Dissertationen zum Thema „Epidemiology“

Taenia solium i Taenia saginata són dos paràsits zoonòtics que causen teniasi en persones (hoste definitiu) i cisticercosi en porcí i boví (hoste intermediari), respectivament. A Europa, T. saginata ha estat present durant segles, tanmateix hi ha poca informació sobre l’ocurrència i impacte d’aquest agent zoonòtic. T. solium es considera absent a Europa però les dades existents sobre aquest paràsit són escasses. En conseqüència, les dades sobre la incidència i prevalença de T. saginata i T. solium en persones i animals a Europa són incompletes i es troben fragmentades. En aquest context, la present tesi va tenir per objectiu general avançar en el coneixement de l’epidemiologia de T. saginata i T. solium a Europa. L’estudi I d’aquesta tesi va consistir en una revisió sistemàtica d’estudis publicats entre 1990 i 2014 que va tenir com a objectiu compilar el coneixement actual sobre l’epidemiologia, impacte i control de la cisticercosi bovina a Europa. Els resultats d’aquest estudi van indicar que existeix una mancança de dades epidemiològiques completes i actualitzades en la majoria de països, especialment en els països de l’Est d’Europa. A més a més, es va concloure que la falta d’informació epidemiològica limita el desenvolupament d’estratègies de vigilància basades en risc i es va recomanar la realització d’estudis de factors de risc per guiar aquestes estratègies. En l’estudi II es va actualitzar el coneixement de l’epidemiologia de T. saginata i T. solium en persones i animals a Europa Occidental a través d’una revisió sistemàtica de literatura científica i grisa publicada entre 1990 i 2015. Igualment, es va realitzar una cerca de dades sobre casos a través d’experts locals en els diferents països. Els resultats van indicar que és necessari millorar tant la detecció com la notificació de les teniasis humanes a Europa Occidental. A més a més, es van identificar casos de persones portadores de la forma adulta de T. solium, casos de cisticercosi humana sospitosos de ser autòctons i casos de T. solium en porcí sense confirmació molecular. Aquestes troballes, juntament amb un augment de la migració des d’àrees on T. solium és endèmic, podrien constituir un risc per a la salut pública i mereixen una major atenció. A més a més, aquest estudi va concloure que els casos sospitosos de T. solium en porcs haurien de confirmar-se amb tècniques moleculars, que tant les teniasis com la cisticercosi humana haurien de ser notificables i que s’hauria de millora la vigilància i notificació en animals. L’estudi III va tenir com a objectiu estimar la prevalença i distribució espacial de la cisticercosi bovina (2008–2015) i l’impacte de T. saginata en sanitat animal i humana (2013–2015) en el nord-est d’Espanya (Catalunya). Durant 2008–2015 es va detectar una prevalença a escorxador de 0.010%. A partir dels registres de moviments de bovins es va identificar el lloc on els animals s’haurien infectat amb una major probabilitat i es va investigar la seva distribució espacial. Tenint en compte la granja on la infecció s’hauria produït amb més probabilitat, es van detectar dos conglomerats. El nombre de pacients amb diagnòstic de teniasi en atenció primària durant 2013–2016 va ser petit (41–63/any) suggerint que el risc en salut pública de T. saginata en l’àrea d’estudi és baix. L’impacte econòmic de T. saginata a Catalunya durant 2013–2015 es va calcular considerant els costos de la inspecció postmortem, les pèrdues causades pel decomís i congelació de canals i els costos associats a casos de teniasis. Els resultats obtinguts van indicar que l’impacte econòmic de T. saginata s’atribueix principalment a la inspecció postmortem i que el desenvolupament d’estratègies de vigilància basades en risc podria ser útil per reduir aquest cost. Els resultats també van evidenciar la importància de tenir en compte la traçabilitat dels animals per al desenvolupament d’aquesta estratègia.
Taenia solium y Taenia saginata son dos parásitos zoonóticos que causan teniasis en personas (hospedador definitivo) y cisticercosis en cerdos y en ganado vacuno (hospedador intermediario), respectivamente. En Europa, T. saginata ha estado presente durante siglos, sin embargo hay poca información acerca de la ocurrencia e impacto de este agente zoonótico. T. solium se considera ausente en Europa pero los datos existentes sobre este parásito son escasos. En consecuencia, los datos sobre la incidencia y prevalencia de T. saginata y T. solium en personas y animales en Europa son incompletos y se encuentran fragmentados. En este contexto, la presente tesis tuvo por objeto general avanzar en el conocimiento de la epidemiología de T. saginata y T. solium en Europa. El estudio I de esta tesis consistió en una revisión sistemática de estudios publicados entre 1990 y 2014 que tuvo como objetivo compilar el conocimiento actual sobre la epidemiología, impacto y control de la cisticercosis bovina en Europa. Los resultados de este estudio indicaron que existe una carencia de datos epidemiológicos completos y actualizados en la mayoría de países, especialmente en los países del Este de Europa. Además, se concluyó que la falta de información epidemiológica limita el desarrollo de estrategias de vigilancia basadas en riesgo y se recomendó la realización de estudios de factores de riesgo para guiar dichas estrategias. En el estudio II se actualizó el conocimiento de la epidemiología de T. saginata y T. solium en personas y animales en Europa Occidental a través de una revisión sistemática de literatura científica y gris publicada entre 1990 y 2015. Así mismo, se realizó una búsqueda de datos sobre casos a través de expertos locales en los diferentes países. Los resultados indicaron que es necesario mejorar tanto la detección como la notificación de las teniasis humanas en Europa Occidental. Además, se identificaron casos de personas portadoras de la forma adulta de T. solium, casos de cisticercosis humana sospechosos de ser autóctonos y casos de T. solium en cerdos sin confirmación molecular. Estos hallazgos, junto con un aumento de la migración desde áreas donde T. solium es endémico, podrían constituir un riesgo para la salud pública y merecen una mayor atención. Además, este estudio concluyó que los casos sospechosos de T. solium en cerdos deberían confirmarse con técnicas moleculares, que tanto las teniasis como la cisticercosis humana deberían ser notificables y que se debería mejorar la vigilancia y notificación en animales. El estudio III tuvo como objetivo estimar la prevalencia y distribución espacial de la cisticercosis bovina (2008–2015) y el impacto de T. saginata en sanidad animal y humana (2013–2015) en el noreste de España (Cataluña). Durante 2008–2015 se detectó una prevalencia en matadero de 0.010%. A partir de los registros de movimientos de bovino se identificó el lugar donde los animales se habrían infectado con mayor probabilidad y se investigó su distribución espacial. Teniendo en cuenta la granja en la que con mayor probabilidad se habría producido la infección, se detectaron dos conglomerados. El número de pacientes con diagnóstico de teniasis en atención primaria durante 2013–2016 fue pequeño (41–63/año) sugiriendo que el riesgo en salud pública de T. saginata en el área de estudio es bajo. El impacto económico de T. saginata en Cataluña durante 2013–2015 se calculó considerando los costes de la inspección postmortem, las pérdidas causadas por el decomiso y congelación de canales y los costes asociados a casos de teniasis. Los resultados obtenidos indicaron que el impacto económico de T. saginata se debe principalmente a la inspección postmortem y que el desarrollo de estrategias de vigilancia basadas en riesgo podría ser útil para reducir dicho coste. Los resultados también evidenciaron la importancia de tener en cuenta la trazabilidad de los animales para el desarrollo de dicha estrategia.
Taenia solium and Taenia saginata are two zoonotic parasites that cause taeniosis in humans (definitive host) and cysticercosis in pigs and cattle (intermediate host), respectively. In Europe, T. saginata has been present for centuries but data showing the occurrence and burden of this zoonotic agent are scarce. T. solium is considered absent in Europe but data about this parasite in this region are limited. In consequence, data on T. saginata and T. solium occurrence in humans and animals in Europe are incomplete and fragmented. In this context, the general aim of this thesis was to advance the knowledge of the epidemiology of T. saginata and T. solium in Europe. In study I a systematic review of studies published between 1990 and 2014 was conducted to present the current knowledge on the epidemiology, impact and control of bovine cysticercosis in Europe. The results of this study indicated that there is a lack of complete and updated epidemiological data in most countries, especially in eastern Europe. Moreover, it concluded that this lack of information is a limitation to guide risk-based interventions against the disease. Conducting studies on risk factors was recommended in order to guide such strategies. In study II, the knowledge on the epidemiology of T. saginata and T. solium in humans and animals in western Europe was updated by undertaking a systematic review of scientific and grey literature published from 1990 to 2015. Additionally, data about disease occurrence were actively sought by contacting local experts in the different countries. The results of this study indicated that the detection and reporting of human taeniosis in western Europe needs to be improved. Furthermore, the study identified reports of T. solium tapeworm carriers, of suspected autochthonous cases of human cysticercosis and of suspected cases of T. solium in pigs without molecular confirmation. These findings, combined with the increased migration from T. solium endemic areas, may constitute a public health risk that deserves further attention. Moreover, in this study it was concluded that suspected cases of T. solium in pigs should be confirmed by molecular methods, that both taeniosis and human cysticercosis should be notifiable and surveillance and reporting in animals should be improved. Study III of this thesis aimed to estimate the prevalence and spatial distribution of bovine cysticercosis (2008–2015) and the burden from T. saginata upon the animal and human sectors (2013–2015) in northeastern Spain (Catalonia). During 2008–2015 a mean prevalence of 0.010% was detected at slaughter. Cattle movement history was used to identify the place where cattle most likely became infected and to investigate its spatial distribution. Based on the farm where the infection was acquired with highest probability, two significant bovine cysticercosis clusters were detected in Catalonia. The number of patients diagnosed with taeniosis in primary care during the period 2013–2016 was low (41–63/year) suggesting that the public health risk of T. saginata in the study area is low. The economic impact of T. saginata in Catalonia during 2013–2015 was estimated considering costs of meat inspection, losses due to carcass condemnation and freezing and taeniosis-associated costs. The results obtained indicated that the economic impact due to T. saginata was mainly attributed to meat inspection and suggested that developing and implementing a risk-based surveillance is needed to lower these costs. Results also indicated that cattle movements need to be taken into account in the development of such a strategy.

Branches of science such as epidemiology, clinical epidemiology, statistics and various statistical methods are by ground for activity of epidemiological-manager indicators. Incidence and prevalence are numbered among epidemiological-manager indicators. In condition of hospital Pelhřimov are these indicators written, analyzed and predicated for department of hospitalized in years 2005 -- 2007. At the same time is appraised use of capacities department of hospitalized, is made analyse and estimation of most often treated diagnosis and is watched progress their average time of treatment. The watching indicators are by one of series others records for manager decision-making by control of hospital.

Dance greatly contributes to social, cultural and economic development, as well as entertainment and recreational physical activity. There are many different motivators and benefits to dance participation at the recreational, elite student and professional level. There is also a risk of injury at all levels of dance practise and any injury has the potential for significant consequences. In order to effectively prevent injuries it is critical to understand their magnitude and characteristics. However, there is a paucity of data relating to dance participation and injuries in the recreational dancer, as well as research investigating injuries in professional dancers across all different styles and employment situations. Therefore, six studies were conducted in this thesis, which aimed to develop a better understanding of the epidemiology of injuries across the full spectrum of dance participation. This thesis addressed current gaps in the literature, including the incorporation of recreational dancers and the use of high quality nationally representative data. It also contributed to the local professional dance industry through Safe Dance IV, which incorporated a broader scope of professional dancers than previous Australian studies. Overall this thesis highlighted the high prevalence of injuries in dance and emphasised that injury prevention and management are important considerations for all levels of dancers.

Orientador: Maria da Luz Rosario de Sousa
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
Made available in DSpace on 2018-08-06T03:03:49Z (GMT). No. of bitstreams: 1 Meirelles_MariaPaulaMacielRando_M.pdf: 1259646 bytes, checksum: e7fec81dc3b154afea7a206aad1b4442 (MD5) Previous issue date: 2006
Resumo: Nos últimos anos houve uma evidente mudança na epidemiologia e no padrão da doença cárie. Neste contexto, métodos tradicionais de diagnóstico podem estar subestimando as lesões de cárie, principalmente em superfícies oclusais. Esta pesquisa teve como objetivo verificar a prevalência de lesões de cárie oculta oclusal em escolares de 12 a 15 anos de idade através de métodos complementares de diagnóstico em levantamentos epidemiológicos. A amostra constituiu-se de 179 escolares de 12 a 15 anos matriculados em 20 escolas públicas de Piracicaba. Após o exame visual (EV) segundo os critérios da OMS, (1997) 1290 dentes sem sinal de cavitação na superfície oclusal foram reavaliados por meio do exame visual com secagem prévia (EVS); exame radiográfico (ER) e com o auxílio do aparelho Diagnodent (DD). A média do Índice CPO- D na população estudada foi de 2,3 e 32,5% dos escolares estavam livres de cárie segundo EV. Das 1290 superfícies examinadas no exame visual, 918 superfícies oclusais foram diagnosticadas como hígidas. Destas, 241 (26,3%) apresentaram imagem radiolúcida sugerindo cárie em dentina pelo ER. Das 41 superfícies que apresentaram escurecimento da dentina sob esmalte íntegro, 25 também apresentaram imagem radiolúcida sugerindo cárie em dentina. Incluindo as lesões em dentina diagnosticadas pelo ER o CPO-D dos escolares seria de 3,1, e apenas 13,4% dos escolares estariam livres de cárie. A prevalência de cárie oculta foi de 56,4%, com média de 1,68 superfícies oclusais afetadas por escolar. Quando comparados os resultados do exame com o aparelho Diagnodent em relação ao Exame Radiográfico, a sensibilidade foi de 64% e a especificidade de 74%. Diante desses resultados, conclui-se que a prevalência de lesões de cárie oculta oclusal obtida através de levantamentos epidemiológicos sem o uso de métodos auxiliares está sendo subestimada. Sendo assim, estudos epidemiológicos que busquem estimar este subestimação são importantes para contribuir para o planejamento dos serviços de saúde bucal. O Diagnodent pode ser indicado como método auxiliar ao diagnóstico de lesões de cárie ao exame visual, na impossibilidade de utilização do exame radiográfico
Abstract: In recent years there has been a clear change in the epidemiology and pattern of dental caries. In this context, traditional methods of diagnosis may be underestimating caries lesions, mainly at occlusal surfaces. The aim of this research was to verify the occlusal hidden caries prevalence in surveys and if laser fluorescence may be indicated to be used in surveys for its diagnosis. The sample comprehended 1290 occlusal surfaces of permanent molars, examined in 179 students, aged 12-15. The methods used were: Visual Inspection (VI), Visual Inspection with previous drying (VID), bitewing radiography (BI) and laser fluorescence by Diagnodent. The mean DMFT value was 2.3, and 32.5% of the students were free from caries on the VI. From the 918 surfaces scored as clinically sound on VI, 41 demonstrated grayish discolouration under sound enamel by VID, and 241 demonstrated dentine radiolucency on BI. From the 41 surfaces which demonstrated darkening dentin under sound enamel, 25 demonstrated dentin radiolucency. Including the dentin lesions diagnosis on BI, the mean DMFT was 3.1 and 13.4% of the students were free from caries. The occlusal hidden caries prevalence was 56.4% with an average of 1.68 affected occlusal surfaces by each student. When compared the results of Diagnodent with BI, the sensitivity was 64% and the specificity was 74%. From these results we can conclude that the occlusal hidden caries prevalence in surveys must be considered and the Diagnodent, in this case, can be used as an auxiliary tool on Visual Inspection, but not as a substitute of Bitewing Radiographic
Mestrado
Cariologia
Mestre em Odontologia

La carga de enfermedad y las muertes relacionadas con la malaria han disminuido a nivel global, principalmente gracias a las mejoras en la implementación de las intervenciones para prevenir y tratar la malaria, y en particular al uso de las mosquiteras impregnadas con insecticidas de larga duración y al tratamiento de los episodios clínicos con terapias combinadas con artemisinina. El reciente aumento de los fondos mundiales destinados a financiar los esfuerzos de control de la malaria ha permitido que la mayoría de la población pobre que vive en países endémicos de malaria tenga acceso a medidas de prevención, a diagnóstico en caso de sospecha de malaria y a terapias combinadas con artemisinina. De acuerdo a los datos de 104 países recopilados por la OMS en el Informe Mundial sobre el Paludismo del 2012, se estima que se evitaron 274 millones de casos de malaria y 1.1 millones de muertes relacionadas con la malaria. El éxito de las medidas de control actuales ha reactivado el objetivo de la eliminación de la malaria y su erradicación del globo. Sin embargo, la mayor parte de los logros globales se deben a la reducción de enfermos graves y muertes debidos a Plasmodium falciparum, principalmente en los países africanos. Fuera de África, la mayoría de las regiones endémicas de malaria cuentan con más de una especie del parásito Plasmodium. Medidas actuales como las mosquiteras impregnadas con insecticidas de larga duración y las terapias combinadas de artemisinina se han mostrado más eficaces contra P. falciparum que contra Plasmodium vivax. En la mayoría de los países endémicos donde P. vivax y P. falciparum coexisten, con programas eficaces de control de la malaria, parece haberse producido un incremento proporcional de la prevalencia de P. vivax, sustituyendo a P. falciparum como especie predominante. P. vivax es más difícil de controlar que P. falciparum a causa de la fase hepática de P. vivax llamada hipnozoito. Los hipnozoitos pueden permanecer inactivos en el hígado durante largos períodos de tiempo antes de volver a activarse para reinfectar la sangre y causar una recaída de malaria por P. vivax en el huésped humano. En las regiones tropicales los hipnozoitos se activan rápidamente, y son comunes las recaídas múltiples a intervalos de cerca de 3 semanas, mientras que en las zonas subtropicales las recaídas pueden producirse con intervalos más largos (de 8 a 10 meses). Lograr la eliminación y erradicación de la malaria será difícil sin la erradicación de los hipnozoitos del hígado, especialmente en regiones endémicas con transmisión de la malaria perenne como Papúa Nueva Guinea. Actualmente, la primaquina es el único fármaco autorizado en el mercado que tiene efecto sobre los hipnozoitos. Las terapias combinadas de artemisinina, aunque son muy eficaces contra la infección en fase sanguínea de ambos Plasmodium, no tienen ningún efecto sobre los hipnozoitos. Una de las estrategias para la eliminación de la malaria es la administración masiva de medicamentos. Sin embargo, para que esta estrategia sea eficaz en áreas endémicas de P. vivax, debe incluir la primaquina en el régimen de tratamiento para así erradicar los hipnozoitos en el hígado, pero el uso indiscriminado de este fármaco puede conllevar problemas de seguridad importantes. Los futuros posibles sustitutos de la primaquina deben ser fármacos con una fase de eliminación terminal larga con el fin de proporcionar una profilaxis post-tratamiento eficaz para detener la transmisión de P. vivax, previniendo las recaídas desde el hígado. La mayoría de las infecciones por P. vivax en niños mayores y adultos como resultado de las recaídas por activación del hipnozoito en el hígado son asintomáticas. Por otro lado, la gametogénesis (producción de gametos, los estadios infectivos responsables de la transmisión desde el humano al siguiente mosquito vector) de P. vivax ocurre de forma espontánea con el desarrollo de la infección en fase sanguínea, hecho que lleva a una gametocitemia temprana que incrementa la probabilidad de transmisión a mosquitos antes incluso de la aparición de síntomas y por tanto del tratamiento de los casos sintomáticos. Se ha demostrado que la primaquina también es el único fármaco eficaz contra los gametocitos de estadío V de P. falciparum, los verdaderos responsables de la transmisión en esta especie El uso de la primaquina para la administración masiva de medicamentos será, por lo tanto, una herramienta efectiva para la prevención de la transmisión de P. vivax y P. falciparum. En la actualidad se desconoce la contribución de los hipnozoitos a la carga de infección y enfermedad por P. vivax, especialmente en los niños que viven en zonas de alta endemicidad. La primaquina, el único fármaco efectivo contra los hipnozoitos de P. vivax y P. ovale conocido, existe desde hace más de 60 años pero, sin embargo, se sabe muy poco de su seguridad y tolerabilidad en los niños, la población que sufre la mayor carga de infección y enfermedad por P. vivax. Incluso en su uso en adultos, todavía no se sabe mucho acerca de la dosificación y modo de acción. Existen importantes limitaciones en el uso de la primaquina en regímenes de tratamiento de la malaria. En primer lugar, el riesgo letal de anemia hemolítica grave asociada al tratamiento con primaquina para las personas con las variantes graves de deficiencia de deshidrogenasa de glucosa-6-fosfato (G6PD). En segundo lugar, la falta de un test de diagnóstico rápido barato, fiable y accesible para detectar la deficiencia de G6PD durante la actividad clínica rutinaria, así como durante el ejercicio preventivo de administración masiva de medicamento. En Papua Nueva Guinea, varios estudios de cohorte longitudinales han demostrado que P. vivax es la causa más común de infección y enfermedad por malaria en los niños menores de 3 años de edad, mientras que P. falciparum predomina como causa de morbilidad en niños de 3 a 10 años de edad. La enfermedad clínica secundaria a P. vivax tiene su punto culminante a los 3 años de edad. A pesar de que la prevalencia de la infección por P. vivax y P. falciparum son similares en el grupo de mayor edad, los niños con infección de P. vivax permanecen asintomáticos o presentan enfermedad clínica leve. No hay variación estacional en la prevalencia de P. vivax en comparación con la de P. falciparum. Esto puede ser debido a las recaídas por activación de los hipnozoitos en el hígado, que contribuyen a la reinfección de la fase sanguínea, sin requerir la transmisión mediante el vector anofelino. Esta tesis presenta datos de dos estudios de cohortes longitudinales en niños de 1 a 10 años de Papua Nueva Guinea con niveles normales de G6PD para evaluar el efecto de la primaquina sobre los hipnozoitos en el hígado. Los objetivos eran dos: El primero: determinar la contribución de las recaídas de la activación desde los hipnozoitos a la carga de infección y enfermedad por P. vivax en los niños que viven en una zona de alta transmisión de malaria, después de un pre-tratamiento con primaquina. El segundo: evaluar la seguridad y tolerabilidad del uso de la primaquina en los niños como pre-tratamiento en el terreno. Tras los estudios de cohortes, se estudiaron las propiedades farmacocinéticas de una dosis única de primaquina en niños de Papua Nueva Guinea para evaluar la viabilidad de un eventual tratamiento corto con dosis altas de primaquina para la cura radical de la malaria por P. vivax. Estos estudios constituyen la base de esta tesis. En el primer estudio, niños de entre 1 y 5 años con G6PD normal fueron seleccionados y distribuidos aleatoriamente en tres grupos: grupo control sin medicación pre-tratamiento; grupo pre-tratado con artesunato + primaquina, y aquellos solamente tratados con artesunato. Las dosis de tratamiento se administraron bajo observación directa, y siempre junto con comida. Los niños fueron seguidos activamente cada dos semanas durante los primeros tres meses, luego mensualmente hasta nueve meses haciendo detección de casos con infección de malaria asintomática y de casos clínicos. La detección pasiva de casos se hizo mediante las enfermeras establecidas en las clínicas locales durante la duración total del estudio. Los resultados de este estudio de cohorte muestran que el pre-tratamiento con artesunato más primaquina (14d, 0.5 mg) redujo la incidencia de malaria por P. vivax en un 49% durante los 3 primeros meses (p = 0.031) y un 19% para los meses 4 a 9 (p = 0,25). También redujo el tiempo de la primera detección por microscopía óptica y por PCR de los casos positivos por infección en un 57% y 48%, respectivamente (p < 0,001), en comparación con el grupo que sólo tomó artesunato. El efecto preventivo del pre-tratamiento en el grupo de primaquina se limitó a los primeros 3 meses de seguimiento y el 30% de los niños sufrieron una reinfección a las 2 semanas de seguimiento. En el segundo estudio, se realizó un ensayo aleatorizado, doble ciego, controlado con placebo para estudiar el efecto de la primaquina en niños de 5 a 10 años de edad con niveles normales de G6PD. Todos los niños del estudio recibieron cloroquina en los días 1 a 3, y arteméter lumefantrina en los días 15 a 17 días de la fase de pre-tratamiento. Los niños fueron asignados aleatoriamente en dos grupos para recibir primaquina o placebo, juntamente con cloroquina. Todas las dosis pre-tratamiento se administraron bajo observación directa y junto con comida utilizando el mismo programa de seguimiento del primer estudio. Los resultados del segundo estudio muestran que el pre-tratamiento con primaquina redujo el riesgo de adquirir una infección en fase sanguínea nueva en un 78% (p<0.0001), y de enfermedad clínica en un 68% (p<0.0035). La edad se asoció con un riesgo menor de presentar episodios clínicos causados por P. vivax de cualquier densidad (p<0.0167) y de alta densidad (p<0.016). La mayoría de reinfecciones ocurrieron durante las 12 semanas de pre-tratamiento. El tercer estudio, diseñado para monitorear la seguridad y la tolerabilidad del tratamiento con primaquina en los niños del estudio, se llevó a cabo durante la fase de seguimiento de los dos estudios de pre-tratamiento de cohortes. Se utilizó un cuestionario semi-estructurado de todos los posibles eventos adversos a medicamentos antes de la toma de la dosis de primaquina. Todas las dosis de primaquina se administraron con alimentos excepto en el grupo de edad más joven, en el que los niños fueron amamantados/alimentados por las madres. Los resultados de este estudio mostraron que se necesitaban 14 dosis diarias de 0.5mg/kg de primaquina para garantizar la seguridad y la tolerabilidad en los niños de ambos estudios de cohortes. En ninguno de ellos hubo eventos adversos graves y/o abandonos asociados con la toma de primaquina. En los niños que reportaron náuseas o vómitos debido a la ingestión de primaquina, la recuperación fue casi inmediata a la ingesta de alimentos. A raíz de los estudios de cohortes, se estudiaron las propiedades farmacocinéticas de dos dosis únicas de primaquina en niños de Papua Nueva Guinea de entre 5 y 10 años de edad, para evaluar la viabilidad de un tratamiento corto, con regímenes de tratamiento con primaquina en dosis altas para la cura radical de malaria por P. vivax. Se evaluaron los perfiles de las dosis de 0.5 mg/kg y 1.0 mg/kg. Durante el reclutamiento, los niños del estudio fueron ingresados en el Centro de Salud durante 2 días para poder hacer un seguimiento exhaustivo y permitir la toma de muestras de sangre frecuentes. Durante todo este tiempo los participantes llevaron una cánula intravenosa permanente para tomar muestras de sangre. Las dosis de primaquina se co-administraron con alimentos. El estudio de monitorización de la seguridad y tolerabilidad mostró que ambas dosis de primaquina fueron bien toleradas, sin efectos adversos graves. No hubo cambios observados en los síntomas y la gravedad de las náuseas o dolores abdominales en ninguno de los grupos de dosificación de primaquina. No hubo diferencias entre los grupos en la concentración de hemoglobina y niveles de metahemoglobina. Los regímenes cortos de dosis altas simulados mostraron que las concentraciones de primaquina y carboxyprimaquina en plasma predichas y obtenidas no fueron significativamente mayores que las observadas en los estudios farmacocinéticos anteriores en adultos. Esto sugiere que tanto los regímenes de dosis de 0.5 mg/kg como de 1.0mg/kg de primaquina podrían ser evaluados con más detalle en estudios de seguridad y eficacia sobre terreno. Varios estudios hechos en el pasado sobre la primaquina reportaron un aumento de la eficacia de la primaquina cuando asociada a una droga con una fase de eliminación terminal larga. La primaquina es más eficaz cuando se administra conjuntamente con cloroquina debido a su efecto profiláctico post-tratamiento más largo, tal y como se muestra en el segundo estudio de cohortes. Los estudios también han demostrado que la dosis terapéutica de primaquina se basa en el efecto de la dosis total, y no en los intervalos de dosificación, ya que una mayor dosis diaria durante 7 días parece ser tan eficaz como el régimen de 14 días con eventos adversos mínimos cuando se co-administraron con comida. La actual dosis diaria de primaquina durante 14 días es más eficaz cuando se administra en las condiciones de investigación con la observación directa de la ingesta del fármaco, mientras que en la vida real, debido a la falta de cumplimiento, el tratamiento con primaquina tiene un efecto más reducido. Un tratamiento corto con altas dosis de primaquina compatible con el régimen de 3 días de aplicación de las terapias combinadas con artemisinina sería óptimo para mejorar el cumplimiento durante el tratamiento de rutina y facilitar la administración como administración masiva de medicamentos para la eliminación de la malaria. Por tanto, el último artículo de esta tesis revisa el posible uso de la primaquina como herramienta no sólo de control sino que también para la eliminación de la malaria en el contexto de una zona como Papúa Nueva Guinea. Los resultados de estas cohortes longitudinales y los estudios de dosis de primaquina contribuirán al conocimiento científico sobre la epidemiología y el manejo de P. vivax, la seguridad del uso de primaquina en niños y a la mejora del cumplimiento de las tomas preventivas del fármaco. Esta será una herramienta útil para el control y eliminación del paludismo para combatir los hipnozoitos en el hígado del huésped humano. La estrategia de la administración masiva de medicamentos tendría potencialmente capacidad para detener la transmisión de la malaria no sólo eliminando hipnozoitos de P. vivax en el hígado, sino también los gametocitos en fase V de P. falciparum.
Globally, the burden of malaria related disease and deaths has decreased in the last 10 years, mainly due to interventions for malaria prevention and treatment with long lasting insecticide treated bed nets and the artemisinin combination therapies, respectively. The recent increase in Global funding for malaria control efforts has enabled majority of impoverished populations living in malaria endemic countries to access preventative measures, diagnosis of presumptive malaria cases and artemisinin combination therapies. According to data summaries from 104m countries compiled by WHO in the 2012 malaria report, an estimated 274 million malaria cases were averted and 1.1 million lives saved from dying, from malaria related illness. The success of current control measures has once again, renewed the goal of malaria elimination and its eradication from the globe. However, most of the global achievements are due to reductions in severe disease and deaths from Plasmodium falciparum malaria mostly in African countries. Outside of Africa, most malaria endemic regions have more than one Plasmodium parasite species present. The current measures, using long lasting insecticide treated nets and artemisinin combination therapies are more effective against Plasmodium falciparum compared to P. vivax malaria. In most P. vivax endemic countries with effective malaria control programs, there has been a relative increase in the prevalence of P. vivax, replacing Plasmodium falciparum as the predominant species. P. vivax is more difficult to control than Plasmodium falciparum. This is due to the liver stages of P. vivax called hypnozoites. The hypnozoites remain dormant in the liver for prolonged periods of time before activation, to re-infect the blood leading to P. vivax relapse infection and malaria in the human host. In Tropical regions, the hypnozoites activate quickly, and multiple relapses commonly occur, at about 3 weekly intervals, while in the subtropics, relapses occur at about 8-10 month intervals. Achieving the goal of malaria elimination and eradication will be difficult without eradication of the hypnozoites from the liver, especially in endemic regions with perennial malaria transmission such as Papua New Guinea. Currently, primaquine is the only licensed drug in the market that has an effect upon the hypnozoites. The artemisinin combination therapies while highly effective against the blood stage infection of both Plasmodium falciparum and P. vivax, have no effect upon the hypnozoites. One of the strategies for malaria elimination is mass drug administration. However, for this strategy to be effective in P. vivax endemic areas, primaquine must be included in the treatment regimen to eradicate the hypnozoites from the liver. The partner drug of primaquine must have a long terminal elimination phase in order to provide effective post-treatment prophylaxis to prevent relapses from the liver to stop P. vivax transmission. Most P. vivax infections in older children and adults as a result of relapses from hypnozoite activation in the liver are asymptomatic. Moreover, the gametocytogenesis of P. vivax occur spontaneously with the development of blood stage infection leading to early gametocytemia with high probability of transmission to mosquitoes before treatment of symptomatic cases. Primaquine has also been shown to be the only drug effective against the gametocyte stage five of Plasmodium falciparum. Primaquine use for mass drug administration will therefore be an effective tool for preventing P. vivax and P. falciparum transmission. Currently, the contribution of the hypnozoites to the burden of P. vivax infection and disease especially in children living in highly endemic areas is not well understood. Primaquine, the only licensed drug known to be effective against the hypnozoites of P. vivax (and P. ovale) existed for over 60 years, yet very little is known of its safety and tolerability in children; the population with the highest burden of P. vivax infection and disease. Even in adult use, much is still not known about dosing and mode of action. There are major limitations to primaquine use in malaria treatment regimens. Firstly, the risk of severe life threatening haemolytic anaemia associated with primaquine treatment in persons with the severe variants of glucose- 6-phosphate dehydrogenase deficiency. Secondly, the lack of cheap and reliable, point of care rapid diagnostic test for glucose-6-phosphate dehydrogenase deficiency for routine use and during mass drug administrations. In Papua New Guinea, several longitudinal cohort studies have shown P. vivax to be the commonest cause of malarial infection and disease in children less than 3 years old; while Plasmodium falciparum accounts for the majority of malarial disease burden in children over 3-10 years old. The clinical disease of P. vivax peaks at 3 years of age. Even though the prevalence of infection with P. vivax and P. falciparum are similar in the older age group, children with P. vivax infection remain asymptomatic with less clinical illness. There is much less seasonal variation in P. vivax prevalence compared to that of P. falciparum. This may be due to relapses from hypnozoite activation in the liver contributing to blood stage re-infection. Two longitudinal cohort studies in G6PD normal Papua New Guinean children aged 1 to 10 years were carried out to assess the effect of primaquine on the hypnozoites in the liver. There were two aims for the cohort studies. Firstly, to determine the contribution of relapses from hypnozoite activation to the burden of P. vivax infection and disease in children living in an area of high malaria transmission, following treatment with primaquine. Secondly, to assess the safety and tolerability of primaquine use in the children as part of the cohort studies, drug treatment phase in the field. Following the cohort studies, pharmacokinetic profiles of two single high-dose primaquine in Papua New Guinean children were determined to assess the feasibility of short course, highdose primaquine treatment regimens for radical cure of P. vivax malaria. These studies form the basis of this thesis. In the first study, G6PD normal children aged 1-5 years old were screened and randomized into three groups: control group with no pre-treatment drugs; primaquine plus artesunate group; and those with artesunate only, as pretreatment. The treatment doses were administered by direct observed therapy with food. Children were followed actively every two weeks for the initial three months, then monthly up to nine months for asymptomatic malarial infection and clinical case detection. Passive case detection was done by nurses based at the local clinics throughout the study duration. The result from this cohort study show, pre-treatment with artesunate plus primaquine (14d, 0.5mg) reduced incidence of P. vivax malaria by 49% for the initial 3 months (p = 0.031) and 19% for months 4- 9 (p = 0.25); and reduced time to first light microscopy and PCR-positive infections by 57% and 48%, respectively (p < 0.001), when compared to the artesunate only group. The effect of pretreatment in the primaquine group was limited to the first 3 months of follow-up and 30% of children had re-infection by 2 weeks of follow-up. In the second study, a randomized, double-blind, placebo controlled trial of primaquine effect was performed in G6PD normal children aged 5 to 10 years old. All study children received chloroquine at days 1-3 and artemether lumefantrine at days 15-17 of the pre-treatment phase. The children were randomized to receive either primaquine or placebo, to be administered with chloroquine. All pre-treatment doses were administered by direct observed therapy with food using the same follow up schedule as study one. The results from this study show, pre-treatment with primaquine reduced the risk of acquiring a new blood stage infection by 78%, (p <0.0001), and clinical disease by 68%, (p <0.0035). Age was associated with a reduced risk of P. vivax clinical episodes of any density (p <0.0167) and high density (p <0.016). Most reinfections occurred within 12 weeks of pre-treatment. The third study, monitoring of safety and tolerability of primaquine treatment in the study children was performed during the pre-treatment phase of follow up in the two cohort studies. A semi-structured questionnaire of all possible drug adverse events was performed prior to primaquine dose ingestion. All primaquine doses were administered with food, however in the younger age group, children were fed by the mothers. The results from this field-based study show, 14 daily doses of 0.5mg/kg primaquine to be safe and well tolerated in children in both cohort studies. There were no serious adverse events and/or withdrawals of children associated with primaquine ingestion in the two cohorts studies. In children with reported nausea or vomiting due to primaquine ingestion, recovery was almost immediate upon food intake. Following on from the cohort studies, pharmacokinetic properties of two single-dose primaquine in Papua New Guinean children aged 5-10 years old was performed; to assess the feasibility of short course, high-dose primaquine treatment regimens for radical cure of P. vivax malaria. The profiles of single doses of primaquine 0.5mg/kg and 1.0mg/kg were assessed in the children. At recruitment, study children were admitted to the Health Centre for 2 days for close monitoring, and, to allow for frequent blood sampling. During all this time participants had indwelling intravenous cannula in place for blood sampling. The primaquine doses were co-administered with food. The safety and tolerability monitoring showed both primaquine doses were well tolerated, with no severe adverse events. There were no observed changes in symptoms and severity of nausea or abdominal pains in the two primaquine dosage groups. There was no betweengroup difference in haemoglobin concentration and methemoglobin levels. The simulated short course high dose regimens showed predicted plasma primaquine and carboxyprimaquine concentrations achieved were not significantly greater than those seen in previous pharmacokinetic studies of adults. This suggests both 0.5mg/kg and 1.0mg/kg primaquine dose regimens could be further assessed in safety and efficacy field studies. Several primaquine studies in the past observed the efficacy of primaquine enhanced by a partner drug with a long terminal elimination phase. Primaquine is more effective when coadministered with chloroquine due to its longer post-treatment prophylactic effect as shown in the second cohort study. Studies have also shown that the therapeutic dose of primaquine is based on the total dose effect, and not the dosing intervals. Indeed, a higher daily dose for 7 days was as effective as the 14 day regimen with minimal adverse events when coadministered with food. The current 14 day, daily dosing of primaquine is most effective when given in research conditions with direct observation of drug treatment; whereas in real life situations, due to poor compliance, primaquine treatment has a reduced effect. A shorter course of high dose primaquine treatment compatible with the 3 day dosing regimens of artemisinin combination therapies would be ideal; to improve compliance during routine treatment and easier to administer as mass drug administration for malaria elimination. Thus, the last manuscript of this thesis reviews the potential use of primaquine as a tool for control and eventually elimination of malaria in the PNG context. The results from these longitudinal cohorts and the primaquine dose studies will contribute to the scientific knowledge on P. vivax epidemiology and the safety of primaquine use in children and an attempt to improve compliance. This will be a useful tool for malaria control and elimination to tackle the hypnozoites in the liver of the human host. The mass drug administration strategy would have an effective arsenal to potentially, not only eliminate hypnozoites of P. vivax from the liver, but stage five gametocytes of P. falciparum as well, to stop malaria transmission.

Giardiasis, cause by the parasitic protozoan Giardia duodenalis, is one of the most common infectious gastrointestinal diseases in humans worldwide. However, its true population burden and epidemiology and in particular its zoonotic transmission potential are still poorly understood. Furthermore, G. duodenalis is not a uniform parasite but a complex of seven genetic assemblages or cryptic species (named A to G) that infect humans and a variety of domesticated and wild animals, and that can only be distinguished using molecular genotyping methods. Although there is some evidence that the two Giardia assemblages infecting humans (namely A and B) may differ in their virulence and major transmission routes, data are still scarce. In the UK, several studies suggested that giardiasis is considerably under-diagnosed and a few data are available on the genetic diversity of the parasite causing infection and disease in this country. We investigated the burden, clinical outcomes, risk factors and molecular diversity of giardiasis in North West England using both a descriptive and analytical approach. In Chapter 2, we analysed the self-reported clinical and exposure data collected over four years from clinical cases of giardiasis in Central Lancashire, as part of an enhanced surveillance program on the illness. The resulting average disease rate of 22.5 cases/100,000 population was high when compared to the available national figures. Giardiasis was particularly abundant in adults in their 30s and children under five, and the disease rate in males was significantly higher than in females. Furthermore, the clinical picture of the cases confirmed the high morbidity associated with this infection particularly in terms of the length of illness and severity of symptoms. Only 32% of the cases reported foreign travel during the exposure window. The results suggested the presence of a hidden burden of disease in adults and males, and indicated that local transmission of Giardia can be more common than expected. In Chapter 3, we performed a case-control study to determine the significant risk factors for symptomatic giardiasis in North West England, by recruiting clinical cases of Giardia and age and sex matched controls from Central and East Lancashire and Greater Manchester. The multivariable logistic regression analysis done on 118 cases and 226 controls revealed that overall travelling abroad (particularly to developing countries) was an important risk factor for the illness (OR 9.59). Following the exclusion of participants that reported foreign travel, four risk factors were significant for the acquisition of giardiasis: going to a swimming pool (OR 2.67), changing nappies (OR 3.38), suffering irritable bowel syndrome (OR 3.66) and drinking un-boiled water from the tap (OR 8.17). The results indicated the important role of swimming pools and contact with children in nappies for the transmission of the parasite. In Chapter 4, whole faecal DNA was extracted from the faecal samples of the cases part of the surveillance and case-control studies and the Giardia assemblages and sub-assemblages causing infection were determined using PCR amplification and DNA sequencing of up to four parasite genes (beta-giardin, glutamate dehydrogenase, triose-phosphate isomerase and small-subunit ribosomal RNA). The majority of infections (64%) were caused by assemblage B, followed by assemblage A (33%), whereas mixed-assemblage infections were rare (3%). The majority of the assemblage A isolates belonged to the sub-assemblage AII and showed completed identity with previously described isolates, and six multi-locus genotypes were identified. The level of genetic sub-structuring as revealed by phylogenetic analysis was significantly higher in assemblage B isolates compared with A isolates: a higher proportion of novel assemblage B sequences was detected compared to what was observed in assemblage A isolates. A high number of assemblage B sequences showed heterogeneous nucleotide positions that prevented the unambiguous assignment to a specific sub-assemblage. Up to 17 different assemblage B multi-locus genotypes were found. The molecular genotyping results showed that Giardia assemblage B was responsible for the majority of the clinical infections and confirmed the occurrence of a high diversity of parasite multi-locus genotypes. In Chapter 5, we integrated the epidemiological and the molecular data generated by the enhanced surveillance and case-control studies and we studied the clinico-epidemiological differences between cases infected with Giardia assemblage A or B. Our results showed a difference in the age prevalence between the two assemblages, with assemblage A being more common in older cases. Cases infected with assemblage B reported a series of symptoms more frequently than cases infected with assemblage A, as well as reporting a longer illness. Although the exposure profile of the cases largely overlapped between the two assemblages, two different types of exposures were reported more frequently in the two groups of cases: keeping a dog in assemblage A cases and the presence in the household of children and children at nursery in assemblage B cases. The results suggested that assemblage A could have a major zoonotic reservoir, whereas assemblage B could be transmitted more commonly via the human-to-human route.

Aquesta tesi proporciona dades sobre la prevalença de la resistència antibiòtica en Mycoplasma genitalium i suggereix la implementació de noves estratègies terapèutiques per fer front a les infeccions causades per aquest patogen de transmissió sexual. A través d’una anàlisi exhaustiva de la infecció en el nostre entorn, aquest estudi ofereix reflexions globals al voltant de la infecció per M. genitalium i els seus mecanismes de resistència antimicrobiana. El capítol 1 actualitza i resumeix l’evidència clínica i epidemiològica en relació a la infecció , destacant alhora alguns aspectes bàsics de la fisiologia i la patogènesi del bacteri. El capítol 2 “Antibiotic resistance: where are we now?” proporciona estimacions sobre la resistència a macròlids i fluoroquinolones en M. genitalium a Barcelona, Espanya, a través d’un estudi de cohorts realitzat entre l’any 2016 i el 2017. A més, el capítol revisa i descriu l’evolució regional i europea de la resistència antibiòtica en M. genitalium durant l’última dècada. D’altra banda, el capítol 3 “Mycoplasma genitalium: should we screen and how?” i el capítol 4 “Transmission dynamics in Mycoplasma genitalium” se centren en les infeccions asimptomàtiques, aprofundint en la prevalença de M. genitalium, així com en les resistències antibiòtiques en la població asimptomàtica, tot revelant la dinàmica de transmissió de la infecció. Finalment, el capítol 5 resumeix les principals conclusions de la tesi, culminant amb la proposta d’un nou algoritme terapèutic basat en els resultats i evidències obtinguts al llarg d’aquest treball.
Esta tesis proporciona las primeras estimaciones en relación a la resistencia antibiótica en Mycoplasma genitalium y sugiere la implementación de nuevas estrategias terapéuticas para hacer frente a las infecciones causadas por este patógeno de transmisión sexual. A través de un análisis exhaustivo de la infección en nuestro entorno, este estudio ofrece reflexiones globales en torno a la infección por M. genitalium y sus mecanismos de resistencia antimicrobiana. El capítulo 1 actualiza y resume la evidencia clínica y epidemiológica en relación a la infección, destacando también algunos aspectos básicos de la fisiología y patogénesis de la bacteria. El capítulo 2 “Antibiotic resistance: where are we now?” proporciona estimaciones sobre la resistencia a macrolidos y fluoroquinolonas en M. genitalium en Barcelona, España, a través de un estudio de cohortes realizado entre 2016 y 2017. Además, el capítulo revisa y describe la evolución regional y Europea de la resistencia antibiótica en M. genitalium durante la última década. Por otro lado, el capítulo 3 “Mycoplasma genitalium: should we screen and how?” y el capítulo 4 “Transmission dynamics in Mycoplasma genitalium” se centran en las infecciones asintomáticas, profundizando en la prevalencia de M. genitalium y las resistencias antibióticas en población asintomática, y revelando la dinámica de transmisión de la infección. Finalmente, el capítulo 5 resume las principales conclusiones de la tesis, culminando con la propuesta de un novedoso algoritmo terapéutico basado en los resultados y evidencias obtenidos a lo largo de este trabajo.
This thesis provides the first antibiotic resistance estimates in Mycoplasma genitalium in Spain and suggests the implementation of novel treatment strategies against infections caused by this sexually transmitted pathogen. This study offers, through a comprehensive analysis of the infection in our settings, global insights regarding M. genitalium infection and its antimicrobial resistance mechanisms. Chapter 1 updates and summarizes the clinical and epidemiological evidence regarding the infection, highlighting also some basic aspects of the physiology and pathogenesis of the bacterium. Chapter 2 "Antibiotic resistance: where are we now?" provides estimates regarding macrolide and fluoroquinolone resistance in M. genitalium in Barcelona, Spain, through a cohort study performed between 2016 and 2017. Additionally, the chapter reviews and describes the regional and European evolution of antibiotic resistance in M. genitalium in the last decade. On the other hand, chapter 3 "Mycoplasma genitalium: should we screen and how?" and chapter 4 "Transmission dynamics in Mycoplasma genitalium" are focused on asymptomatic infections, addressing the prevalence of M. genitalium and antimicrobial resistance among asymptomatic individuals, and revealing the transmission dynamics of the infection. Finally, chapter 5 summarizes the main conclusions of this thesis work, culminating with the proposal of a novel treatment algorithm based on the results and the evidence obtained along this manuscript.
Universitat Autònoma de Barcelona. Programa de Doctorat en Microbiologia

El gènere Legionella va ser descobert el 1976 a arran d’un brot de pneumònia per Legionella pneumophila a Philadelphia (Estats Units) que va causar més d’una vintena de morts. Des d’aleshores, s’han publicat nombrosos estudis per conèixer més d’aquest peculiar bacteri. El gènere Legionella és un gènere present a la natura i amb un reservori principalment relacionat amb el medi aquàtic. S’estima que les seves concentracions a la natura són baixes però poden augmentar en sistemes d’aigua artificials. A l’inici de la dècada dels 1980, Rowbotham va veure que el gènere era capaç de multiplicar-se intracel·lularment a l’interior de protozous. A més, els protozous podien fer de reservori i ajudar a la disseminació de la malaltia. I així, va proposar una nova idea al camp de la microbiologia: bacteris com el gènere Legionella podien parasitar organismes unicel·lulars com les amebes i utilitzar els mateixos processos i estratègies per infectar els macròfags humans. El mecanisme de transmissió inclou la inhalació d’aerosols que continguin el bacteri i que un cop arriben als alvèols pulmonars, poden causar legionel·losi, sobretot en determinats grups de risc en la població. Amb l’era de la genòmica, aquest concepte s’ha estudiat en profunditat i s’ha vist que no només utilitzen els mateixos processos per infectar humans, sinó que manipulen les funcions de l’hoste amb proteïnes “impostores” per poder replicar-se i créixer en detriment de l’hoste. Així, utilitzen proteïnes amb motius eucariotes molt similars a les de l’hoste per dur a terme les seves funcions. Però la vida del gènere Legionella encara pot ser molt més complicada. A part de ser un bacteri intracel·lular, pot formar part de complexos biofilms o passar a un estat més resistent al qual anomenem VBNC. Així doncs, el gènere té múltiples estratègies per protegir-se i per sobreviure a la natura i, conseqüentment, es poden colonitzar els sistemes d’aigua artificials. Per evitar la disseminació i les elevades concentracions de legionel·la en aquests sistemes, s’han descrit una sèrie de mesures preventives de control d’instal·lacions i de desinfecció en continu de l’aigua. La concentració baixa d’aquests bacteris a l’aigua és la principal mesura preventiva per evitar possibles brots i disseminació de la legionel·losi. Malgrat aquestes mesures, les colonitzacions persistents en edificis d’alt risc encara són un problema de Salut Pública degut a la complexa biologia del microorganisme. L’estudi en profunditat d’aquests bacteris intracel·lulars d’aquesta tesi és clau per entendre la seva complexa ecologia i per aplicar estratègies efectives per una bona prevenció.
Legionella genus was discovered after a pneumonia outbreak in Philadelphia (United States) in 1976 that caused up to twenty deaths. Since then, many research studies have been conducted to clarify different aspects of these peculiar bacteria. Legionella spp. are present naturally in different environmental ecosystems with special mention to aquatic environments. Their concentration in those habitats are estimated to be low but this may change when they are in more comfortable environmental conditions such as in man-made water systems. In the early 1980s, Rowbotham discovered that Legionella spp is capable of multiplying intracellularly inside protozoa. Moreover, they act as an environmental reservoir and can help to disseminate these bacteria. This discovery led him to a new perspective in Microbiology: Legionella genus can parasite unicellular eukaryotes like FLA and use the same processes and strategies to infect human macrophages. Aerosols containing these bacteria are responsible for the transmission of the disease and they cause LD when they arrive to the lung alveoli, especially in immunocompromised people. These concepts have been studied since then and they have been amplified using genomic techniques. Legionella spp not only they use the same processes for infecting humans but also, they can hijack important host functions and cell pathways using their “eukaryotic-like” proteins or proteins with eukaryotic domains. Those proteins mimicry the ones present in host cell pathways to manipulate host functions to the pathogen’s advantage. However, Legionella life cycle can be even more complicated. Apart from being intracellular bacteria, they can be part of complex biofilms or change into a more resistant form known as VBNC. These bacteria have several and different strategies to protect them and to survive in nature and, consequently, in colonized artificial water systems. To avoid high concentrations of Legionella in water systems and to avoid LD dissemination, many prevention strategies and disinfection methods have been described and regulated by law. Maintenance of low concentrations of Legionella in water is the key to prevent outbreaks and LD cases. Despite all these measures, there are buildings permanently colonized by Legionella spp which are still a concern for Public Health authorities. The need for studying these bacteria is what is done in this thesis and it is important to have a broader picture and to understand their complex ecology and, ultimately, to apply effective prevention strategies.

La podridura marró causada per Monilinia spp. és la malaltia més important en la fruita de pinyol. Tot i que les pèrdues d'aquesta malaltia són molt importants en la postcollita, es creu que la major part de les infeccions Monilinia spp provenen de camp. En canvi, hi ha un buit de coneixement pel que fa a l'epidemiologia de la podridura marró durant la postcollita, per tal de complementar el coneixement de la dinàmica de la malaltia en camp i així planificar estratègies de control més efectives. La present tesi doctoral té com objectius estudiar alguns aspectes epidemiològics de Monilinia spp. en el context de la postcollita, tenint en compte la condició dels fruits a la seva arribada a la central fructícola. Concretamet es va determinar l'efecte de la temperatura (Capítol 1) i de cada un dels processos postcollita que es duen a terme en un central fructícola de pinyol (Capítol 2) en el desenvolupament de la podridura marró en fruits infectats. Es va analitzar la capacitat dels conidis de Monilinia spp. present en la superfície dels fruits per infectar-los durant els processos de la seva conservació en fred i durant el bolcat (Capítol 3) i finalment, es va mostrejar la població fúngica present en dues centrals fructícoles de la zona de la Vall de l'Ebre (Capítol 5) i es van avaluar desinfectants d'origen natural, per a la desinfestación de materials, zones i instal•lacions de les centrals fructícoles (Capítol 6).
La podredumbre marrón causada por Monilinia spp. es la enfermedad más importante en la fruta de hueso. Aunque las pérdidas de esta enfermedad son muy importantes en la poscosecha, se cree que la mayor parte de las infecciones Monilinia spp provienen de campo. En cambio, hay un vacío de conocimiento en cuanto a la epidemiología de la podredumbre marrón durante la postcosecha, para complementar el conocimiento de la dinámica de la enfermedad en campo y así planificar estrategias de control más efectivas. La presente tesis doctoral tiene como objetivos estudiar algunos aspectos epidemiológicos de Monilinia spp. en el contexto de la poscosecha, teniendo en cuenta la condición de los frutos a su llegada a la central frutícola. Concretamente se determinó el efecto de la temperatura (Capítulo 1) y de cada uno de los procesos postcosecha que se llevan a cabo en un central frutícola de hueso (Capítulo 2) en el desarrollo de la podredumbre marrón en frutos infectados. Se analizó la capacidad de las conidias de Monilinia spp. presente en la superficie de los frutos para infectar durante los procesos de conservación en frío y durante el volcado (Capítulo 3) y finalmente, se muestreó la población fúngica presente en dos centrales frutícolas de la zona del Valle del Ebro (Capítulo 5) y se evaluaron desinfectantes de origen natural, para la desinfestación de materiales, zonas e instala • instalaciones de las centrales frutícolas (Capítulo 6).
Brown rot caused by Monilinia spp. is the most important disease in stone fruit. Most of the losses of this disease occured in postharvest, althoughit it is believed that most of the infections come from orchards. However, there is a lack of knowledge about the epidemiology of brown rot during postharvest in order to complement the knowledge of the dynamics of the disease at orchard and to plan more effective control strategies. The objective of this thesis was study some epidemiological aspects of Monilinia spp. in the context of postharvest, taking into account the condition of the fruits on arrival at the packinghouse. Specifically, the effect of temperature (Chapter 1) and the effect of each postharvest operations that are carried out at packinghouse (Chapter 2) on the development of brown rot in infected fruits, was determinated. Also it was studied the infection capacity of the conidia of Monilinia spp. present in the fruits surface during cold storage and inmersion in the water dump (Chapter 3), and finally the fungal population present in two packinghouses in the Ebro Valley area (Chapter 5) was sampled and natural disinfectants were evaluated for materials, areas and facilities of the fruit packinghouses (Chapter 6).

A infecção pelo vírus da imunodeficiência humana na Amazônia tem-se mostrado como um dos mais recentes desafios para o enfrentamento da epidemia de HIV/aids no Brasil. Estudos epidemiológicos baseados em dados de incidência mostram tendência de crescimento da epidemia na região Norte do país. O Serviço de Assistência Especializada de Santarém é referência em assistência às pessoas com HIV/aids de 25 municípios das mesorregiões do baixo Amazonas e sudoeste do Pará. Os objetivos do presente trabalho consistem em descrever as características sociodemográficas, clínicas e laboratoriais de pessoas vivendo com HIV à admissão nesse serviço de referência, comparando-as entre os períodos: 1999 a 2002(P1), 2003 a 2006(P2) e 2007 a 2010(P3) e analisar as tendências de incidência de aids em Santarém entre 1999 e 2010. As informações referentes às variáveis de interesse foram obtidas em revisão de prontuários. Foram calculados os coeficientes de incidência padronizados a partir dos casos notificados de aids em Santarém, obtidos em bases de dados nacionais e locais. A análise de tendência de incidência foi realizada por modelos de regressão polinomial. A maioria dos 527 sujeitos (62,4%) foi admitida em P3, com 24,1% e 13,5% em P2 e P1, respectivamente. Observou-se aumento significativo da participação de indivíduos não procedentes de Santarém em P3 em comparação a P1. Verificou-se diferença significativa entre os sexos com relação ao motivo de realização da testagem pelo fato do conhecimento da soropositividade do parceiro ter motivado a testagem entre as mulheres em P1 e P2. Enquanto a presença de sinais e sintomas sugestivos de HIV/aids motivou o teste em homens durante todo o período avaliado. Houve redução significativa das medianas de linfócitos T CD4+ à admissão em P3, em relação a P1 e P2. Foram notificados 336 casos novos de aids em Santarém no período de 1999 a 2010. Foi encontrada tendência significativa de crescimento da epidemia em Santarém em ambos os sexos, e nas categorias de exposição ao HIV heterossexual e homo/bissexual no sexo masculino. O crescimento da demanda assistencial no serviço de Santarém, com incremento do número de pacientes procedentes de municípios menores e, admitidos em estadios tardios da infecção, associada à tendência de crescimento de incidência de aids em Santarém no período estudado, sugerem que as intervenções programáticas implementadas na região podem ter contribuído para o reconhecimento de maior número de casos de aids, porém ainda não possibilitaram o diagnóstico mais precoce. Acredita-se que estratégias de vigilância epidemiológica de segunda geração poderiam subsidiar de modo mais eficiente as intervenções programáticas voltadas ao controle da epidemia em uma região caracterizada por apresentar fatores individuais, sociais e programáticos que conferem vulnerabilidade acrescida à infecção pelo HIV.
Infection with human immunodeficiency virus within the Amazon region has been shown as one of the latest challenges confronting the HIV/AIDS epidemic in Brazil. Epidemiological studies based on incidence data show an increasing trend in AIDS incidence in the Brazilian North region. The specialized HIV/AIDS outpatient clinic of Santarém is the reference healthcare setting that provides care for people living with HIV/AIDS (PLHA) from 25 municipalities of the Lower Amazon and southwestern Pará regions. The aims of this study are to describe socio-demographic, clinical and laboratory features of PLHA at time of admission to this reference clinic, comparing them among the following periods: 1999 to 2002 (P1), 2003 and 2006 (P2) and 2007 and 2010 (P3), and to analyze AIDS incidence trends in Santarém between 1999 and 2010. Information about variables of interest was obtained by review of medical records. Standardized AIDS incidence rates were calculated, based on cases reported in Santarém, using data obtained from national and local databases. Incidence trend analysis was performed by polynomial regression. Out of 527 records, 62.4% of patients were admitted to the clinic in P3, 24.1% and 13.5% in P2 and P1, respectively. A significant increase was seen in the participation of individuals from cities other than Santarém in P3, as compared to P1. There was a significant gender difference in the reason to be tested for HIV, as women were more likely to have been tested due to a seropositive partner in P1 and P2, whereas existing signs and symptoms of HIV/AIDS predominated among men as the reason for testing throughout the study period. A significant reduction in median CD4+ cell counts at admission was noticed comparing P3 to P1 and P2. 336 AIDS cases were reported in Santarém from 1999 to 2010. An increasing AIDS incidence trend was found for both genders, and for both heterosexual and homo/bisexual among males. The increasing local demand for HIV/AIDS care, with larger numbers of cases coming from smaller cities and admitted in later stages of HIV infection, taken together with the increasing AIDS incidence trend in Santarém during the study period suggest that even though programmatic interventions may have succeeded in identifying more AIDS cases, they were not able to lead to an earlier diagnosis. We believe that the implementation of second generation surveillance strategies in this region could guide programmatic interventions for the control of the epidemic more efficiently, in a context characterized by individual, social and programmatic factors related to a high vulnerability to HIV infection.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Introdução: A epidemiologia é uma ciência que estuda os processos de saúde e doença na população, sejam eles individuais ou coletivos. A lista Nacional de Notificação compulsória teve sua última atualização em 17 de fevereiro de 2016 por meio da portaria nº 204, que define novas doenças, agravos e eventos de saúde nos serviços públicos e privados em todo o território nacional, sendo a comunicação destes acontecimentos obrigatória. A coqueluche, que se encontra na lista das doenças de notificação compulsória, define-se por uma doença infecciosa aguda do trato respiratório inferior sendo seu agente etiológico a bactéria Bordetella pertussis. Apesar dos esforços dispendidos pelo Programa Nacional de Imunizações, da Vigilância Epidemiológica e outros Centros de Vigilância internacionais, no mundo, ainda, estima-se que a cada ano ocorram de 20 a 50 milhões de casos de coqueluche, com aproximadamente 200 a 400 mil mortes, sendo a maior parte em lactentes que não foram vacinados ou com a vacinação incompleta. Mesmo com a disponibilidade da vacina contra difteria, tétano e pertussis incluída no calendário vacinal da criança através da pentavalente, a imunidade não é permanente, surgindo então a pergunta deste estudo: Apenas a vacinação na gestante com dTpa elimina a coqueluche em crianças até dois anos? Objetivo: Analisar em dois municípios do interior do Estado de São Paulo, se as crianças menores de dois anos, filhos de mulheres vacinas pela dTpa tiveram coqueluche. Método: Trata-se de um estudo epidemiológico, observacional descritivo antes e depois de delineamento transversal, sobre avaliação das crianças que desenvolveram a coqueluche, notificadas nos municípios de Botucatu e Marília, interior do estado de São Paulo, no período retrospectivo (2008 a 2014) e prospectivo à vacina da dTpa na gestante (2014 a 2016). Resultados: Percebe-se que há uma carência de publicação sobre a abordagem da coqueluche na criança, sua prevenção, tratamento e controle. Todas as fichas de notificação avaliadas no estudo estavam parcialmente preenchidas, comprometendo a qualidade das informações. Em relação à avaliação comparativa entre os dois municípios em estudo, percebe-se que, no período retrospectivo o número de casos confirmados de coqueluche nos dois municípios totalizou-se em 56 casos, dos quais 25% (14) em Botucatu e 75% (42) em Marília. Já no período prospectivo, após a implantação da vacina ainda houve casos confirmados nos dois municípios, perfazendo 21 casos – 71,42% (15) em Botucatu e 28,58% (6) em Marília – e mesmo havendo redução, os casos ainda persistem apresentando exposição do público vulnerável, crianças menores de um ano a coqueluche. Conclusão: A introdução da dTpa no calendário vacinal da gestante não foi suficiente para impedir a transmissão do microorganismo Bordetella pertussis às crianças com idade inferior a dois anos, conforme a proposta do Ministério da Saúde.
Introduction: Epidemiology is an area of public health aimed at understanding health-disease processes within the population, an aspect that differentiates it from the clinic, since its objective is the study of these processes, individual or collective. The National Compulsory Notification list was last updated on February 17th, 2016 through ordinance No. 204, which defines new diseases, injuries and health events in public and private services throughout the national territory, and the communication is mandatory. Pertussis on the list of compulsorily notifiable diseases is defined as an acute infectious disease of the lower respiratory tract, its etiological agent being Bordetella pertussis. Despite the efforts made by the National Immunization Program (PNI), Epidemiological Surveillance and other International Surveillance Centers, it is still estimated that 20 to 50 million cases of pertussis occur every year, with approximately 200 to 400,000 deaths, most of them in infants who were not vaccinated or had incomplete vaccination. Even though the DTP vaccine is in the child's immunization schedule, immunity is not permanent, so the question arises in this study, only vaccination in the pregnant woman reduces the infection of the Bordetella pertussis bacterium in children up to 4 (four) years? Objective: To analyze in two municipalities of the interior of the State of São Paulo, if children under two years of age, children of dTpa vaccine women had pertussis. Method: This is a descriptive and observational epidemiological study before and after a cross-sectional study on the evaluation of children who developed the disease by the Bordetella pertussis microorganism reported in the municipalities of Botucatu and Marília, in the state of São Paulo, in the period retrospective and prospective study of the dTpa vaccine in the pregnant woman from 2008 to 2016. Results: It is noticed that there is a lack of publication about the pertussis approach in the child its prevention, treatment and control. All of the notification sheets evaluated in the study were partially completed. Regarding the comparative evaluation between the two municipalities under study, it can be seen that in the retrospective period from January 2008 to October 31th, 2014, the number of confirmed cases in the two municipalities was analyzed, in a total of 56 cases, of which 14 (25%) in Botucatu and 42 (75%) in Marília. Since the prospective period analyzed after the implementation of the vaccine from November 1th, 2014 to December 31th, 2016, there are still positive cases in the two municipalities, 21 cases, of which 15 (71.42%) were in Botucatu and six (28.58 %) in Marília, that even reducing still persist presenting risk to the vulnerable public. Conclusion: The introduction of dTpa into the pregnant woman's immunization schedule was not sufficient to prevent transmission of the Bordetella pertussis microorganism to children under two years of age, as proposed by the Ministry of Health.

Background. Susceptibility to a complex disease such as tuberculosis generally involves interactions among several genes and environmental factors. Several association studies have been conducted to examine the association between candidate genes and tuberculosis. However, the genetic risk factors are not fully understood.
Objective. To examine the effect of several candidate genes, including natural resistance associated macrophage protein 1 (NRAMP1), vitamin D receptor (VDR), surfactant proteins (SFTPA1), and mannose-binding lectin (MBL), and also to assess the effect of several risk factors on their association with tuberculosis. The other objectives were to test for mode of inheritance and also to estimate the relative risks of disease for different genotypes.
Methods. A prospective case-parental control study was conducted. Ninety-five nuclear families were selected from an existing database of families with tuberculosis in Ethiopia. Each family consisted of one affected child and two parents. The primary outcome was transmission/nontransmission of alleles from parents to affected offspring.
Results. The transmission disequilibrium test showed that marker SFTPA1-294 was significantly associated with the outcome (chi 2 = 4.297; p = 0.038). When other risk factors such as age, sex, ethnicity, certain symptoms or other genes were allowed to modify the transmission probabilities in a logistic regression model, several other markers were found to be significantly associated with the outcome.
Conclusions. Despite the limitations of this study, this thesis provided evidence for inheritance of susceptibility to tuberculosis in Hadiayan families in Ethiopia. To confirm the findings in this thesis, it would be useful to conduct similar research in populations with different ethnic origins, where genetic and environmental exposures can be examined and compared.

In recent years awareness of childhood obesity as a clinical and public health problem has increased. However, a number of important issues related to childhood obesity were unclear when this thesis began. The aims of this thesis were as follows: 1. To estimate the prevalence of obesity in British and Iranian children. 2. To assess the strengths and weaknesses of the body mass index (BMI) as a way of identifying obese children/estimating obesity prevalence. 3. To investigate the factors associated with early 'adiposity rebound'. 4. To identify risk factors for obesity in British children. This thesis showed that prevalence of childhood obesity in British and Iranian children was significantly higher than expected and that obesity prevalence in children increased during the 1990s. These results are consistent with reports of increased childhood obesity in the USA, Europe, and some other countries. Using BMI 95th centile as the definition of childhood obesity has moderately high sensitivity and high specificity, though a definition of BMI 92nd centile was shown in this thesis to be optimum. This thesis indicated that the typical age of AR in British children must be sometime between 5-7 years. Further research on the factors associated with timing of AR is recommended. A number of independent risk factors for childhood obesity are identified. Parental obesity, birth weight, fizzy drink consumption, and time spent in the car had the strongest association.

Collection of papers submitted to the Faculty of Medicine, University of Cape Town, in fulfilment of the requirements of Part III of the Degree Master of Medicine in Psychiatry.
The following five papers are included in this collection. Paper 1. Flisher AJ, Joubert G, Yach D. Mortality from external causes in South African adolescents, 1984 - 1986. South African Medical Journal 1992; 81: 77-80. Paper 2. Flisher AJ, Chalton DO. High school dropouts in a working-class South African community: selected characteristics and risk-taking behaviour. Journal of Adolescence (in press). Paper 3. Flisher AJ, Roberts MM, Blignaut RJ. Youth attending Cape Peninsula day hospitals. Sexual behaviour and missed opportunities for contraception counselling. South African Medical Journal 1992; 82: 104-106. Paper 4. Flisher AJ, Parry CDH. Suicide in South Africa. An analysis of nationally registered mortality data for 1984-1986. Acta Psychiatrica Scandinavica (in press). Paper 5. Flisher AJ, Parry CDH, Bradshaw D, Juritz J. Suicide in South Africa - seasonal variation. Acta Psychiatrica Scandinavica (to be submitted) .

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system commonly affecting young adults. Pathologically, there are patches of inflammation (plaques) with demyelination of axons and associated loss of oligodendrocytes. Genome-wide association studies have identified over 105 loci of susceptibility, but the total number of possible contributory loci may be considerably higher. Family recurrence risks are available for several northern hemisphere countries, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. The published family data could provide useful recurrence risks if appropriately analysed. Segregation analysis can be used to model the genetic architecture of MS. There is a global latitude gradient in MS prevalence, and the incidence of MS is increasing (particularly in females). These changes suggest a major role for environmental factors in the causation of disease. In the last 20 years there has been increasing evidence for the role of smoking in the aetiology of multiple sclerosis. Cigarette smoking is also associated with increased risk of developing the progressive form of MS. This risk factor has not previously been analysed in Queensland. Furthermore, cigarette smoking represents a possible cause of the changing prevalence of MS over time. Methods The family risks in Australia were measured in three regions at different latitudes. Immediate and extended family pedigrees were collected for three cohorts of MS patients in Queensland, Victoria and Tasmania. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. Meta-analysis of all available family recurrence risk data was performed to define risks to relatives. Standard methods of meta-analysis were combined with novel approaches to age adjustment to provide directly comparable estimates of lifetime risk. Segregation analysis was used to estimate the proportion of the overall genetic risk that can be attributed to identified susceptibility genes. To evaluate risks from smoking in Queensland, a large case-control study was performed, comparing risk of MS (by smoking habit) using regression modelling. The risk of developing progressive disease was measured in a cohort from an MS clinic in Queensland, followed from first clinic attendance until the onset of clinically determined progressive disease. Risk of progression was analysed with gender, age, age of onset, exposure to disease modifying therapy, and smoking status as covariates in a Cox proportional hazards analysis. Finally, a comprehensive meta-analysis was performed of eligible casecontrol and cohort studies that evaluated the risk of MS in smokers and exsmokers. The influence of study design, gender, latitude and year of study were explored with regression modelling. Results Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.1% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the relative risk for siblings (lS) was similar across all sites. From the meta-analysis of family recurrence risks, the overall recurrence risk for monozygotic twins was 18.2% and for siblings 2.7%. The recurrence risk for dizygotic twins was significantly higher than for siblings. The overall estimate of sibling relative risk (lS) was 16.8. Risks for older relatives (parents, siblings, aunts, uncles and cousins) show a latitudinal gradient, in line with population risk. No latitudinal gradient for lS was seen. Segregation analysis supports a multiplicative model of one locus of moderate effect with many loci of small effect. The estimated contribution of the known MS loci is 18–24% of lS. The case-control study in Queensland confirmed an association between increased risk of MS and smoking. The overall adjusted odds ratio was 1.9 (95% confidence interval, CI 1.5–2.5) for ever smokers. There was no statistically significant difference in the risks for males and females. In the progression study, there were significantly higher risks of secondary progressive disease in males (Hazard Ratio, HR 1.83, 95% CI 1.3–2.7) and in ever smokers (HR 1.4, 95% CI 1.0–2.0). Progressive disease occurred approximately 4 years earlier in ever smokers. Smoking did not affect age of onset of primary progressive disease. The meta-analysis of smoking risk included 26 studies representing 8615 cases and 392,352 controls and an additional 792 cases included from a total cohort population of 601,492 individuals, representing more than 9 million person-years. There was a consistent association between smoking and MS with an odds ratio of approximately 1.5, with males at higher risk. This finding was independent of study design. However, latitude and year of study may have unexpected influence. Smoking appeared to confer a greater risk to females living closer to the equator than to females at higher latitudes. Additionally, the effect of cigarette smoke exposure on MS risk may not be fixed over time, but could be increasing. Discussion The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the lS is similar to that seen in the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture. The meta-analysis of family data supports the notion of MS risk being derived from multiple susceptibility genes and environmental factors. Genetic susceptibility appears to be independent of latitude, and the latitudinal gradient of MS prevalence is likely due to environmental factors. The results of the case-control study in Queensland replicate existing work that has shown cigarette smoking increases the risk of MS. Cigarette smoking represents an important modifiable risk factor for the development of MS. Cigarette smoking was also associated with earlier onset of progressive disease in the large clinical cohort studied in Queensland. For patients with relapsing-remitting disease, smoking cessation should be encouraged. The results of the meta-analysis of smoking studies suggest a threshold model of MS risk that includes a fairly constant genetic risk (for Caucasian populations) together with variable environmental risks which are dominated by vitamin D deficiency at higher latitudes and are more significant in women who have an intrinsically lower threshold for development of disease.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medicine
Griffith Health
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Este trabalho é baseado em um estudo observacional, prospectivo e longitudinal, com o objetivo de analisar a prevalência, as formas de tratamento e os índices de complicações dos casos de trauma de face atendidos pela Área de Cirurgia Buco-Maxilo-Facial da Faculdade de Odontologia de Piracicaba (FOP) ? Unicamp, na cidade de Piracicaba e região, no período de abril de 1999 a março de 2004. Foram incluídos no estudo 1857 pacientes, cuja análise estatística descritiva demonstrou uma prevalência por indivíduos do gênero masculino (76,8%), da cor branca (58,6%), predominantemente na faixa etária de 21 a 30 anos (27%) e pertencentes ao grupo de pessoas economicamente ativas da população (52,3%). A etiologia mais freqüente destes traumatismos foram os acidentes de trânsito (45,8%), predominantemente os acidentes ciclísticos, fortemente caracterizados por baixos índices de uso de dispositivos de segurança. O atendimento inicial aos pacientes foi realizado principalmente pelo SUS (88,2%) e dentro de 48 horas após o trauma em 69,3% dos casos, sendo que 38,1% dos pacientes com indicação de tratamento cirúrgico foram operados entre 8 e 15 dias após o traumatismo. Dentre as fraturas faciais, houve predominância na região do terço médio da face (56,4%), porém com maior acometimento do osso mandibular (41,3%). As lesões de tecidos moles da face foram representadas principalmente pelas lacerações (31,8%) e abrasões (28,6%). Dos pacientes com trauma de face, 41,1% apresentou também outras lesões corporais associadas, sendo as mais comuns localizadas nos membros superiores (24,1%) e membros inferiores (15,4%). Quanto às formas de tratamento, 55,6% dos casos foram conduzidos conservadoramente, 42,2% foram submetidos ao tratamento cirúrgico e 2,2% dos casos não receberam tratamento algum. A fixação interna rígida por meio de placas e parafusos foi a principal forma de tratamento quando as fraturas faciais foram submetidas à redução aberta e fixação (99,8%). As complicações foram observadas em 4,4% de todos os casos atendidos, sendo a infecção o tipo mais comum (43,7% dos casos com complicações). Portanto, avaliações periódicas da epidemiologia dos traumatismos faciais permitem uma análise detalhada sobre estas lesões, que assistem na instituição de prioridades clínicas e de pesquisa para um melhor atendimento e prevenção de traumatismos futuros. _________________________________________________________________________________________ ABSTRACT: This study is based on an observational, prospective and longitudinal research with the purpose of analyzing the prevalence, treatment modalities and complications rates of the facial trauma attended by the Division of Oral and Maxillofacial Surgery of Piracicaba Dental School ? Unicamp occurred in the region of Piracicaba from April 1999 to March 2004. A total of 1,857 patients were included in the study, and analysis of obtained data demonstrated a prevalence for males (76.8%), white individuous (58.6%), most of them in the 3th decade of life (27%) and afflicting people economically active (52.3%). The main etiological factor was traffic accident (45.8%), predominantly involving bicycle accidents, roughly associated to low scores of protective devices use. The initial care was carried out in 88.2% of cases through public health insurance and within the first 48 hours after the injury in 69.3% of patients. The majority of patients (38.1%) who required surgical interventions were operated between the days 8 and 15. According to the facial fractures, there was a greater incidence of middle third facial fractures (56.4%), although the bone most fractured was the mandible (41.3%). The soft tissue lesions were mainly represented by lacerations (31.8%) and abrasions (28.6%). Associated body lesions were diagnosed in 41.1% of patients sustaining facial injury, especially those involving the upper limbs (24.1%) and lower limbs (15.4%). Patients were treated conservatively in 55.6% of cases, surgically in 42.2% of cases and no treatment was instituted in 2.2% of patients. Rigid internal fixation using plates and screws were performed in 99.8% of patients requiring open surgery and fixation of facial fractures. Complications developed in 4.4% of all cases evaluated and infection was responsible for 43.7% of cases of complications. Therefore, regular epidemiologic evaluations of facial injuries allow a detailed analysis of theses lesions providing important support to install clinical and research priorities. This may improve attendance and prevention of maxillofacial injuries in the future.

Orientador: Luis Augusto Passeri
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Este trabalho é baseado em um estudo observacional, prospectivo e longitudinal, com o objetivo de analisar a prevalência, as formas de tratamento e os índices de complicações dos casos de trauma de face atendidos pela Área de Cirurgia Buco-Maxilo-Facial da Faculdade de Odontologia de Piracicaba (FOP) ¿ Unicamp, na cidade de Piracicaba e região, no período de abril de 1999 a março de 2004. Foram incluídos no estudo 1857 pacientes, cuja análise estatística descritiva demonstrou uma prevalência por indivíduos do gênero masculino (76,8%), da cor branca (58,6%), predominantemente na faixa etária de 21 a 30 anos (27%) e pertencentes ao grupo de pessoas economicamente ativas da população (52,3%). A etiologia mais freqüente destes traumatismos foram os acidentes de trânsito (45,8%), predominantemente os acidentes ciclísticos, fortemente caracterizados por baixos índices de uso de dispositivos de segurança. O atendimento inicial aos pacientes foi realizado principalmente pelo SUS (88,2%) e dentro de 48 horas após o trauma em 69,3% dos casos, sendo que 38,1% dos pacientes com indicação de tratamento cirúrgico foram operados entre 8 e 15 dias após o traumatismo. Dentre as fraturas faciais, houve predominância na região do terço médio da face (56,4%), porém com maior acometimento do osso mandibular (41,3%). As lesões de tecidos moles da face foram representadas principalmente pelas lacerações (31,8%) e abrasões (28,6%). Dos pacientes com trauma de face, 41,1% apresentou também outras lesões corporais associadas, sendo as mais comuns localizadas nos membros superiores (24,1%) e membros inferiores (15,4%). Quanto às formas de tratamento, 55,6% dos casos foram conduzidos conservadoramente, 42,2% foram submetidos ao tratamento cirúrgico e 2,2% dos casos não receberam tratamento algum. A fixação interna rígida por meio de placas e parafusos foi a principal forma de tratamento quando as fraturas faciais foram submetidas à redução aberta e fixação (99,8%). As complicações foram observadas em 4,4% de todos os casos atendidos, sendo a infecção o tipo mais comum (43,7% dos casos com complicações). Portanto, avaliações periódicas da epidemiologia dos traumatismos faciais permitem uma análise detalhada sobre estas lesões, que assistem na instituição de prioridades clínicas e de pesquisa para um melhor atendimento e prevenção de traumatismos futuros
Abstract: This study is based on an observational, prospective and longitudinal research with the purpose of analyzing the prevalence, treatment modalities and complications rates of the facial trauma attended by the Division of Oral and Maxillofacial Surgery of Piracicaba Dental School ¿ Unicamp occurred in the region of Piracicaba from April 1999 to March 2004. A total of 1,857 patients were included in the study, and analysis of obtained data demonstrated a prevalence for males (76.8%), white individuous (58.6%), most of them in the 3th decade of life (27%) and afflicting people economically active (52.3%). The main etiological factor was traffic accident (45.8%), predominantly involving bicycle accidents, roughly associated to low scores of protective devices use. The initial care was carried out in 88.2% of cases through public health insurance and within the first 48 hours after the injury in 69.3% of patients. The majority of patients (38.1%) who required surgical interventions were operated between the days 8 and 15. According to the facial fractures, there was a greater incidence of middle third facial fractures (56.4%), although the bone most fractured was the mandible (41.3%). The soft tissue lesions were mainly represented by lacerations (31.8%) and abrasions (28.6%). Associated body lesions were diagnosed in 41.1% of patients sustaining facial injury, especially those involving the upper limbs (24.1%) and lower limbs (15.4%). Patients were treated conservatively in 55.6% of cases, surgically in 42.2% of cases and no treatment was instituted in 2.2% of patients. Rigid internal fixation using plates and screws were performed in 99.8% of patients requiring open surgery and fixation of facial fractures. Complications developed in 4.4% of all cases evaluated and infection was responsible for 43.7% of cases of complications. Therefore, regular epidemiologic evaluations of facial injuries allow a detailed analysis of theses lesions providing important support to install clinical and research priorities. This may improve attendance and prevention of maxillofacial injuries in the future
Mestrado
Cirurgia e Traumatologia Buco-Maxilo-Faciais
Mestre em Clínica Odontológica

Orientador: Roger William Fernandes Moreira
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Este estudo retrospectivo teve por objetivo avaliar as características epidemiológicas da prevalência, tratamento e taxas de complicação das fraturas dos côndilos mandibulares. Os dados foram coletados dos prontuários do arquivo da Área de Cirurgia Buco-Maxilo-Facial da Faculdade de Odontologia de Piracicaba/Unicamp no período de 1999 a 2007. Foram encontrados 263 pacientes com 317 fraturas de côndilo mandibular. Houve 209 pacientes com fraturas unilaterais e 51 com fraturas bilaterais; com a proporção de 3,05:1 entre homens e mulheres respectivamente; média de idade de 28,4 anos; e predominância da raça branca. A causa mais comum de fratura condilar foram os acidentes de trânsito (57,8%). De forma geral, os dispositivos de proteção induziram uma redução nas fraturas condilares em acidentes de trânsito, contudo o capacete apresentou os piores índices de proteção que o cinto de segurança. As fraturas foram comumente associadas a outros tipos de trauma, sendo relação com a fratura de sínfise e a laceração em mento estatisticamente relevante. O tratamento conservador foi o mais aplicado com 78,55%, principalmente nas fraturas unilaterais, contra 21,45% dos tratamentos cirúrgicos, aplicados em maiores proporções nas fraturas bilaterais. A taxa de complicações foi menor no tratamento conservador com 7,9%, frente aos 33,33% no tratamento cirúrgico, o qual está exposto a mais variáveis como a acesso cirúrgico e a fixação interna rígida. A complicação mais comum foi a má-oclusão tanto no tratamento cirúrgico quanto no conservador. Houve uma relação significativa entre o consumo de substâncias nocivas a saúde (39,16% dos pacientes) e as complicações. Concluiu-s e q u e população afetada tem características urbanas, formada principalmente por adultos jovens do gênero masculino. O tratamento mais empregado é o conservador, o qual possui menores taxas de complicação, mas que não exclui o tratamento cirúrgico.
Abstract: The aim of this study was to evaluate the epidemiological characteristics of prevalence, treatment modalities and complication rates of the condylar fractures of the mandible. Data was collected from patients' records of Oral and Maxillofacial Surgery Area at Piracicaba Dental School - Unicamp from 1999 to 2007. The research results a sample of 263 patients with 317 condylar fractures. There were 209 unilateral fractures and 54 bilateral fractures, with a male:female ratio of 3.05:1,amean age of 28.4 years and white race predominance. Protective devices statistically decreased the prevalence of condylar fractures in car and bicycles accidents; however, seatbelts presents lesser protection in comparison with helmets. Fractures were usually associated with others traumas, with symphysis fracture and soft tissue injury to the chin region the most common ones. The conservative treatment was applied in 78.55%, mainly in unilateral fractures, against 21.45% of the surgical treatment, applied in the majority of the bilateral cases. The complication rate was lesser in the conservative treatment with 7.9%, in comparison with 33.33% of the surgical treatment cases that are more vulnerable to variables like surgical access and rigid internal fixation. The most common complication was malocclusion, both in surgical and non-surgical treatments. There were a significant relation between the use of harmful substances and complications (39.16% of the patients). In conclusion, the population affected had urban characteristics and is composed mainly by male young adults. The most adopted treatment was the conservative, that presented lesser complication rates, but it does not exclude the surgical treatment in some specific cases.
Doutorado
Cirurgia e Traumatologia Buco-Maxilo-Faciais
Doutor em Clínica Odontológica

Orientador: Roger William Fernandes Moreira
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: O presente estudo retrospectivo teve por objetivo avaliar a complexidade dos traumatismos faciais decorrentes de acidente de trânsito considerando diagnóstico, tratamento e complicações e relacioná-los com o uso de dispositivos de segurança. Os dados foram coletados dos prontuários do arquivo da Área de Cirurgia Buco-Maxilo-Facial da Faculdade de Odontologia de Piracicaba/Unicamp no período de 1999 a 2007. A amostra foi de 657 pacientes dos quais 76,7% foram vítimas de acidente automobilístico e 23,3% de acidente motociclístico. Pacientes do gênero masculino e na faixa etária de 18 a 30 anos (63,7%) sofreram um maior número de acidentes de trânsito. Quanto à utilização do dispositivo de segurança de trânsito foi mais freqüente no gênero masculino e entre os motociclistas (73,8%). O tipo de trauma facial mais freqüente foram as fraturas ósseas (68,6%) localizadas no terço médio e na mandíbula. Em relação aos traumas associados à outros órgãos observou-se uma maior associação entre os traumas faciais e traumas ortopédicos, verificando-se uma maior freqüência (60,7%) em pacientes que não estavam utilizando nenhum tipo de dispositivos de segurança. O tratamento conservador foi o mais aplicado em 70,5% dos pacientes e a infecção foi a complicação mais freqüente. Os acidentes de trânsito ocorreram com maior freqüência nos pacientes adultos jovens do gênero masculino e os traumas de face associados a de outros órgãos quando as vítimas não estavam utilizando dispositivo de segurança. Dessa forma as campanhas educacionais e preventivas devem ser direcionadas para este público
Abstract: This retrospective study had as aim to evaluate the complexity of facial trauma due to traffic accident, considering diagnosis, treatment and complications and to relate them to the use of safety tools. The data were collected from the patient files of the department of Oral and Maxillo Facial Surgery in the Piracicaba/Unicamp Dental School in the period of 1999 to 2007. The sample consisted of 657 patients from wich 76,7% were car accident victms and 23,3% were motorcycle accident victms. Male Patients in the age range of 18 to 30 years old (63,7%) suffered a higher number of traffic accidents. Regarding to the use of traffic safety tools, the frequency was higher for male motorcycle users (73,8%). The most frequent types of facial trauma were bone fracture (68, 6%) located in the middle third of the face and mandible. Regarding to the trauma associated to other organs, it was observed a higher association between facial trauma and orthopedic trauma, with a higher frequency (60, 6%) in patients without safety traffic tools. The most applied treatment was the conservative in 70,5% of the patients and infection was the most frequent complication. The traffic accidents happened in a higher frequency in male young adults and the facial trauma associated to other organs occurred when the victims did not used safety tolls. Thus, preventive and educational campaigns should be targeted to this public
Doutorado
Cirurgia e Traumatologia Buco-Maxilo-Faciais
Doutor em Clínica Odontológica

Orientador: Roger William Fernandes Moreira
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Este trabalho foi baseado em um estudo observacional, seccional, retrospectivo do tipo caso-controle, com o objetivo de analisar a prevalência e características epidemiológicas da associação entre traumas faciais e traumas cervicais nos pacientes atendidos pela Área de Cirurgia Buco-Maxilo-Facial da Faculdade de Odontologia de Piracicaba (FOP)-Unicamp, na cidade de Piracicaba e região, no período de abril de 1999 a dezembro de 2009. Um total de 3095 pacientes com trauma facial foi incluído na amostra. Pacientes apresentando trauma facial e alguma forma de trauma cervical concomitantemente corresponderam a 76 (2,5%) casos onde a análise estatística descritiva demonstrou uma prevalência por indivíduos do gênero masculino (81,6%), de cor branca (60,0%) predominantemente na faixa etária de 21 a 30 anos (27,9%). A etiologia mais frequente destes traumatismos foram os acidentes de trânsito (63,2%). Dentre as fraturas faciais, houve maior prevalência na região mandibular (57,5%), seguida pelas fraturas zigomáticas (30,0%). Estiveram também associadas aos traumatismos cervicais, as lesões de tecidos moles da face (39,4%) e dento-alveolares (7,8%) isoladamente. Nos pacientes do grupo estudo que concomitantemente apresentaram lesões traumáticas em outras áreas do corpo, as mais frequentes foram nos membros superiores (47,3%) e no tórax (44,7%). Foi possível observar que na presença de trauma facial, há chance de ocorrência de lesão traumática cervical concomitante, dessa forma, requerendo atenção e cuidado para o seu tratamento
Abstract: This study was based on an observational, seccional, retrospective, case control study with the aim of analyze the prevalence of association of facial trauma and cervical trauma in patients attended by the Division of Oral and Maxillofacial Surgery of Piracicaba Dental School - Unicamp occurred in Piracicaba region from april1999 and December 2009. A total of 3095 patients of facial trauma were included in the study. Patients with concomitant facial and some kind of cervical trauma corresponded to 76 (2,5%) cases wich data analysis demonstrated a prevalence for males (81,6%), white subjects (60,0%) predominantly in the third decade of life (27,9%). The main etiological factor was traffic accident (63,2%). Among facial fractures, there was a major prevalence at the mandibular region (57%), followed by zygomatic fractures (30,0%). Soft tissue lesions (39,4%) and dental trauma (7,8%) where associated with cervical trauma too. For study group patients presenting other body traumas simultaneously, upper limbs (47,2%) and chest (44,7%) were more frequent. It was possible to note that in the presence of facial trauma, that's a chance of occurring concomitant cervical traumatic lesion, therefore, requiring attention and caution in its treatment
Doutorado
Cirurgia e Traumatologia Buco-Maxilo-Faciais
Doutor em Clínica Odontológica

Orientador: Marcelo de Castro Meneghim
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba
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Resumo: Até o ano de 2025 o Brasil será o sexto país do mundo em maior número de idosos. Estima-se que os mesmos irão constituir em 2050 29,7% da população. Segundo dados do levantamento SB Brasil 2010, 15,8% necessita de prótese total em ambas as arcadas e 21% de prótese parcial em um dos arcos. O objetivo deste estudo foi investigar a associação entre as condições de saúde bucal de idosos não institucionalizados e as variáveis sociais, autopercepção, condição cognitiva e depressão. Amostra composta por 78 idosos independentes e parcialmente dependentes, com média de idade de 68,5 anos, ambos os gêneros, dentados ou não. Utilizou-se para a avaliação clínica o índice CPOD (OMS,1999), o índice de placa de O'Leary (1972) índice de placa para próteses de Shubert & Shubert (1979) e índice gengival de Loe e Silness (1963). Para avaliar a autopercepção foi aplicado o Geriatric Oral Health Assessment Index (GOHAI)(Atchison & Dolan, 1990) além de responderam a uma questão aberta. Para apontar a presença da depressão nessa amostra foi aplicado o Geriatric Depression Scale (GDS) (Almeida & Almeida, 1999) e para avaliar estado de cognição empregou-se o Mini-Exame do Estado Mental (MMental) (Folnstein et al, 1975). A estatística foi realizada utilizando-se o teste qui-quadrado e exato de Fisher com nível de significância de 5% e de 10%, para a questão aberta utilizou-se a Análise de Conteúdo de Bardin, 2011. Os resultados obtidos apresentaram um CPOD médio para coroa de 24,5 e para raiz de 21,5. O GOHAI médio encontrado de 31,92 (autopercepção moderada); GDS médio de 3,15 com 25,7% da amostra com sugestão de depressão leve a profunda; MMental de 21,7 com 91,1% dos indivíduos com cognição normal. Na avaliação do Índice de Placa de O'Leary, 69,4% estavam excelentes e no índice de Placa de prótese 86,1% estavam excelentes. Na questão aberta a categoria mais citada foi problemas com a mastigação. Concluiu-se com esse estudo que dentre as variáveis sociais, o estado civil apresentou associação com necessidade de prótese em ambas as arcadas; a autopercepção em saúde bucal de moderada a alta (GOHAI) apresentou associação significativa com não necessidade de prótese; o estado cognitivo (MMental) não apresentou associação com uso e necessidade de prótese; o GDS apresentou associação significativa com o uso de prótese em ambas as arcadas
Abstract: By the year 2025, Brazil will be the sixth country in the world in greater numbers of elderly. It is estimated that they will be in 2050 30.0% of the population. According to the SB Brazil 2010 survey, 15.8% need dentures in both arches and 21% partial denture in one of the arches. The objective of this study was to investigate the association between oral health status of non-institutionalized elderly and social variables, selfperception, cognitive status and depression. Sample composed of 78 independent and partially dependent elderly, mean age 68.5 years, both genders, serrated or not. Was used to evaluate the clinical DMFT (OMS1999), plaque index of O'Leary (1972), plaque index for prosthetic & Shubert Shubert (1979) and gingival index of Loe and Silness (1963). To evaluate the perception was administered the Geriatric Oral Health Assesment (GOHAI) (Atchison & Dolan, 1990) and respond to an open question. To point to the presence of depression in this sample was applied to the Geriatric Depression Scale (GDS) (Almeida & Almeida, 1999) and to assess the state of cognition we used the Mini-Mental State Examination (Mmental) (Folstein et al., 1975.) Statistical analysis was performed using the chi-square and Fisher's exact with significance level of 5% and 10% for the open question was used Bardin's Content Analysis (2011). The results showed a mean DMFT of 24.5 for crown and root of 21.5. The GOHAI average of 31.92 found (moderate self); GDS average of 3.15 with 25.7% of the sample with the suggestion of mild to profound depression; Mmental average of 21.7 with 91.1% of individuals with normal cognition. In assessing the O'Leary plaque index, 69.4% were excellent and the plaque index prosthesis were 86.1% excellent. In the open question was the category most frequently cited problems with chewing. It was concluded from this study that among the social variables, marital status was associated with need for prostheses in both arches; self-perception of oral health from moderate to high (GOHAI) showed significant association with no need for prostheses; the cognitive state (Mmental) was not significantly associated with the use of prostheses in both arches
Mestrado
Saude Coletiva
Mestre em Odontologia

Realizamos uma investigação epidemiológica em uma zona que fora inundada pela rio Aricanduva e seus afluentes, a leste do município de São Paulo, em 61 coabitantes de casos confirmados laboratorialmente de leptospirose humana ocorridos em 1983, residentes nessa área, com o objetivo de conhecer o nível de infecção por leptospiras nesse grupo de pessoas. Para pesquisa de anticorpos anti-leptospiras realizamos o teste de soroaglutinação microscópica nas 61 amostras de soro colhidas, tendo sido considerado soro reagente aquele que apresentou um título mínimo igual ou superior a 1:100. Para diferenciarmos se a infecção encontrada era recente ou passada, além de outros dados epidemiológicos investigamos a presença de anticorpos da classe IgM nesses soros por meio da prova de hemaglutinação passiva, considerando significante o título igual ou maior que 1:128. Os resultados nos mostraram que 18 pessoas, ou seja 29,6 por cento dos coabitantes eram de prendas domésticas, enquanto que 18,2 por cento eram menores e 6,6 por cento eram aposentados; 6,6 por cento eram operários não qualificados, ficando outras ocupações com 3,3 por cento ou 1,6 por cento . Em relação ao meio ambiente, as unidades residenciais investigadas eram diferentes daquelas descritas na literatura no tocante a casos de leptospirose humana. Estas apresentavam codições de urbanismo, ou seja, eram servidas por transporte coletivo nas proximidades em 95,8 por cento , tinham iluminação pública em 79,2 por cento , apresentavam ruas pavimentadas em 75 por cento , além de serem servidas por rede de esgoto em 70,8 por cento e por rede pública de abastecimento de água em 100. por cento . Quanto ao tipo de construção, 100 por cento era de alvenaria. Em relação a fatores que poderiam favorecer a infecção humana por leptospiras verificamos que quase 90 por cento das unidades residenciais estudadas tinham terrenos baldios a menos de 100 m de distincia, 58,4 por cento apresentavam ratos ou nas próprias dependências ou nas suas proximidades e 79,1 por cento das casas estavam localizadas até 200 m de correntes fluviais. Dos 61 coabitantes estudados, 42 (67,8 por cento ) tiveram um ou mais contato com enchentes, a maioria das quais ocorreram nos meses de janeiro e fevereiro de 1983, época aproximada em que 127 (63,5 por cento ) dos 200 doentes desse ano também o fizeram. Quanto ao nível de infecção, encontramos 6(9,8 por cento ) amostras de soro, reagentes para os sorotipos panama (2), copenhageni (1), javanica (2) e patoc (1). Todos esses dados sugeriram influência do binômio enchente-população murina sobre esse nível de infecção. As 61 amostras de soro examinadas foram negativas para pesquisa de IgM fazendo-nos considerar os soros reagentes como relativos a uma infecção passada, presumivelmente relacionados à época de infecção do caso.
It was investigated actual leptospirosis prevalence, using epidemiological methodology, in a zone that was flood in 1983 by Aricanduva river and their tributaries situated at the east side of São Paulo country. On that time, this zone was affected by human leptospirosis, diagnosticated through laboratory. The population selected for the present survey was a group of 61 human beings who dwelled together with subjects affected by leptospirosis, in order to establish the actual level of infection by leptospira remaining on such a population. In 61 serum samples it was determined the antileptospira anti-body activity following microscopic agglutination test, considering as a reagent serum that having a lower tittle equal or higher than 1:100. In order to differentiate if the infection was either recent or anciently adquired, it was investigated, together with epidemiological data, the presence of antibodies concerning to IgM class using passive hemagglutination test, considering as significant a tittle equalor higher than 1:128. The population distribution according to the occupational activities showed that 29,6 per cent (18subjects) belonged to home task category, 18,2 per cent were children, 6,6 per cent were retired by social security laws, 6,6 per cent non-qualified manual workers. The rest of surveyed population belonged to indetermined or to different labor activities. In relation to living environment, the residential units were different to those previously descrived in cases of human leptospirosis. Houses showed characteristics of an urban environment, having 95,8 per cent a public transport system, 79,2 per cent had public lighting, 75 per cent had streets with pavement, 70,8 per cent showed drainage system and 100 per cent drinking water service. Masonry was detected in 100 per cent of buildings. Those factors which could favor human infection development by leptospira were also studied. It was verified that 90 per cent of residential units showed uncultivated yards in a radio lower to 100 m around the house, 58,4 per cent of cases studied had rats in or near the house and 79,1 per cent of houses were localized near the river (less than 200m). 67,8 per cent (42 subjects) had the chance to contact with flood water once or many times, ocurred most of them, during the months of january or february 1983. At that time, also 127 from 200 patients affected by leptospirosis (63,5 per cent ) had a similar chance of contact with flood water in 1983. It was found that 9,8 per cent (6 cases) of serum samples showed reagents for serovars panama (2), copenhageni (1), javanica (2) and patoc (1). All the data obtained from this research suggest the influence of flood-rat population binomial on the level of infection detected. Looking for IgM, 61 serum samples were found negative, which could be interpreted as the serum reagents were compatible with an past infection, may be related to the time of infection of the cases considered as leptospirosis in 1983.

O objetivo geral deste trabalho é contribuir para o desenvolvimento tanto da Epidemiologia, campo de investigação do processo saúde-doença na sociedade, como do conhecimento epidemiológico sobre a desnutrição proteico-energético (DPE) em crianças brasileiras. Procurou-se aplicar a interpretação materialista-histórica na construção de um modelo teórico explicativo da ocorrência endêmica da DPE. Esta análise teórica orientou a elaboração de um diagnóstico conjuntural e também a escolha de características individuais e familiares que melhor expressasse o vínculo das condições biológicas com as sociais. Os dados empíricos referem-se ás crianças menores de dois anos de uma amostra de 12 por cento da população civil não institucionalizada da cidade de Botucatu-SP. Foram colhidos no período compreendido entre abril de 83 a março de 84, por um inquérito antropomêtrico-social executado mediante entrevistas domiciliares. O estado nutricional foi avaliado pelo perfil do crescimento (distribuições centilares do comprimento/idade e do peso/comprimento em relação ao padrão NCHS/USA), e pela prevalência da DPE (deficiência de peso, segundo Gómez, em relação ao padrão Santo André IV). Utilizaram-se as informações sobre a idade da criança, os rendimentos familiares, a escolaridade da mãe e o peso ao nascer para analisar o estado nutricional. O estado nutricional encontrado mostrou-se compatível com as condiçbes de desenvolvimento locais e regionais, expressando um padrão médio de consumo alimentar e de outros bens básicos melhor do que o observado em outras regiões brasileiras. Encontrou-se risco de DPE à partir dos seis meses de idade semelhante ao encontrado para o segundo ano de vida. Explicou-se tal achado pelo maior grau de exposição das crianças daquela faixa etária a conjuntura mais adversa do período em foco. Rendimentos familiares inferiores a 1,28 salários-mínimos \"per-capita\", escolaridade materna inferior ao primário (menos que 4 anos) e peso ao nascer inferior a 2.500g mostraram-se associados a maiores riscos de DPE. Rendimentos familiares de 1,5 ou mais salários mínimos \"per-capita\" e escolaridade superior (12 ou mais anos) mostraram-se isentos de DPE moderada, grau II. Peso e comprimento mostraram-se correlacionados diretamente com o peso ao nascer, mais fortemente para menores de 1 ano e para rendimentos familiares de 1 salário-mínimo \"per capita\" ou mais. Recomendou-se o esclarecimento das relações do tipo de parto com peso ao nascer e aleitamento materno em futuras investigações. Recomendou-se também a aplicação de algumas das conclusões para a melhoria dos serviços de assistência à criança.
The objective of this work is to contribute to the development of Epidemiology, field of study of the health/illness process in society and to the epidemiclogic data on the protein-energy malnutrition (PEM) in Brazil. A materialistic and historical approach was applied in arder to build a theoretical model which could explain the endemic occurrence of PEM. All children under 2 years of age encountered in a 12 per cent stratfied sample of the population of Botucatu were studied from April 1983 te March 1984. A crosssectional anthropometric and social survey of the children at home was carried out. The nutritional status was evaluated by i) the growth profile, considering the age, height and weight, according to NCHS/USA standards, and ii) prevalence of PEM according to Gòmez\'s criteria and Santo Andre IV standards. The nutritional status was correlated with the child\'s age, family income, the mother\'s schooling and birthweight. The overall children\'s nutritional status was compatible with the present local and regional conditions of development and was considered to be satisfactory when compared to other brazilian areas. The prevalence of PEM from the 6th month was higher than that of the first six months and remained unchanged up to the 23rd month. This early rise in prevalence of PEM was attributed to a particular and transitory situation which was related to a socio-economic crisis in the country. The investigation showed some risk factors for PEM such as family income below 1.28 minimum wage, mother with less than 4 years of shooling, birthweight below 2.500 g. It was showed a positive relationship between the present weight and height with the birthweight. This relationship was even stronger for the under one year old children and to those belonging to families with the income of one minimum wage \"per capita\". It is suggested that relationship among the variables \"kind of delivery, birthweight value and breastfeeding duration\" should deserve further studies. PEM was not detected among families with income higher than 1.5 minimum wage \"per capita\" and mother with university degree. The investigation opened new avenues for further studies and sugests some practical issues to be considered in the planning of child health care services.

La candidemia es una de las manifestaciones clínicas más frecuentes de la infección fúngica invasora, con una incidencia globalmente superior a la aspergilosis y una elevada morbi-mortalidad asociada. El colectivo de pacientes susceptibles para desarrollar esta infección es amplio y heterogéneo, siendo especialmente vulnerables los pacientes afectos de una enfermedad neoplásica, aquellos ingresados en las Unidades de Cuidados Intensivos (UCIs) y la población neonatal. Sin embargo, la candidemia es una infección en constante evolución, cuyos cambios epidemiológicos se relacionan estrechamente con las prácticas sanitarias. Por ello, conocer su epidemiología, la distribución de especies de Candida y el patrón de resistencia a los diferentes antifúngicos en cada zona geográfica es fundamental para guiar la selección de un tratamiento empírico adecuado y mejorar así el pronóstico de los pacientes. En este contexto clínico, a principios de la década del año 2010, aún existían en España lagunas de conocimiento a nivel epidemiológico, microbiológico y clínico-terapéutico sobre el manejo de la candidemia. Por este motivo, entre mayo del año 2010 y abril del 2011 se realizó el primer estudio poblacional nacional (estudio CANDIPOP) que pretendía resolver estas cuestiones a partir de la información obtenida en cinco grandes áreas metropolitanas: Barcelona, Bilbao, Madrid, Sevilla y Valencia. La presente tesis doctoral “Epidemiología y optimización del manejo clínico de la candidemia: Resultados de un estudio poblacional en España”, escrita como un compendio de 4 publicaciones muestra los principales resultados del estudio CANDIPOP. El primer artículo, “Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain” proporciona una perspectiva global del problema y una estimación de la incidencia de la candidemia en nuestro entorno geográfico. En resumen, la incidencia poblacional de candidemia fue de 8,1 casos/100.000 habitantes/año y las especies predominantes fueron Candida albicans (45,4%), C. parapsilosis (24,9%) y C. glabrata (13,4%). La sensibilidad global a fluconazol fue del 79%. La mortalidad acumulada a los 7 y 30 días fue del 12,8% y del 30,6%, respectivamente. En el análisis multivariado se observó que el inicio de un tratamiento antifúngico adecuado en las primeras 48 horas (OR 0,51, IC95% 0,27–0,95) y la retirada precoz del catéter venoso central (OR 0,43, IC95% 0,21–0,87) estaban asociados con una menor mortalidad a los 7 días. En contraposición, la mortalidad tardía (8-30 días) estaba asociada principalmente con las comorbilidades propias del paciente y con una presentación clínica grave de la infección. Los artículos segundo y tercero, “Impact of therapeutic strategies on the prognosis of candidemia in the intensive care unit “ y “Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain” se centran en dos subpoblaciones de alto riesgo para desarrollar un episodio de candidemia, como son los enfermos adultos ingresados en las UCIs y los pacientes con una neoplasia oncohematológica de base. El objetivo de ambos trabajos es proporcionar nuevos conocimientos que permitan optimizar las estrategias terapéuticas en grupos poblacionales con características propias diferenciales. Finalmente, el cuarto artículo, “Propensity score analysis of the role of initial antifungal therapy in the outcome of Candida glabrata bloodstream infections”, evalúa la eficacia de fluconazol en comparación con las equinocandinas y/o anfotericina B liposomal como tratamiento inicial de la candidemia por C. glabrata. Los resultados de este análisis muestran que el tratamiento inicial con fluconazol no se asocia con un peor pronóstico de los pacientes (OR para mortalidad a los 14 días: 1,16, IC95% 0,22-6,17 y OR para fracaso terapéutico: 0,83, IC95% 0,27-2,61). Estos datos sugieren que en contextos epidemiológicos con una baja tasa de resistencias a fluconazol, este antifúngico aún podría ser una opción razonable como tratamiento empírico de la candidemia, antes de tener la identificación de especie y descartar la posibilidad de una infección por C. glabrata.
Candidaemia is one of the most common manifestations of invasive fungal infection, with an incidence higher than aspergillosis and significant morbidity and mortality. A large and heterogeneous group of patients is susceptible to develop this infection, being especially vulnerable those with neoplastic diseases, those admitted to intensive care units (ICUs), and the neonatal population. However, candidaemia is an evolving disease, whose epidemiological changes are closely related to healthcare practices. Therefore, a basic knowledge of its epidemiology, the distribution of Candida species and the antifungal susceptibility pattern of each geographical region is essential to guide the selection of adequate empirical treatment and, ultimately, to improve the patients’ prognosis. In this clinical scenario, in early 2010, updated information regarding the epidemiology of candidaemia, the microbiological features of the isolated species, and basic clinical and therapeutic information about the management of this condition was still lacking in Spain. Hence, between May 2010 and April 2011 the first national population-based study (CANDIPOP) was conducted in 5 of the largest metropolitan areas of Spain (Barcelona, Bilbao, Madrid, Seville, and Valencia), with the aim of filling these local gaps of uncertainty. This thesis, “Epidemiology and optimization of the clinical management of candidaemia: Results of a population-based study in Spain”, written as a compendium of 4 publications, attempts to show the main results of the CANDIPOP study. The first article, “Epidemiology and predictive factors for early and late mortality in Candida bloodstream infections: a population-based surveillance in Spain” offers an updated, general overview of this infection and estimates the incidence of candidaemia in Spain. Briefly, the annual incidence of candidaemia was 8.1 cases/100 000 inhabitants and the predominant Candida species were Candida albicans (45.4%), C. parapsilosis (24.9%), and C. glabrata (13.4%). Overall, 79% of Candida isolates were susceptible to fluconazole. Cumulative mortality at 7 and 30 days after the first episode of candidaemia was 12.8% and 30.6%, respectively. Multivariate analysis showed that therapeutic measures within the first 48 hours might improve 7-day mortality: antifungal treatment (OR 0.51, 95%CI 0.27-0.95) and central venous catheter removal (OR 0.43, 95%CI 0.21-0.87). Conversely, predictors of late death (8-30 days) were mainly related to the patients’ comorbid status and infection severity at onset. The second and third articles, “Impact of therapeutic strategies on the prognosis of candidemia in the intensive care unit“ and “Epidemiology and outcome of candidaemia in patients with oncological and haematological malignancies: results from a population-based surveillance in Spain” focus on two populations at high risk for developing an episode of candidaemia: adult patients admitted to ICUs and patients with oncological and haematological malignancies. The main objective of these publications was to provide further information that would allow physicians to optimise therapeutic strategies in patients who have some differential characteristics. Finally, the fourth article, “Propensity score analysis of the role of initial antifungal therapy in the outcome of Candida glabrata bloodstream infections”, aimed to evaluate whether the choice of initial antifungal treatment (fluconazole vs. echinocandins or liposomal amphotericin B-based regimens) has an impact on the outcome of candidaemia caused by C. glabrata. Our results show that initial use of fluconazole is not associated with an unfavourable evolution (adjusted OR for 14-day mortality: 1.16, 95%CI 0.22-6.17; adjusted OR for treatment failure: 0.83, 95%CI 0.27-2.61). These data suggest that in settings with low rates of fluconazole-resistant strains, this agent may be still a reasonable option for treating stable patients with candidaemia before the Candida species is identified.

Necrotising enterocolitis (NEC) is a potentially devastating intestinal inflammation of multifactorial aetiology in premature or otherwise vulnerable neonates. Because of the broad spectrum of presentations, diagnosis and timing of surgical intervention may be challenging, and imaging needs to be an integrated part of management. The first four studies included in this thesis used routinely collected, nationwide register data to describe the incidence of NEC in Sweden 1987‒2009, its variation with time, seasonality, space-time clustering, and associations with maternal, gestational, and perinatal factors, and the risk of intestinal failure in the aftermath of the disease. Early infant survival increased dramatically during the study period. The incidence rate of NEC was 0.34 per 1,000 live births, rising from 0.26 per 1,000 live births in the first six years of the study period to 0.57 in the last five. The incidence rates in the lowest birth weights were 100‒160 times those of the entire birth cohort. Seasonal variation was found, as well as space-time clustering in association with delivery hospitals but not with maternal residential municipalities. Comparing NEC cases with matched controls, some factors, positively associated with NEC, were isoimmunisation, fetal distress, caesarean section, persistent ductus arteriosus, cardiac and gastrointestinal malformations, and chromosomal abnormalities. Negative associations included maternal pre-eclampsia, maternal urinary infection, and premature rupture of the membranes. Intestinal failure occurred in 6% of NEC cases and 0.4% of controls, with the highest incidence towards the end of the study period. The last study investigated current practices and perceptions of imaging in the management of NEC, as reported by involved specialists. There was great consensus on most issues. Areas in need of further study seem mainly related to imaging routines, the use of ultrasound, and indications for surgery. Developing alongside the progress of neonatal care, NEC is a complex, multifactorial disease, with shifting patterns of predisposing and precipitating causes, and potentially serious long-term complications. The findings of seasonal variation, spacetime clustering, and negative associations with antenatal exposure to infectious agents, fit into the growing understanding of the central role of bacteria and immunological processes in normal maturation of the intestinal canal as well as in the pathogenesis of NEC. Imaging in the management of NEC may be developed through future studies combining multiple diagnostic parameters in relation to clinical outcome.

In under a century, melioidosis, the infection due to Burkholderia pseudomallei, has emerged from Whitmore’s series of glanders-like infections amongst the morphia addicts in Burma to a major cause of mortality in northeastern Thailand and northern Australia. Also endemic in other parts of south-east Asia, melioidosis may have varied presentations ranging from severe, overwhelming infection to chronic, low grade disease. Observational evidence had suggested that granulocyte colony stimulating factor (G-CSF), a naturally occurring substance produced by the body in response to infection, may have been useful in reducing the high mortality associated with the more severe forms of this infection. Other observations linked the occurrence of this disease to various environmental factors, such as contamination of drinking water and the annual rainfall. This thesis explores and attempts to quantify these associations. There are three parts to this thesis. In the first part, I reviewed the epidemiology and management of patients with melioidosis. The use of G-CSF and meropenem was associated with a fall in mortality, although other factors may have at least partially contributed to this effect. In the second part, I progressed towards a clinical trial of G-CSF. There was no other evidence supporting the use of G-CSF in severe sepsis and ethical issues precluded a trial in Darwin. There was not evidence from laboratory models of G-CSF action in melioidosis to support the use of G-CSF in patients, although there remained some doubt regarding the applicability of such models to human disease. I examined clinical methods to identify patients at high risk of death from melioidosis. A simple scoring system based on clinical and laboratory parameters was developed and externally validated. However, clinical definitions of severe sepsis appeared to be better predictors of mortality. A clinical trial based on clinical definitions was commenced in Thailand. In the final part, I explored the question of whether different strains or B. pseudomallei or different environmental conditions caused different patterns of infection. There was no evidence that strain types of this bacterium determine the pattern or severity of disease, but weather conditions appeared to influence the distribution of disease in northern Australia.

The most intriguing problems in genetics epidemiology are to predict genetic disease susceptibility and to associate single nucleotide polymorphisms (SNPs) with diseases. In such these studies, it is necessary to resolve the ambiguities in genetic data. The primary obstacle for ambiguity resolution is that the physical methods for separating two haplotypes from an individual genotype (phasing) are too expensive. Although computational haplotype inference is a well-explored problem, high error rates continue to deteriorate association accuracy. Secondly, it is essential to use a small subset of informative SNPs (tag SNPs) accurately representing the rest of the SNPs (tagging). Tagging can achieve budget savings by genotyping only a limited number of SNPs and computationally inferring all other SNPs. Recent successes in high throughput genotyping technologies drastically increase the length of available SNP sequences. This elevates importance of informative SNP selection for compaction of huge genetic data in order to make feasible fine genotype analysis. Finally, even if complete and accurate data is available, it is unclear if common statistical methods can determine the susceptibility of complex diseases. The dissertation explores above computational problems with a variety of methods, including linear algebra, graph theory, linear programming, and greedy methods. The contributions include (1)significant speed-up of popular phasing tools without compromising their quality, (2)stat-of-the-art tagging tools applied to disease association, and (3)graph-based method for disease tagging and predicting disease susceptibility.

We conducted a molecular epidemiologic study of tuberculosis (TB) transmission during the years 1996--98 on the Island of Montreal. By combining public health data on the 528 reported cases with IS6110 DNA fingerprints for 430, we detected an overall low frequency of transmission manifesting as secondary cases of active disease. We also identified an important sub-group of TB patients who harbour isolates with matching patterns. Depending on the matching criterion used we attributed between 6% (95% CI: 4, 9%) and 22% (95% CI: 18, 27%) of TB cases to recent transmission; the vast majority of active TB disease reflects infection acquired at an earlier time and/or a different place. However, Haitian-born TB patients yielded a disproportionately high frequency of isolates belonging to matching "clusters" (21%; 95% CI: 13, 32%), while, other foreign-born patients have disproportionately low numbers of clustered isolates (5%; 95% CI: 3, 9%).
The classical interpretation of such results is that there is more ongoing transmission within this immigrant sub-group. We explored an alternative hypothesis: that M. tuberculosis isolates from Haitian-born patients demonstrate reduced genetic diversity reflecting TB transmission patterns in their previously isolated country of origin---hence that a bacterial founder effect accounts for the higher frequency of matching fingerprints. Using a recently introduced measure of fingerprint similarity, genetic distance, we assessed the extent of pattern diversity. The median nearest genetic distance (NGD) was 130 months (inter-quartile range (IQR): 98--201 months) among the 47 distinct isolates from Haitian-born patients; among the non-Haitian foreign-born, the median NGD for the 191 distinct isolates was 128 months (IQR: 103--170 months). Hence the overall genetic heterogeneity of M. tuberculosis organisms among Haitian-born Montrealers was as great as that among a group of patients born in 70 other countries. Local transmission among the Haitian-born remains the most likely scenario.
We demonstrated that a continuous measure, such as genetic distance, may also permit researchers to address a challenge to the interpretation of M. tuberculosis molecular typing results: how to determine whether highly similar, non-identical fingerprint patterns in fact reflect underlying "matches." The distribution of NGD for isolates initially classified as identical (10--27 months), similar (15--108 months) and unique (40--244 months) suggested a possible cut-point of 40 months. Use of this cut-point labelled 19% of isolates as "clustered", suggesting that 14% of Montreal TB cases reflected transmission during the study period.

Traditionally, epidemiologists have used methods that categorize or assume a linear or log-linear form to model dose-response associations between continuous independent variables and binary or continuous outcomes. Recent advances in both statistical methodology and computing resources have made it possible to model relationships of greater complexity. Generalized additive models (GAMs) are a flexible nonparametric modelling tool that allows the user to model a variety of non-linear dose-response curves without imposing a priori assumptions about the functional form of the relationship. In GAMs, the extent of smoothing is controlled by the user-defined degrees of freedom (df). GAMs are generally used to: (i) suggest the parametric functional form for the association of interest; (ii) model the main effect nonparametrically; and (iii) control confounding by continuous covariates. By way of a series of simulation studies, this thesis addresses several unresolved methodological issues involving all three of these uses. Although GAMs have been used to detect and estimate thresholds in the association of interest, the methods have been mostly subjective or ad hoc, and the statistical properties have not been evaluated for the most part. In the first simulation study, a formal approach to the use of GAMs for this purpose is suggested and compared with simpler approaches. When GAMs are used to estimate the effect of the primary exposure of interest different approaches to determining the amount of smoothing are employed. In the second simulation study, the impact on statistical inference of various a priori and automatic df-selection strategies is investigated and a method to correct the type I error is introduced and evaluated.
In the final simulation study, parametric multiple logistic regression was compared with its nonparametric GAM extension in their ability to control for a continuous confounding variable and several issues related to the implementation of GAMs in this context are investigated.
The results of these simulations will help researchers make optimal use of the potential advantages of flexible assumption-free modelling.