No description available.

Introducción: Las deficiencias en el sistema sanitario, social y económico del país han hecho que esta enfermedad se propague y afecte a la población. Objetivo. Se comparó la letalidad por COVID-19 de dos hospitales COVID de la Región Lambayeque, Chiclayo, 2020 – 2021.Metodología. Se realizó un estudio de tipo cuantitativo, observacional, transversal y retrospectivo. Se obtuvo la base de datos de ambos hospitales con muestra de 4844 fallecidos desde Abril (2020) -Diciembre (2021) en Microsoft Excel. Las variables categóricas se expresaron como frecuencia y porcentaje, las numéricas como medias. La tasa de letalidad se obtuvo dividiendo el total de fallecidos entre total de infectados de la misma enfermedad. Resultados. Se reportaron 4844 fallecidos de los cuales el sexo masculino fue el más afectado 68,0% para el Hospital Luis Heysen (HLH) y 65,0% para el Hospital Regional Lambayeque (HRL), la tasa de letalidad fue 72,1% y 45,2% respectivamente de los hospitales antes mencionados. La edad promedio más afectada fue 63 años. La región más afectada fue Lambayeque – Chiclayo 52,0% HLH y 45,2% HRL, en este último se apreció que la comorbilidad más frecuente fue Hipertensión Esencial 30%. Conclusión. La tasa de letalidad más alta fue del HLH 72,1% respecto al HRL 45,2%, la edad promedio más afectada fue 65 años, el sexo más afectado fue el masculino 65,0%, la región más afectada fue Lambayeque – distrito Chiclayo. La comorbilidad más frecuente en el HRL fue la Hipertensión Esencial 30,0%. / Introduction: Deficiencies in the country's healthcare, social, and economic systems have facilitated the spread and impact of this disease on the population. Objective: This study aimed to compare the lethality of COVID-19 between two COVID hospitals in the Lambayeque Region, Chiclayo, during 2020-2021. Methodology: A quantitative, observational, crosssectional, and retrospective study was conducted. Data were obtained from the databases of both hospitals, with a sample of 4844 deceased individuals from April 2020 to December 2021 in Microsoft Excel. Categorical variables were expressed as frequency and percentage, while numerical variables were presented as means. Lethality rate was calculated by dividing the total number of deaths by the total number of infected individuals. Results: A total of 4844 deaths were reported, with males being the most affected, accounting for 68,0% in Hospital Luis Heysen (HLH) and 65,0% in Hospital Regional Lambayeque (HRL). The lethality rates were 72.1% and 45.2% respectively for the mentioned hospitals. The average age most affected was 63 years. The most affected region was Lambayeque - Chiclayo, with 52,0% in HLH and 45.2% in HRL. Conclusion: The highest lethality rate was observed in HLH, at 72,1%, in the latter we appreciated that the most frequent comorbidity was Essential Hypertension 30%. The average age most affected was 65 years, and the most affected gender was male, representing 65,0%. Additionally, it was identified that the most affected region was Lambayeque, specifically the district of Chiclayo. The most frequent comorbidity in the HRL was Hypertension with 30,0%

京都大学 / 新制・課程博士 / 博士(医学) / 甲第25487号 / 医博第5087号 / 新制||医||1073(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小濱 和貴, 教授 妹尾 浩, 教授 寺田 智祐 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Das Neuroblastom ist eines der häufigsten Tumoren im Kindesalter. Bei Hochrisko-Neuroblastomen weisen etwa 25 % der Patienten eine MYCN-Amplifikation auf. Die Behandlung dieser Patienten bleibt eine Herausforderung. Bei genauerer Betrachtung der amplifizierten Regionen umfasst diese große genomische Bereiche, die nicht nur MYCN, sondern auch Passagiergene und genregulatorische Elemente enthalten. Um MYCN-amplifizierte Neuroblastome zu behandeln, versuchten wir festzustellen, ob Co-Amplifikationen von Passagiergenen kollaterale therapeutische Vulnerabilitäten darstellen könnten. Durch die Analyse von Kopienzahl-Daten von 238 MYCN-amplifizierten Patienten identifizierten wir das DEAD-Box-Helicase-1 (DDX1)-Gen als ein Gen, welches häufig mit MYCN auf dem gleichen genomischen Fragment amplifiziert ist. Die Analyse eines CRISPR-Cas9-Funktionsverlust- Screens aus der Cancer Dependency Map, welche über 700 humanen Krebszelllinien beinhalten, zeigt, dass das Überleben von MYCN-amplifizierten Krebszellen mit DDX1-Co-Amplifikation von der gesteigerten Aktivität des mammalian target of rapamycin complex 1 (mTORC1) abhängt. Interaktionsproteomik identifizierte Dihydrolipoyl-S-Succinyltransferase (DLST), ein Bestandteil des Tricarboxylsäure (TCA)-Zyklusenzyms α-Ketoglutarat-Dehydrogenase (α-KGDH)-Komplexes, als Interaktionspartner von DDX1 in Mitochondrien. Lebendzell- Stoffwechselanalysen legten nahe, dass diese Interaktion die TCA-Aktivität beeinträchtigen und zu einer Anhäufung von α-Ketoglutarat (α-KG) führen kann, indem sie dessen Umwandlung in Succinyl-CoA stört. Die Anhäufung von α-KG verursacht metabolischen Stress und löst Zelltod aus, der durch eine gesteigerte mTORC1-Aktivität in Krebszellen kompensiert wird. Folglich führte die Störung der mTORC1-Funktion zu Zelltod, insbesondere in Zellen mit hoher DDX1-Kopienzahl. So kann die strukturell verknüpfte Co-Amplifikation eines Passagiergens (DDX1) und eines Onkogens (MYCN) auf dem gleichen Amplicon zu kollateralen Vulnerabilitäten bei Neuroblastomen führen. / Neuroblastoma is one of the most common childhood tumors. In high-risk neuroblastoma, around 25% of patients harbor MYCN amplification. Treating neuroblastoma patients with MYCN amplification remains challenging. Taking a closer look at MYCN-amplified regions, DNA amplification encompasses large genomic regions harboring not only MYCN but also containing passenger genes and gene regulatory elements. To treat MYCN-amplified neuroblastoma, we sought to determine whether passenger co-amplifications can create collateral therapeutic vulnerabilities. By analyzing copy number data from 238 MYCN-amplified patients, we identified the DEAD-Box Helicase 1 (DDX1) gene to be frequently co-amplified with MYCN on the same genomic fragment. Analysis of CRISPR-Cas9 loss-of-function screens from the Cancer Dependency Map across over 700 human cancer cell lines revealed that the survival of MYCN-amplified cancer cells with DDX1 co-amplification depends on the enhanced activity of the mammalian target of rapamycin complex 1 (mTORC1). Interaction proteomics identified dihydrolipoamide S-succinyltransferase (DLST), a component of the tricarboxylic acid (TCA) cycle enzyme α-ketoglutarate dehydrogenase (α-KGDH) complex, as an interaction partner of DDX1 in mitochondria. Live-cell metabolomics suggested that this interaction can impair TCA activity and lead to the accumulation of α-ketoglutarate (α-KG) by interfering with its conversion to succinyl-CoA. Accumulation of α-KG, in turn, caused metabolic stress and triggered cell death, which was compensated for by enhanced mTORC1 activity in cancer cells. Consequently, disruption of mTORC1 function resulted in cell death, specifically in cells with an aberrantly high copy number of DDX1. Thus, structurally linked co-amplification of a passenger gene (DDX1) and an oncogene (MYCN) on the same amplicon can result in collateral vulnerabilities in neuroblastoma.

Le cancer occupe le premier rang parmi les causes de décès au Québec. Les taux de mortalité diffèrent cependant à travers les régions du Québec. En considérant les territoires des Centres de santé et de services sociaux (CSSS), ce mémoire propose dans un premier temps d’étudier la distribution des taux de mortalité pour les principaux sièges de cancer, d’identifier les régions où une différence significative du taux avec le reste du Québec est perceptible et d’approfondir des éléments impliqués dans la mortalité, soit l’incidence et la létalité. D’autre part, dans le but d’expliquer les variations des taux de mortalité, des variables socio-économiques liées aux territoires retenus serviront de variables explicatives au modèle de régression utilisé. Les résultats ont permis de constater que c’est pour le cancer du poumon que les écarts significatifs sont les plus nombreux. Quant au cancer colorectal, un seul territoire présentait un écart significatif. Pour ce qui est du cancer de la prostate et du sein, aucun écart n’est perceptible dans les taux de mortalité. Concernant la partie explicative de la mortalité, dans le cas du cancer du poumon, les taux d’incidence sont fortement corrélés aux taux de mortalité. On ne peut cependant faire le même constat pour les cancers colorectal, du sein et de la prostate. De plus, les variables socio-économiques considérées pour les territoires de CSSS ne permettaient pas d’arriver à un modèle explicatif convaincant. Ces résultats montrent la nécessité d’avoir des données longitudinales permettant de suivre les individus dès le moment où le diagnostic de cancer est établi afin d’être en mesure de mieux mesurer les liens entre l’incidence, la survie, le niveau socio-économique et la mortalité. / Cancer is the leading cause of death in Québec. However, mortality rates vary significantly throughout Quebec’s regions. Using the CSSS (Centre de santé et de services sociaux) territories as a base of comparison, the present thesis will study the regional distribution of mortality rates amongst the territories with the highest cancer rates, identify those territories that have a significant variation from the overall cancer rate of the province, and investigate the relation between incidence rates and lethality. Moreover, to help explain variations in mortality rates, a regression analysis was undertaken using socioeconomic variables of each territory. The analysis demonstrated that territorial disparity was the greatest for lung cancer. As for colorectal cancer, only one territory showed a rate different with that of Quebec as a whole. For prostate and breast cancer no variations were identified. Lung cancer mortality rates were found to be strongly correlated with incidence rates, but that wasn’t the case for the other cancers (colorectal, breast and prostate). Further, the analysis of the socio-economic variables in the regression model did no present any convincing results. The need for longitudinal data to study mortality rates by cancer and its associated factors is deemed to be a major issue.

Aujourd’hui, les traitements du cancer colorectal métastatique ont évolué grâce à la combinaison de chimiothérapies conventionnelles à base de 5-FU, oxaliplatine et/ou Irinotécan et de thérapies ciblées dirigées contre le récepteur de l’EGF ou le VEGF. Malgré un taux de survie amélioré par la combinaison de ces drogues, la résistance innée et acquise aux traitements est une cause fréquente d'échec thérapeutique.Dans le but de découvrir de nouvelles cibles thérapeutiques nous avons effectué plusieurs criblages phénotypiques en utilisant des modèles cellulaires de résistance acquises aux chimiothérapies (oxaliplatine et irinotécan) générés au laboratoire ainsi que la lignée HCT116 qui présente une résistance innée aux thérapies anti-EGFR (cétuximab, panitumumab, Erlotinib). Le but final de ce projet étant de révéler des gènes, dont l’inhibition permet de rétablir la sensibilité à l’un de ces traitements, affichant ainsi une interaction létale avec le médicament.Une fois les kinases potentiellement impliquées dans la résistance aux thérapies du CCR identifiées, une inhibition spécifique par shRNA et/ou un inhibiteur spécifique a été effectuée afin de confirmer les potentielles cibles thérapeutiques et/ou biomarqueurs de réponse aux traitements. La cible la plus prometteuse, identifiée comme un déterminant de la résistance à l’oxaliplatine est la protéine ATR (Ataxia-telangiectasia mutated and rad3 related). Une protéine jouant un rôle clé dans la réparation de l'ADN et qui est activée en réponse à la présence d'ADN simple brin persistant (ssDNA) ou de stress réplicatif, pouvant être généré par certaines thérapies anticancéreuses.L’inhibition ATR via son inhibiteur pharmacologique VE-822 (VX-970) combinée à l’oxaliplatine a alors été étudiée par l’utilisation de tests cytotoxiques complétés par une étude d’additivité. Ainsi, nous avons démontré que l’inhibition d’ATR combinée avec l’oxaliplatine entraine une forte synergie dans la lignée HCT116-R1 à la fois en 2D et en 3D. Cet effet est également retrouvé dans d’autres lignées clonales résistantes à l’oxaliplatine (HCT116-R2, SW48-R1) ainsi que dans les lignées cellulaires à l’origine de ces dernières (HCT116, SW48). Nous avons également montré que l'effet synergique de l’oxaliplatine et du VE-822 dans la lignée HCT116-R1 s'accompagne d'une augmentation de la présence d’ADN simple brins suivie de nombreuses cassures double brins de l’ADN, d'un arrêt de la prolifération et d'une induction de l'apoptose. L'apparition de ces dommages à l'ADN est également corrélée avec l'activation de la voie ATM, de p53 et l'inhibition de l'activité CDK2. De plus, in vitro le double traitement provoque une induction des signaux moléculaires à l’origine de la mort immunogène équivalente ou bien supérieure aux traitements par l’oxaliplatine seul. Enfin, l'association d'oxaliplatine + VE-822 est également efficace in vivo, sur des souris immunodéprimées xénogreffées avec les cellules HCT116-R1 ainsi que sur des souris immunologiquement compétentes, avec un effet synergique plus élevé indiquant que la mort immunitaire (ICD) fait partie du mécanisme de cette combinaison de médicaments. En conclusion, toutes ces données confirment l’intérêt du criblage phénotypique dans la découverte de nouvelles cibles thérapeutiques en démontrant pour la première fois le rôle fonctionnel de l'ATR dans la sensibilité à l’oxaliplatine. / Today, treatments for metastatic colorectal cancer have evolved through the combination of conventional chemotherapy 5-FU, oxaliplatin and / or Irinotecan and targeted therapies directed against the EGF receptor or VEGF. Despite an improved survival rate through the combination of these drugs, innate and acquired resistance to treatment is a common cause of therapeutic failure.In order to discover new therapeutic targets we carried out several phenotypic screenings using cellular resistance models acquired to chemotherapies (oxaliplatin and irinotecan) generated in the laboratory as well as the HCT116 line which exhibits an innate resistance to anti-EGFR therapies (cetuximab , panitumumab, Erlotinib). The ultimate goal of this project is to reveal genes, whose inhibition restores sensitivity to one of these treatments, thus displaying a lethal interaction with the drug.Once the kinases potentially involved in resistance to CCR therapies identified, specific inhibition by shRNA and / or a specific inhibitor was performed to confirm the potential therapeutic targets and / or biomarkers for response to treatments. The most promising target, identified as a determinant of resistance to oxaliplatin is the ATR protein (Ataxia-telangiectasia mutated and rad3 related). A protein that plays a key role in DNA repair and is activated in response to the presence of persistent single stranded DNA (ssDNA) or replicative stress, which can be generated by certain anti-cancer therapies.The inhibition of ATR via its pharmacological inhibitor VE-822 (VX-970) combined with oxaliplatin was then studied by the use of cytotoxic tests supplemented by an additivity study. Thus, we demonstrated that the inhibition of ATR combined with oxaliplatin leads to a strong synergy in the HCT116-R1 cell line in both 2D and 3D. This effect is also found in other oxaliplatin resistant clonal lines (HCT116-R2, SW48-R) as well as in the cell lines originating from them (HCT116, SW48).We have also shown that the synergistic effect of oxaliplatin and VE-822 in the HCT116-R1 line is accompanied by an increase in the presence of single-stranded DNA followed by numerous double-stranded DNA breaks, stopping proliferation and inducing apoptosis. The occurrence of this damage to DNA is also correlated with activation of the ATM pathway, p53 and inhibition of CDK2 activity. Moreover, in vitro the double treatment causes an induction of the molecular signals triggering the immunogenic cell death equivalent or superior to the treatments by oxaliplatin alone.Finally, the combination of oxaliplatin + VE-822 is also effective in vivo in immunodeficient mice xenografted with HCT116-R1 cells as well as in immunologically competent mice with a higher synergistic effect indicating that immune death (ICD ) is part of the mechanism of this combination of drugs.In conclusion, all these data confirm the interest of phenotypic screening in the discovery of new therapeutic targets by demonstrating for the first time the functional role of ATR in sensitivity to oxaliplatin.

INTRODUÇAO: A leishmaniose atinge milhões de indivíduos mundialmente, relacionada a mudanças ambientais, urbanização, migração e susceptibilidade do hospedeiro. O aumento de casos de leishmaniose visceral (LV) em áreas urbanas pode ser explicado, não só pela adaptação do vetor a diferentes situações ambientais, circulação do parasito e introdução de hospedeiro infectado, como também pela intersecção com áreas de transmissão do HIV. No Brasil, a distribuição dos coinfectados acompanha os grupos de risco para HIV/AIDS (adultos, sexo masculino). A coinfecção LV-HIV/AIDS é registrada com grande frequência no Estado de São Paulo, onde há aumento da prevalência desta coinfecção, assim como da recidiva e da letalidade por LV. Fatores contribuintes para esta elevação, como possíveis determinantes da gravidade da LV em pacientes HIV/AIDS, não estão claros, sejam relacionados ao hospedeiro ou ao parasito. OBJETIVOS: Avaliar o comportamento clínico, epidemiológico, terapêutico e imunológico e a variação genotípica do parasito na coinfecção LV-HIV/AIDS, comparando com pacientes HIV-negativos, em pacientes do Estado de São Paulo. MATERIAIS E MÉTODOS: Coorte retrospectiva, utilizando dados secundários de programas de rotina epidemiológica da Secretaria de Estado da Saúde de São Paulo e do Ministério da Saúde do Brasil, entre 1999-2010. Análise molecular por PCR-RFLP do kDNA de Leishmania (L.) infantum de aspirado de medula óssea para desenvolvimento de uma árvore fenética, comparando os indivíduos entre si quanto ao desfecho, sexo, idade e infecção pelo HIV. RESULTADOS: 1614 casos de LV e 117 (7,25%) de coinfectados LV-HIV/AIDS, com predomínio destes no sexo masculino, entre os 31-50 anos de idade. Tríade febre e hepatoesplenomegalia foi mais frequente no grupo HIV-negativo. Maior letalidade por LV (24,2 x 8,2 - p =0,000) e recidiva (10,5 x 1,8 - p = 0,000) nos pacientes HIV-positivos comparando aos HIVnegativos. Entre os coinfectados, observou-se maior taxa de cura quando a LV foi tratada com Antimonial Pentavalente (69,44%) e Anfotericina B lipossomal (63,82%), p=0,223. Maiores falhas (16,66%, p = 0,034) e letalidade (41,66%, p = 0,192) quando tratado com Anfotericina B deoxicolato. Maiores recidivas (14,89% - p = 0,076) e nenhuma falha com Anfotericina B lipossomal. Houve maior mediana de linfócitos T CD4+ (135) e T CD8+ (550) no grupo de cura dos pacientes LV-HIV/AIDS e houve 50% de recidivas em uso de terapia antirretroviral. A distribuição dos genótipos de Leishmania (L.) infantum não apresentou relação com nenhum dos desfechos avaliados. CONCLUSÕES: Os resultados obtidos revelam pela primeira vez a magnitude da comorbidade LV-HIV/AIDS no Estado de São Paulo, com repercussão direta na recidiva e na letalidade da LV. Há aumento do número de casos de LV e LV-HIV/AIDS nessa região, com maior prevalência de coinfectados em adultos do sexo masculino. Maior letalidade e recidiva nos HIV-positivos e com pior desfecho quando tratado com Anfotericina B deoxicolato. Recidiva elevada quando tratado com Anfotericina B lipossomal, embora sem falhas. Pouca proteção da terapia antirretroviral na proteção das recidivas. Muitos dados incompletos quanto à infecção pelo HIV. PCR-RFLP não discrimina casos HIV-positivos dos HIV-negativos, nem mostra relação direta das recidivas e óbitos com um genótipo específico do parasita, podendo a evolução do paciente estar relacionada diretamente com a resposta do hospedeiro / INTRODUCTION: Leishmaniasis affects millions of individuals worldwide, related to environmental changes, urbanization, migration, and host susceptibility. The increase in cases of visceral leishmaniasis (VL) in urban areas can be explained not only by the vector adaptation to different environmental situations, movement of the parasite and introduction infected host, as well as the intersection with areas of HIV transmission. In Brazil, the distribution of coinfected is accompanying risk groups for HIV/AIDS (adult male). Coinfection VL-HIV/AIDS is recorded with great frequency in São Paulo State, where there is an increased prevalence of co-infection, as well as relapse and lethality by VL. Factors contributing to this increase, as possible determinants of severity of VL in HIV/AIDS patients are not clear, either related to the host or the parasite. OBJECTIVES: To evaluate the clinical, epidemiological, therapeutic and immunological aspects of coinfection VL-HIV/AIDS and genotypic variation in the parasite, compared with HIV-negative patients in the State of São Paulo. MATERIALS AND METHODS: Retrospective cohort study using secondary data from epidemiological routine programs of the State Department of Health of São Paulo and the Ministry of Health of Brazil, between 1999 to 2010. Molecular analysis by PCRRFLP kDNA of Leishmania (L.) infantum from bone marrow aspirate to develop a phenetic tree, comparing individuals with each other about the outcome, gender, age and HIV infection. RESULTS: 1614 cases of VL and 117 (7.25%) of coinfected VLHIV/ AIDS, predominantly those in males, between 31-50 years old. Triad of fever and hepatosplenomegaly was more frequent among HIV-negative. Increased mortality by VL (24.2 x 8.2 - p =0,000) and recurrence (10.5 x 1.8 - p = 0,000) in HIV-positive patients compared to HIV-negative. Among coinfected, there was a higher cure rate when the VL was treated with pentavalent antimony (69.44%) and liposomal amphotericin B (63.82%), p = 0.223. Major failures (16.66%, p = 0.034) and mortality (41.66%, p = 0.192) when treated with amphotericin B deoxycholate. Major recurrences (14.89% - p = 0.076) and no failure with amphotericin B liposome. There were a higher median TCD4+ (135) and TCD8+ (550) lymphocytes in the group of cures and relapse was 50% in those using antiretroviral therapy. The genotype distribution of Leishmania (L.) infantum was not associated with any of the outcomes assessed. CONCLUSIONS: These results show for the first time the magnitude of comorbidity VL-HIV/AIDS in São Paulo State, with direct impact on recurrence and mortality of VL. There are increasing numbers of cases of VL and VL-HIV/AIDS in this region, with the highest prevalence of coinfection in adult males. There is an increased mortality and recurrence in HIV-positive and with worse outcome when treated with amphotericin B deoxycholate. High relapse when treated with liposomal amphotericin B, although flawless. There is little protection of antiretroviral therapy in relapses. There are many incomplete data regarding HIV infection. PCR-RFLP does not discriminate HIVpositive cases from HIV-negative ones or showed direct nexus from recurrences and deaths with a specific genotype of the parasite, but instead could be directly related to the host response

INTRODUÇAO: A leishmaniose atinge milhões de indivíduos mundialmente, relacionada a mudanças ambientais, urbanização, migração e susceptibilidade do hospedeiro. O aumento de casos de leishmaniose visceral (LV) em áreas urbanas pode ser explicado, não só pela adaptação do vetor a diferentes situações ambientais, circulação do parasito e introdução de hospedeiro infectado, como também pela intersecção com áreas de transmissão do HIV. No Brasil, a distribuição dos coinfectados acompanha os grupos de risco para HIV/AIDS (adultos, sexo masculino). A coinfecção LV-HIV/AIDS é registrada com grande frequência no Estado de São Paulo, onde há aumento da prevalência desta coinfecção, assim como da recidiva e da letalidade por LV. Fatores contribuintes para esta elevação, como possíveis determinantes da gravidade da LV em pacientes HIV/AIDS, não estão claros, sejam relacionados ao hospedeiro ou ao parasito. OBJETIVOS: Avaliar o comportamento clínico, epidemiológico, terapêutico e imunológico e a variação genotípica do parasito na coinfecção LV-HIV/AIDS, comparando com pacientes HIV-negativos, em pacientes do Estado de São Paulo. MATERIAIS E MÉTODOS: Coorte retrospectiva, utilizando dados secundários de programas de rotina epidemiológica da Secretaria de Estado da Saúde de São Paulo e do Ministério da Saúde do Brasil, entre 1999-2010. Análise molecular por PCR-RFLP do kDNA de Leishmania (L.) infantum de aspirado de medula óssea para desenvolvimento de uma árvore fenética, comparando os indivíduos entre si quanto ao desfecho, sexo, idade e infecção pelo HIV. RESULTADOS: 1614 casos de LV e 117 (7,25%) de coinfectados LV-HIV/AIDS, com predomínio destes no sexo masculino, entre os 31-50 anos de idade. Tríade febre e hepatoesplenomegalia foi mais frequente no grupo HIV-negativo. Maior letalidade por LV (24,2 x 8,2 - p =0,000) e recidiva (10,5 x 1,8 - p = 0,000) nos pacientes HIV-positivos comparando aos HIVnegativos. Entre os coinfectados, observou-se maior taxa de cura quando a LV foi tratada com Antimonial Pentavalente (69,44%) e Anfotericina B lipossomal (63,82%), p=0,223. Maiores falhas (16,66%, p = 0,034) e letalidade (41,66%, p = 0,192) quando tratado com Anfotericina B deoxicolato. Maiores recidivas (14,89% - p = 0,076) e nenhuma falha com Anfotericina B lipossomal. Houve maior mediana de linfócitos T CD4+ (135) e T CD8+ (550) no grupo de cura dos pacientes LV-HIV/AIDS e houve 50% de recidivas em uso de terapia antirretroviral. A distribuição dos genótipos de Leishmania (L.) infantum não apresentou relação com nenhum dos desfechos avaliados. CONCLUSÕES: Os resultados obtidos revelam pela primeira vez a magnitude da comorbidade LV-HIV/AIDS no Estado de São Paulo, com repercussão direta na recidiva e na letalidade da LV. Há aumento do número de casos de LV e LV-HIV/AIDS nessa região, com maior prevalência de coinfectados em adultos do sexo masculino. Maior letalidade e recidiva nos HIV-positivos e com pior desfecho quando tratado com Anfotericina B deoxicolato. Recidiva elevada quando tratado com Anfotericina B lipossomal, embora sem falhas. Pouca proteção da terapia antirretroviral na proteção das recidivas. Muitos dados incompletos quanto à infecção pelo HIV. PCR-RFLP não discrimina casos HIV-positivos dos HIV-negativos, nem mostra relação direta das recidivas e óbitos com um genótipo específico do parasita, podendo a evolução do paciente estar relacionada diretamente com a resposta do hospedeiro / INTRODUCTION: Leishmaniasis affects millions of individuals worldwide, related to environmental changes, urbanization, migration, and host susceptibility. The increase in cases of visceral leishmaniasis (VL) in urban areas can be explained not only by the vector adaptation to different environmental situations, movement of the parasite and introduction infected host, as well as the intersection with areas of HIV transmission. In Brazil, the distribution of coinfected is accompanying risk groups for HIV/AIDS (adult male). Coinfection VL-HIV/AIDS is recorded with great frequency in São Paulo State, where there is an increased prevalence of co-infection, as well as relapse and lethality by VL. Factors contributing to this increase, as possible determinants of severity of VL in HIV/AIDS patients are not clear, either related to the host or the parasite. OBJECTIVES: To evaluate the clinical, epidemiological, therapeutic and immunological aspects of coinfection VL-HIV/AIDS and genotypic variation in the parasite, compared with HIV-negative patients in the State of São Paulo. MATERIALS AND METHODS: Retrospective cohort study using secondary data from epidemiological routine programs of the State Department of Health of São Paulo and the Ministry of Health of Brazil, between 1999 to 2010. Molecular analysis by PCRRFLP kDNA of Leishmania (L.) infantum from bone marrow aspirate to develop a phenetic tree, comparing individuals with each other about the outcome, gender, age and HIV infection. RESULTS: 1614 cases of VL and 117 (7.25%) of coinfected VLHIV/ AIDS, predominantly those in males, between 31-50 years old. Triad of fever and hepatosplenomegaly was more frequent among HIV-negative. Increased mortality by VL (24.2 x 8.2 - p =0,000) and recurrence (10.5 x 1.8 - p = 0,000) in HIV-positive patients compared to HIV-negative. Among coinfected, there was a higher cure rate when the VL was treated with pentavalent antimony (69.44%) and liposomal amphotericin B (63.82%), p = 0.223. Major failures (16.66%, p = 0.034) and mortality (41.66%, p = 0.192) when treated with amphotericin B deoxycholate. Major recurrences (14.89% - p = 0.076) and no failure with amphotericin B liposome. There were a higher median TCD4+ (135) and TCD8+ (550) lymphocytes in the group of cures and relapse was 50% in those using antiretroviral therapy. The genotype distribution of Leishmania (L.) infantum was not associated with any of the outcomes assessed. CONCLUSIONS: These results show for the first time the magnitude of comorbidity VL-HIV/AIDS in São Paulo State, with direct impact on recurrence and mortality of VL. There are increasing numbers of cases of VL and VL-HIV/AIDS in this region, with the highest prevalence of coinfection in adult males. There is an increased mortality and recurrence in HIV-positive and with worse outcome when treated with amphotericin B deoxycholate. High relapse when treated with liposomal amphotericin B, although flawless. There is little protection of antiretroviral therapy in relapses. There are many incomplete data regarding HIV infection. PCR-RFLP does not discriminate HIVpositive cases from HIV-negative ones or showed direct nexus from recurrences and deaths with a specific genotype of the parasite, but instead could be directly related to the host response

Le cancer occupe le premier rang parmi les causes de décès au Québec. Les taux de mortalité diffèrent cependant à travers les régions du Québec. En considérant les territoires des Centres de santé et de services sociaux (CSSS), ce mémoire propose dans un premier temps d’étudier la distribution des taux de mortalité pour les principaux sièges de cancer, d’identifier les régions où une différence significative du taux avec le reste du Québec est perceptible et d’approfondir des éléments impliqués dans la mortalité, soit l’incidence et la létalité. D’autre part, dans le but d’expliquer les variations des taux de mortalité, des variables socio-économiques liées aux territoires retenus serviront de variables explicatives au modèle de régression utilisé. Les résultats ont permis de constater que c’est pour le cancer du poumon que les écarts significatifs sont les plus nombreux. Quant au cancer colorectal, un seul territoire présentait un écart significatif. Pour ce qui est du cancer de la prostate et du sein, aucun écart n’est perceptible dans les taux de mortalité. Concernant la partie explicative de la mortalité, dans le cas du cancer du poumon, les taux d’incidence sont fortement corrélés aux taux de mortalité. On ne peut cependant faire le même constat pour les cancers colorectal, du sein et de la prostate. De plus, les variables socio-économiques considérées pour les territoires de CSSS ne permettaient pas d’arriver à un modèle explicatif convaincant. Ces résultats montrent la nécessité d’avoir des données longitudinales permettant de suivre les individus dès le moment où le diagnostic de cancer est établi afin d’être en mesure de mieux mesurer les liens entre l’incidence, la survie, le niveau socio-économique et la mortalité. / Cancer is the leading cause of death in Québec. However, mortality rates vary significantly throughout Quebec’s regions. Using the CSSS (Centre de santé et de services sociaux) territories as a base of comparison, the present thesis will study the regional distribution of mortality rates amongst the territories with the highest cancer rates, identify those territories that have a significant variation from the overall cancer rate of the province, and investigate the relation between incidence rates and lethality. Moreover, to help explain variations in mortality rates, a regression analysis was undertaken using socioeconomic variables of each territory. The analysis demonstrated that territorial disparity was the greatest for lung cancer. As for colorectal cancer, only one territory showed a rate different with that of Quebec as a whole. For prostate and breast cancer no variations were identified. Lung cancer mortality rates were found to be strongly correlated with incidence rates, but that wasn’t the case for the other cancers (colorectal, breast and prostate). Further, the analysis of the socio-economic variables in the regression model did no present any convincing results. The need for longitudinal data to study mortality rates by cancer and its associated factors is deemed to be a major issue.

In this thesis, red flags for dangerousness/lethality established from domestic violence and homicide research provided the social framework for an examination of legal responses to violence in intimate heterosexual relationships. The research investigated these gendered, structural patterns of violence and the effectiveness of criminal justice interventions in keeping victims safe. Agency interactions with offenders and victims prior to women's deaths were reviewed in selected cases. Criminal law constructions of violence in intimate relationships were evaluated for their recognition and understanding of primary risk factors for dangerousness/lethality. The research found major red flags remain invisible in criminal law stereotypes of violence between intimates. The significance of these risk factors for dangerousness/lethality is therefore overlooked, misunderstood and even misrepresented in defence of violent offenders. Although the aim of the Domestic Violence Act 1995 is to ensure effective protection for victims, the study found a significant number of women (and sometimes other family members and children) experience further sub-lethal and lethal violence following legal interventions with perpetrators. Lacking a principled policy foundation, central focus on victim safety and clear framework for interventions, legal responses are internally incoherent and inconsistent with New Zealand Family Violence Prevention Strategy. The New Zealand government has committed to principled domestic violence intervention and consistency in law and policy. This will require: a) legislative reform; b) public and professional education on the dynamics of violent relationships, including the interrelationship between sublethal and lethal assaults; and c) monitoring of criminal justice interventions to improve accountability. Until this is accomplished, stories of abused women and their children, including informal attempts to seek help and contact with state and community agencies will continue to be dishonoured by a legal system which silences their voices and fails to learn lessons from their injuries and deaths.