switzerland last March. In the intentions of the organization, a last global mass campaign to tackle yaws should permit to reach zero cases in 2017, and the subsequent certification of worldwide interruption of transmission by 2020. / Cada año, a través de la administración masiva de medicamentos (MDA), cientos de millones de personas, las más pobres del mundo, reciben una dosis única de uno o más medicamentos para eliminar ciertas infecciones, parasitarias o bacterianas. Algunas de estas infecciones, frecuentes sobre todo en las zonas tropicales, han sido tradicionalmente desatendidas desde el punto de vista de salud pública e investigación. Estas enfermedades, conocidas comúnmente como las enfermedades tropicales desatendidas (ETD), aún causan, en el inicio de la segunda década del siglo 21, una cantidad significativa de morbilidad y mortalidad. Las medidas de control actuales para ETDs tienen un enorme potencial, pero todavía existen algunas cuestiones que requieren investigación. Para algunas de estas infecciones, son necesarias estrategias alternativas, incluyendo una mayor duración de los programas de MDA o regímenes modificados de medicamentos. Para otras enfermedades, como la enfermedad de pián, el trabajo debe comenzar casi desde cero, ya que poco se ha logrado, en términos de control de esta enfermedad, en los últimos 50 años. Aunque ocho ETDs afectan a la región, dos enfermedades constituyen un problema importante de salud pública en las Islas del Pacífico Sur, a saber: el pián y la filariasis linfática y son la base de esta tesis. Estas dos infecciones fueron elegidas por muchas razones. En primer lugar, afectan a la región del Pacífico Sur de forma desproporcionada. En segundo lugar, pocas investigaciones se han llevado a cabo en los últimos años. Y en tercer lugar, pero lo más importante, varios factores epidemiológicos, tecnológicos e históricos hacen que estas dos enfermedades sean susceptibles de eliminación. Existen armas terapéuticas seguras y eficaces para lograr este objetivo, y esfuerzos coordinados para ejecutar los programas de control pueden conducir al éxito. El pián es una de las más olvidadas de las ETDs. Ésta fue una de las primeras enfermedades en ser objetivo de erradicación a escala global. Los esfuerzos de un programa de tratamiento masivo, que se inició en la década de 1950, casi llevaron a la desaparición de la enfermedad. Después de las exitosas campañas de erradicación, los sistemas de salud de atención primaria debían dar el último empujón hacia la erradicación del pián. Sin embargo, una combinación de varios factores, incluyendo un pobre compromiso político y una financiación limitada, dieron como resultado el abandono progresivo de los esfuerzos y el resurgimiento de la enfermedad. Cada nuevo caso de pián era la decepcionante confirmación de que el mundo de la salud pública había perdido una gran oportunidad. Hoy la enfermedad de pián ha resurgido en muchas áreas tropicales con nuevos desafíos: una situación epidemiológica desconocida, formas clínicas atípicas o atenuadas, poco conocimiento de la enfermedad entre el personal sanitario, la falta de datos acerca de la eficacia del tratamiento clásico con penicilina inyectable y la necesidad de desarrollar esquemas terapéuticos simplificados o investigar en nuevos tratamientos antibióticos, en especial de administración oral. Actualmente hay una enorme brecha de conocimiento entorno a la información epidemiológica fiable sobre la enfermedad. Ciertamente, sabemos poco acerca de la incidencia en los tres países melanesios, donde la enfermedad es altamente endémica, Papúa Nueva Guinea (PNG), Islas Salomón y Vanuatu. En las Islas Salomón y Vanuatu, las cifras de incidencia son muy altas lo que demuestra que el pián es una enfermedad frecuente y ampliamente extendida, pero sabemos que el diagnóstico no es muy fiable. Esto nos lleva al siguiente punto: ¿Cuáles son los criterios diagnósticos del pián? En general, la historia natural de la enfermedad en la época actual, donde la bacteria es objeto de presión antibiótica inadecuada, no es muy clara. Algunos autores han escrito que el pián parece presentar manifestaciones “atenuadas” en las Islas Salomón y Vanuatu. Afirman que la afectación ósea en el pián es poco frecuente, lo que implica que el pián es una enfermedad leve que no requeriría esfuerzos para su eliminación. Sin embargo, el primer trabajo de esta tesis describe la epidemiología del pián en la Isla de Lihir (Papúa Nueva Guinea) y muestra una alta tasa de úlceras primarias clásicas (casi el 60% de casos) y una afectación significativa del hueso y periostio (más del 15%) que sugiere que la "atenuación" no es un tema importante. Cuando nos fijamos en los criterios diagnósticos, únicamente signos y síntomas todavía se utilizan en muchas áreas para el diagnóstico de la enfermedad. Esta confianza en los hallazgos clínicos fue el resultado de la dificultad de realizar pruebas serológicas en las zonas remotas. Hoy en día, las pruebas serológicas rápidas son simples, rápidas, económicas y útiles para orientar la confirmación de los casos. El diagnóstico clínico del pián es complicado debido a que sus manifestaciones pueden ser inespecíficas. Así, es posible, que una proporción significativa de los casos de pián puedan haber sido falsamente diagnosticados. En el primer artículo, presentamos que, en nuestra experiencia, sólo el 60% de los casos con sospecha clínica de pián fueron finalmente confirmados por pruebas serológicas. Por lo tanto, un diagnóstico adecuado del pián requiere la interpretación de los hallazgos clínicos con referencia a los resultados de laboratorio y la historia epidemiológica de los pacientes. Las pruebas serológicas en el pián no sólo son importantes para el diagnóstico de la enfermedad, también son muy útiles en la definición de curación después del tratamiento. En la prueba de la Reagina plasmática rápida (RPR) los títulos deben descender a los 6-12 meses, llegando a ser negativa en menos de 2 años. El segundo artículo de esta tesis combina un enfoque clínico / serológico para evaluar la respuesta a bencilpenicilina benzatina, e identifica una tasa de fracaso terapéutico del 20% a los 12 meses del tratamiento. Esto podría estar relacionado con resistencia al fármaco antimicrobiano, o bien indicar una re-infección por re-exposición. La distinción entre la re-infección y la resistencia verdadera al tratamiento es difícil, pero estos fracasos terapéuticos son preocupantes. En este artículo se describe un modelo multivariante realizado para identificar los factores determinantes del fracaso terapéutico. El riesgo de re-infección causado por el contacto repetido con otros niños infectados parece ser un predictor fundamental de fracaso. También es un factor de riesgo, los títulos basales bajos (< 1:32) de RPR. Este último factor podría estar relacionado con la mayor dificultad para resolver infecciones crónicas (en estadio secundario), habitualmente acompañadas de títulos bajos. Con la enfermedad de pián re-emergiendo, el desarrollo de nuevas estrategias contra la infección para hacer más fácil los esfuerzos de erradicación es esencial. La penicilina inyectable sigue siendo eficaz, pero el tratamiento con un fármaco por vía oral que pueda ser fácilmente administrado a gran escala es el método preferido para el tratamiento, prevención y finalmente eliminación en todas las regiones endémicas del mundo. Hasta la fecha, no ha habido estudios que comparen directamente la eficacia de la penicilina con cualquiera de los agentes alternativos en el tratamiento de las treponematosis no venéreas. El cuarto artículo de esta tesis ha demostrado que una dosis única de azitromicina por vía oral no es inferior a la bencilpenicilina benzatina intramuscular, para el tratamiento del pián en niños en Papúa Nueva Guinea. En un ensayo abierto, aleatorio, el 96% de los pacientes tratados con azitromicina estaban curados a los 6 meses de seguimiento, al igual que el 93% en el grupo de bencilpenicilina benzatina. Las perspectivas de finalmente erradicar el pián son ahora mayores, mediante el uso de una dosis única de azitromicina oral en campañas masivas de tratamiento. El tratamiento masivo con azitromicina ha sido ampliamente utilizado para el control del tracoma, que, al igual que el pián es una enfermedad de comunidades rurales pobres de países en desarrollo. También se ha utilizado de una manera más limitada para controlar el granuloma inguinal y brotes de sífilis venérea. En general, el uso de azitromicina ha demostrado ser seguro, y de hecho ha habido beneficios inesperados de salud en algunos programas. La eliminación del pián y la filariasis linfática en las Islas del Pacífico Sur se considera ahora biológicamente factible y operacionalmente alcanzable. El Programa Global para Eliminar la Filariasis Linfática (GPELF) se ha expandido rápidamente para alcanzar la meta de eliminación en el año 2020. Por otro lado la estrategia para eliminar el pián es nuevamente centro de atención. Además, dado que los seres humanos infectados son la única fuente de la enfermedad, su eliminación podría lograrse en un plazo relativamente corto. El quinto artículo de la tesis revisa de forma integral el tratamiento con antimicrobianos y las estrategias de eliminación contra el pián. Con el fin de controlar el pián hasta la erradicación, se propone pasar de la penicilina a la azitromicina, y el uso de campañas de tratamiento masivo de toda la población en todas las comunidades endémicas. Además, para asegurar que todos los casos son encontrados y tratados, serán necesarias medidas estrictas de seguimiento y tratamiento masivo selectivo hasta llegar al objetivo de cero casos clínicos. Es importante destacar que el principio de interrupción de la transmisión se debe probar en estudios piloto, incluyendo estudios de prevalencia, para monitorizar el impacto de la intervención, y también la valoración de resistencia a macrolidos, que en nuestra opinión, serán herramientas fundamentales que nos guíen en el camino hacia una eliminación sostenible La filariasis linfática (FL), causada por el nematodo Wuchereria bancrofti, es otro de los grandes problemas de salud pública en los países de la Melanesia. Un curso de MDA anual, durante cinco años, es la estrategia que la OMS recomienda para eliminar la FL. Este enfoque tiene como objetivo suprimir la microfilaremia en los individuos infectados y disminuir los niveles de infección por debajo de un umbral que conduzca a la interrupción de la transmisión. Sin embargo, trabajo teórico y experiencia práctica clínica han puesto de relieve cómo la diversidad ecológica, entre diferentes regiones endémicas, puede resultar en que los umbrales de eliminación varíen en diferentes comunidades. Esto significa que la duración requerida podría ser diferente para diferentes áreas. Algunas variables que han sido previamente identificadas como potenciales determinantes en el resultado de un Programa para la eliminación de FL (PELF) son la prevalencia basal de infección por filariasis, la densidad de vectores (mosquitos) o la cobertura del tratamiento en la población. El último artículo de esta tesis, proporciona datos sobre el impacto de un PELF de cinco años en PNG. Los resultados obtenidos apoyan la estrategia descrita para las zonas con baja a moderada tasas de transmisión en regiones donde mosquitos anofelinos transmiten la infección (pe. Melanesia, África). Medidas adicionales o períodos más largos de tratamiento pueden ser necesarios en áreas con una alta tasa de transmisión. La experiencia adquirida en la Isla de Lihir en los programas de tratamiento masivo durante las campañas para la eliminación de la filariasis, será muy valiosa en la aplicación de una estrategia piloto para el control del pián. Además, en un futuro próximo podría ser importante vincular los programas para el control del pián con otros programas de tratamiento masivo (por ejemplo, filariasis) para aumentar la eficiencia y reducir los costos. El plan para la eliminación de la filariasis linfática en PNG fue aprobado como proyecto piloto en 2005 en la provincia de Milne Bay. El programa todavía tiene que ser extendido a un total de 20 provincias en el país, donde la filariasis es endémica. En este contexto, un enfoque integrado para el control de enfermedades tropicales olvidadas podría representar una importante solución global de salud pública en PNG. Poco se ha logrado en la última década en enfermedades tropicales desatendidas. Ahora estamos en una buena posición para traducir los frutos de nuestra investigación en políticas de salud. Durante una consulta celebrada en la sede de la OMS en Ginebra el pasado mes de marzo, ya se ha esbozado una nueva política de eliminación para el pián que toma como pilar el tratamiento con azitromicina. La intención de la OMS es que una última campaña global debe permitir llegar a cero casos de pián en 2017, y la posterior certificación de la interrupción de la transmisión en todo el mundo en el año 2020.

Study questions: Does the proportion of neural tube defects (NTDs) in which there are co-occurring anomalies of other systems vary by geographical area and time in Europe between 1980 and 2015? Which group of factors, e.g., sex, age, family history, condition at discovery, and prenatal screening during pregnancy that potentially affect ascertainment of isolated NTD cases and co-occurring anomalies, are associated with the presence of these anomalies? Methods: Data on fetuses or births with NTDs recorded in 28 European Surveillance of Congenital Anomalies (EUROCAT) registries operating throughout or during a part of the period 1980-2015, were obtained and analysed. Information on the corresponding denominators of total births for each registry were compiled, comprising approximately 15.7 million births. We developed algorithms to classify NTDs that occurred as part of certain recognized genetic and unknown etiology syndromes, isolated NTD cases (either with no other anomaly reported or only an anomaly considered to be secondary to the NTD), and NTDs not occurring as part of recognized syndromes but with one or more co-occurring anomalies. We assessed factors that could impact ascertainment of isolated NTD cases and NTD cases with co-occurring anomalies. We also conducted a sensitivity analysis to evaluate the effect of family history and consanguinity on NTD outcomes. Lastly, we reported on the prevalence of NTDs across Eastern, Western, Northern, and Southern Europe as defined by the World Bank. Results: A total of 14,703 fetuses or births with NTDs were recorded in the EUROCAT registries. The total number of births (live and stillbirths) that occurred during the periods when the EUROCAT registries were operating was 15.7 million. The overall prevalence at birth of NTDs in Eastern Europe was 11.6 per 10,000 births, in Western Europe 11.0 per 10,000 births, in Northern Europe 10.5 cases per 10,000 births and in Southern Europe 6.7 per 10,000 births. The most prevalent genetic syndromes were chromosomal anomalies, particularly trisomy 18. The most common secondary anomaly was Arnold-Chiari syndrome which occurred mostly with spina bifida. The most prevalent associated anomalies were limb defects, followed by congenital heart defects, abdominal wall, and urinary system defects. We found anencephaly to be most prevalent in isolated NTD cases without secondary anomalies and spina bifida in secondary anomalies and most of the co-occurring anomalies. For factors that could affect ascertainment, we found that birth type, birth weight, family history, maternal and paternal age (≥30 years) were risk factors for isolated NTD cases and for co-occurring anomalies. Lastly, approximately 48% of NTDs occurred in Northern Europe, followed 29% in Western Europe, 16% in Southern Europe, and 7.6% in Eastern Europe. Conclusion: In the absence of folate fortification, isolated NTD cases showed higher prevalence than NTDs with co-occurring anomalies over the past 35 years across Europe. This research suggests that Europe should develop and implement policies and guidelines for folate fortification to help prevent simpler NTD cases. Further research and data are needed for newer EUROCAT registries to predict trends and prevalence of NTDs. Contribution and involvement: This project was done in collaboration with the experts from the School of Epidemiology and Public Health (SEPH) and dysmorphologists that provided support with regards to NTD classification. AB spearheaded the development of the research protocol and thesis manuscript with funding and support from JL and TR. Evaluation of the output of cases from the algorithm was provided to AB by JL, TR, JE, FB, AN, EB, ML, and the EUROCAT Joint Research Centre.

Les maladies tropicales négligées, causées par des trypanosomes telles que la leishmaniose, la trypanosomiase africaine (maladie du sommeil) et la trypanosomiase américaine (la maladie de Chagas), imposent une morbidité et un taux de mortalité graves ayant un grand impact sur les populations les plus pauvres. Les traitements contemporains de ces maladies sont limités en raison des effets secondaires toxiques et de l’émergence des souches résistantes. Dans le but de répondre au besoin croissant de traitement, l’exploration de nouveaux agents antiprotozoaires est donc plus que nécessaire. La recherche décrite dans cette thèse vise à développer une nouvelle thérapie pour traiter ces infections parasitaires en ciblant de multiples fonctions vitales pour la survie du parasite. Une série de peptides, petites molécules et combinaison de peptides et petites molécules conjugués ont été préparés et étudiés. Par exemple, les lipopeptides almiramides N-méthylés présentent une activité antiparasitaire avec un indice thérapeutique élevé en ciblant le glycosome, un organite typique des trypanosomes. Une étude de la relation structure-activité a été réalisée pour examiner l’influence de la N-méthylation et de la conformation sur l’activité contre diverses souches de Leishmania et sur la cytotoxicité. La synthèse et l’analyse biologique de vingt-cinq analogues ont démontré que les dérivés portant un acide aminé Na-méthylé aux deux extrémités présentaient une activité supérieure à celle des peptides perméthylés et une puissance relativement élevée contre les souches résistantes. Le remplacement des résidus d’acides aminés dans le peptide par un α-amino γ-lactam (Agl) et N-aminoimidazalone (Nai) réduit l’activité antiparasitaire; cependant, les amides peptidiques possédant des résidus d’Agl à la deuxième position conservaient une puissance significative dans les séries non méthylées et perméthylées. L’étude systématique des effets de la N-méthylation et de la géométrie de tour sur l’activité antiparasitaire a montré la pertinence d’un conformère étendu sur les résidus centraux et la mobilité conformationnelle par isomérisation des amides tertiaires et la géométrie des tours aux extrémités des peptides actifs. L’alcaloïde naturel anisomycine a été étudié en raison de son importance en tant qu’inhibiteur de la synthèse des protéines avec une vaste activité antiparasitaire. L’évaluation des relations structure-activité antiprotozoaires de l’anisomycine a été réalisée en modifiant les groupements fonctionnels du cycle de pyrrolidine ainsi que sa partie aromatique. L’examination de la cytotoxicité et l’activité antiprotozoaire contre diverses souches de Leishmania en comparant avec le produit naturel ont révélé une stratégie de préparation d’analogues à forte puissance et à faible toxicité pour l’hôte. L’étude préliminaire de l’activité antiprotozoaire et de la sélectivité a favorisé ii l’exploration de conjugués phénoliques de l’anisomycine. Une série d’analogues de l’anisomycine ont été synthétisés en conjuguant l’anisomycine sur des peptides almiramides et des résidus d’acides aminés qui peuvent respectivement cibler les fonctions glycosome et transporteur du parasite. La cytotoxicité et l’activité antiprotozoaire contre diverses souches de Leishmania, Trypanosoma brucei et Trypanosoma cruzi ont démontré que la conjugaison de divers acides aminés et résidues insaturées donnait des agents antiparasitaires prometteurs qui ciblaient sélectivement les différents parasites avec une cytotoxité minimale en comparaison avec celle du produit naturel. L’activité antiprotozoaire de l’anisomycine et de ses dérivés a incité à poursuivre l’exploration des relations structure-activité pour le développement d’un traitement antiparasitaire. Compte tenu de l’utilité de l’anisomycine dans cette étude, une synthèse formelle du produit naturel a été développée. En utilisant la (2S,4R)-4-hydroxyproline comme précurseur chiral peu coûteux, une voie de synthèse a été développée impliquant le couplage Negishi. L’introduction dans les analogues de la décacéoxy-anisomycine a également été réalisée par un protocole similaire. Les études de relation structure-activité des peptides almiramides et des analogues de l’anisomycine décrites dans cette thèse ont ouvert une voie prometteuse pour le développement de nouveaux agents antiparasitaires à haute puissance et à faible toxicité pour l’hôte. En ciblant plusieurs points d’intervention, les nouveaux agents offrent la promesse de ralentir les modes de résistance. En outre, la synthèse d’analogues désacétoxy-anisomycine a ouvert la porte à des intermédiaires clés pour une exploration plus approfondie des dérivés de l’anisomycine et pour améliorer la synthèse de prototypes thérapeutiques afin de relever des défis importants dans l’atténuation des maladies tropicales négligées. / Neglected Tropical Diseases (NTDs) which are caused by trypasonomatid infections, such as leishmaniasis, human African trypanosomiasis (HAT) and Chagas disease are known to inflict serious morbidity and mortality with greatest impact on the poorest populations. Contemporary anti-trypanosomatid therapy is limited due to toxic side effects and the rise of resistant stains. A growing need has emerged for novel anti-protozoal agents. The research described in this thesis seeks to develop novel therapy to treat trypasonomatid infection by targeting multiple vital functions for parasite survival. A series of peptide, small molecule, and peptide-small molecule conjugates have been prepared and studied. For example, the almiramide N-methylated lipo-peptides exhibit anti-parasitic activity with high therapeutic index by targeting the glycosome, an organelle without a mammalian counterpart. A structure-activity relationship study has been performed to examine the influences of N-methylation and conformation on activity against various strains of leishmaniasis protozoan and on cytotoxicity. The synthesis and biological analysis of twenty-five analogs demonstrated that derivatives with a single methyl group on specific residue amide nitrogen exhibited greater activity than the permethylated peptides and relatively high potency against resistant strains. Replacement of amino amide residues in the peptide by turn inducing α-amino γ-lactam (Agl) and N-aminoimidazalone (Nai) counterparts reduced typically anti-parasitic activity; however, peptide amides possessing Agl residues at the second residue retained significant potency in the unmethylated and permethylated series. Systematic study of the effects of methylation and turn geometry on anti-parasitic activity indicated the relevance of an extended conformer about the central residues and conformational mobility by tertiary amide isomerization and turn geometry at the extremities of the active peptides. The natural alkaloid anisomycin was studied because of significance as a protein synthesis inhibitor with broad anti-parasitic activity. Assessment of the structure - anti-protozoan activity relationships of anisomycin was performed by modifying pyrrolidine and aromatic functional groups. Examination of cytotoxicity and antiprotozoal activity against various strains of Leishmania and comparison with the natural product revealed a strategy for preparing analogs with high potency and low host toxicity. The preliminary study of antiprotozoal activity and selectivity promoted the exploration phenolic conjugates of anisomycin. A serie of anisomycin analogs were synthesized by conjugating anisomycin onto almiramide peptides and amino acids residues which iv may respectively target the glycosome and transporter functions of the parasite. The cytotoxicity and antiprotozoal activity against various strains of Leishmania, Trypanosoma brucei and Trypanosoma cruzi demonstrated that conjugation of various amino acid and unsaturated moieties yielded promising agents that selectively targeted the different parasites with minimal cytotoxity compared to that of the natural product. The antiprotozoal activity of anisomycin and derivatives has led to a better understanding of structure-activity relationships for the development of anti-parasitic therapy. Considering the utility of anisomycin in this study, a formal synthesis of the natural product was developed. Employing (2S,4R)-4-hydroxyproline as an inexpensive chiral building block, a route was conceived featuring the Negishi coupling. Entry into deacteoxy-anisomycin analogs was also achieved by a similar protocol. The structure-activity relationship studies of almiramide peptides and anisomycin analogs described in this thesis have opened a promissing gateway for developing new anti-parasitic agents with high potency and low host toxicity. By targeting multiple points of intervention, the new agents offer promise to minimize modes of resistance. Moreover, the synthesis of deacetoxyanisomycin analogs has paved the way to key intermediates for further exploration of anisomycin derivatives and for improving the synthesis of therapeutic prototypes to tackle important challenges in mitigating Neglected Tropical Diseases.

信用衍生性商品（credit derivatives）是用於移轉信用風險之契約，契約是由保護買方（protection buyer）與保護賣方（protection seller）所簽定，由保護買方支付保險金（可為躉繳或分期支付）以獲得信用的保護，而保護賣方則需在律定之信用事件發生時支付償金予保護買方做為補償。近年來頻傳金融事件，巴塞爾銀行監理委員會（Basel Committee on Banking Supervision）也不得不制定新版的巴塞爾協定以要求銀行強化信用風險控制與分散，而信用衍生性商品亦有助於信用風險的移轉與抵減的功能。 本篇針對利用conditional Markov chain來建構信用違約交換與第n次信用違約交換之評價模型，並利用模擬的方式來求算出各商品之利差。藉由現實中的資料取得參數的估計值放入模型內則可以模擬出各種不同的狀況，進而做出避險的策略。 此外，本篇亦探討如何利用Gibbs sampler來改良conditional Markov chain的模擬方法，以模擬當信用衍生性商品中的資產組合有傳染效果的情況。