Introdução: A estimativa de sobrevida de pacientes com HIV/aids aumentou após a terapia antirretroviral de alta potência: no entanto, a mortalidade por doenças hepáticas também cresceu. Objetivos: Estimar a probabilidade acumulada de sobrevida após o diagnóstico de aids entre pacientes coinfectados HIV/HCV e realizar análise exploratória para investigar fatores relacionados à sobrevida desses pacientes. Metodologia: Estudo de coorte não concorrente, utilizando sistemas de Informações: o de Agravos de Notificação, o de informação laboratorial e o de informação da vigilância epidemiológica do Centro de Referência e Treinamento DST/AIDS-SP, de pacientes com aids maiores de 13 anos, acompanhados no ambulatório geral. As variáveis estudadas foram: hepatite C, hepatite B, categoria de exposição, contagem de células T CD4+, faixa etária, escolaridade, cor, sexo e períodos de diagnóstico de aids: 1986 a 1993, 1994 a 1996, 1997 a 2002 e 2003 a 2010. Foi utilizado o estimador de Kaplan-Meier, o modelo de Cox e as estimativas das hazard ratio (HR) com os respectivos intervalos de confiança (IC 95 por cento ). Resultados: De um total de 2.864 pessoas incluídas, com idade mediana de 35 anos, 219 foram a óbito (7,5 por cento ). De 358 (12,5 por cento ) coinfectados, 159 (45,1 por cento ) eram usuários de drogas injetáveis (UDI) e de 2.506 não coinfectados, 96 (3,9 por cento ) eram UDI. A probabilidade acumulada de sobrevida entre coinfectados, a partir do diagnóstico de aids, foi 100 por cento aos 60 meses no período de 1986 a 1993; 27,8 por cento aos 168 meses no período de 1994 a 1996; 76,3 por cento aos 168 meses no período de 1997 a 2002 e 92,8 por cento aos 96 meses no período de 2003 a 2010. As curvas de sobrevida foram diferentes entre coinfectados e não coinfectados no período de 1994 a 1996 (log rank = 19,8; p < 0,001) e no período de 1997 a 2002 (log rank = 38,8; p < 0,001). No modelo de Cox multivariado, mostraram-se preditores de óbito, independentemente das outras variáveis: ter hepatite C (HR = 2,9; IC 2,1-3,9), ter hepatite B (HR = 2,5; IC 1,7-3,6), ter até 3 anos de estudo (HR = 2,3; IC 1,5-3,6), ter 50 anos ou mais de idade (HR = 2,1; IC 1,3-3,2). Ter diagnóstico de aids no período entre 1997 a 2002 mostrou-se fator de proteção ao óbito (HR = 0,4; IC 0,3-0,5). Conclusões: Coinfectados HIV/HCV apresentaram menor sobrevida quando comparado com não coinfectados nos períodos de diagnóstico de aids 1994 a 1996 e 1997 a 2002. A partir do período 1994 a 1996, observou-se aumento significativo na probabilidade acumulada de sobrevida entre coinfectados, sendo que no período 2003 a 2010, essa probabilidade foi semelhante entre coinfectados e não coinfectados, refletindo possível impacto do tratamento da hepatite C / Introduction: The estimated survival of patients with HIV/AIDS has increased after highly active antiretroviral therapy; mortality due to liver diseases, however, has also increased. Objectives: To estimate the accumulated probability of survival after AIDS diagnosis among HIV/HCV co-infected individuals and to perform an exploratory analysis to investigate factors related to the survival of these patients. Method: Non-concurrent cohort study, using data from the National Disease Reporting Information System, the laboratory and epidemiological surveillance information systems of the SP-STD Reference and Training Center-CRT, of patients over 13 years of age, followed at the general outpatient clinic. The following variables were studied: hepatitis C, hepatitis B, exposure category, T CD4+ cell count, age group, schooling, color, sex, and AIDS diagnostic periods: 1986 to 1993, 1994 to 1996, 1997 to 2002 and 2003 to 2010. Survival analysis was performed using the Kaplan-Meier estimator and the Cox model, with estimates of the hazard ratio (HR) and respective confidence intervals (95 per cent CI). Results: Of a total of 2,864 individuals included, with a median age of 35 years, 219 died (7.5 per cent ). Of the 358 (12.5 per cent ) HIV/HCV co-infected individuals, 159 (45.1 per cent ) were injecting drug users (IDU), and of the non-co-infected 2,506, 96 (3.9 per cent ) were IDU. The accumulated probability of survival among HIV/HCV co-infected individuals at 60, 168, 168 and 96 months as of AIDS diagnosis, was 100 per cent in the 1986 -1993 period; 27,8 per cent in the 1994-1996 period; 76,3 per cent in the 1997-2002 period; and 92,8 per cent in the 2003-2010 period. The survival curves were different between co-infected and non-co-infected individuals in the 1994-1996 (log rank = 19,8; p < 0,001) and in the 1997-2002 (log rank = 38,8; p < 0,001). In the multivariate model, regardless of other variables, the following were predictors of death: having hepatitis C (HR = 2.9; CI 2.1-3.9); having hepatitis B (HR = 2.5; CI 1.7-3.6); being 50 years old or over (HR = 2.1; CI 1.3-3.2) and having up to 3 years of schooling (HR = 2.3; CI 1.5-3.6). AIDS diagnosis between 1997 and 2010 was shown to be a protective factor for death (HR = 0.4; CI 0.3-0.5). Conclusions: HIV/HCV co-infected individuals had shorter survival, when compared to non-co-infected individuals in the 1994-1996 and in the 1997-2002 AIDS diagnostic periods. As of the 1994-1996 period, a significant increase in the accumulated probability of survival among HIV/HCV co-infected individuals was observed. In the 2003-2010 period, the probability was similar between co-infected and non-coinfected individuals, showing the possible impact of hepatitis treatment

O câncer de mama apresenta alta incidência na população feminina, sendo considerado uma das principais causas de morte por câncer entre mulheres em diversos países; devido a isso, tornam-se essenciais estudos de sobrevivência na área oncológica, para avaliar resultados, fatores relacionados e delinear o comportamento da doença. Este estudo teve como objetivo avaliar a taxa de sobrevida em mulheres com câncer de mama atendidas em um serviço de reabilitação de mulheres mastectomizadas, tratadas em hospital universitário de nível terciário, localizado no interior da região Sudeste do país. A coorte foi identificada a partir de busca de atendimentos realizados no núcleo de reabilitação de 1989 a 2014. A coleta foi realizada em dados secundários, complementado por busca no banco do Sistema de Informação sobre Mortalidade (SIM), contato telefônico e distribuição de cartas. As principais variáveis analisadas foram as sociodemográficas: idade ao diagnóstico, cor da pele, estado civil e procedência; as clínicas e de tratamento: tamanho do tumor, estadiamento, marcadores tumorais, hormonioterapia, cirurgia e radioterapia, entre outras. Os dados foram apresentados de maneira descritiva por meio de números absolutos, medidas de tendência central e de variabilidade. As funções de sobrevida foram calculadas por meio do método de Kaplan- Meier, e para comparação entre as curvas foi utilizado o teste Log Rank. O nível de significância considerado para o estudo foi de 0,05. Não foi realizado neste estudo o modelo de riscos proporcionais de Cox. Os resultados deste estudo indicam que a sobrevida global em 60 meses desta população foi de 78,5%. E a sobrevida livre de doença (SLD) foi 75,8% em 60 meses. Apresentaram diferenças significativas em relação à ocorrência ao desfecho analisado, que foi o óbito, das características sociodemográficas, apenas as variáveis estado civil (p < 0,007) e escolaridade (p < 0,000). Na análise das curvas de sobrevivência, identificamos uma sobrevivência menor para aquelas mulheres que tiveram até 4 anos de estudo. Referente às características clínicas, o tipo histológico mais frequente foi o CDI com (82,2%); 49,9% apresentavam tumor entre 2 e 5 cm e o estádio clínico predominante no diagnóstico foi o IIA (25,7%), o estadiamento e presença de receptor de hormônio estrógeno e progesterona positivos, apresentaram uma relação estatisticamente significativa com a ocorrência do óbito (p < 0,000) e diferenças significativas nas curvas de sobrevivência. Aquelas que não desenvolveram metástase à distância apresentaram sobrevida de 96,9% em cinco anos, comparado com aquelas que tiveram metástase em 5 anos (50%). Houve significância pelo teste de Log-rank (p<0,000) nessa variável. Os resultados deste estudo fortalecem a importância do diagnóstico precoce através do rastreamento por meio do exame clínico das mamas e de mamografia, aliado ao tratamento eficaz. A análise da sobrevivência dessas mulheres possibilitou conhecer o perfil de mulheres atendidas em um serviço público de saúde, de nível terciário/quaternário, de alta complexidade e de referência. Estas informações são extremamente úteis para os gestores de saúde adotarem medidas voltadas para a prevenção e controle da doença, assim como para avaliações da qualidade do cuidado prestado e acessibilidade ao sistema de saúde / Breast cancer has a high incidence in the female population and is considered a major cause of cancer death among women in many countries, there fore it is essential more survival studies in oncology to evaluate results, related factors and outline the behavior disease. This study aimed to evaluate the survival rate of women treated in a rehabilitation service of mastectomies at the university hospital of tertiary level, located in the Southeast region of the country. The cohort was identified from search services performed in the rehabilitation center from 1989 to 2014. The data were collected on secondary data, complemented by search the database of the Mortality Information System (MIS), telephone call and distribution of cards. The main demographic variables were: age at diagnosis, skin color, marital status and origin, clinical and treatment: tumor size, stage, tumor markers, hormone therapy, surgery and radiation, among others. The data were presented descriptively by absolute numbers, measures of central tendency and variability. Survival functions were calculated using the Kaplan-Meier method and to compare the curves we used the log rank test. The level of significance for the study was 0.05. It was not done in this study the model of Cox proportional hazards. The results indicated that overall survival at 60 months of this population was 78.5%, and the specific-survival was 75.8% in 60 months. Only the variables marital status (p <0.007) and education (p <0.000), the sociodemographic characteristics, showed significant differences in the occurrence analyzed the outcome, which was death. In the analysis of the survival curves we identified a lower survival for those women who had up to 4 years of study. Regarding the clinical features, the most common histological type was with CDI (82.2%); 49.9% had tumors between 2 and 5 cm and the predominant clinical stage at diagnosis was the IIA (25.7%), the staging and the presence of the hormone estrogen and progesterone receptor positive showed a statistically significant related to the occurrence of death (p <0.000) and significant differences in survival curves. Those who did not develop distant metastases had a survival rate of 96.9% in five years compared with those who had metastasis in 5 years (50%). There were significant by log-rank test (p <0.000) in this variable. The results of this study reinforce the importance of early diagnosis through screening by clinical breast examination and mammography combined with effective treatment. The analysis of the survival of these women showed the profile of women in reference a public health service, tertiary / quaternary level, high complexity. These informations are extremely useful for health managers to adopt measures aimed at preventing and controlling the disease, as well as the quality of service and accessibility to health care system assessments

O câncer é responsável por aproximadamente 13% de todas as mortes no mundo, sendo que elas ocorrem principalmente em pessoas que são diagnosticadas tardiamente e em estágios avançados. Devido às suas características devastadoras e à prevalência cada vez maior da doença, é inquestionável a necessidade de investigações e pesquisas constantes na área, no sentido de aprimorar a detecção precoce e auxiliar em sua prevenção e tratamento. Dentre as diversas abordagens existentes, uma alternativa é a criação de técnicas para estimar o período de crescimento \"silencioso\" do câncer, que significa conhecer o momento do início do processo cancerígeno, também chamado de período de latência. A partir da revisão da literatura realizada, foi verificada uma escassez de modelos que estimam a latência do câncer, indicando a necessidade de estudo sobre o tema. Nesse contexto, métodos de análise de sobrevivência surgem como uma ferramenta útil para a construção desses modelos. No presente trabalho, é apresentada uma revisão de um modelo já existente, bem como sua formulação e métodos de estimação. Além disso, apresenta-se uma aplicação em um conjunto de dados reais e uma discussão dos resultados obtidos.Foi identificada a necessidade da formulação de um novo modelo, visto que o método estudado apresenta algumas limitações. Com isso são apresentadas 3 alternativas de modelos que solucionam os pontos apresentados na discussão, com respectivas aplicações. / Cancer is responsible for about 13% of all deaths in the world occuring mainly in people who are late diagnosed and in advanced stages. Due to its devastating characteristics and the growing prevalence of the disease, it is unquestionable the need of constant investigation and research in this area, in order to improve the early detection and to help in its prevention and treatment. Among the existing approaches, one alternative is the creation of techniques to estimate the \"silent\" growth period of cancer, which means to know the beginning moment of the carcinogen period, also known as latency period. In a literature review, it was found an shortage of models that estimate the latency of cancer, indicating the need of study about this theme. In this context, survival analysis methods appear as an useful tool to build these models. In this study, a review of an existing model is presented, as well as its formulation and estimation methods. Furthermore, an application on real data and a discussion of the obtained results are made. As a result, it was identified the need to formulate a new model, because of the limitations of the studied one. We present 3 alternative models that solve the points presented in the discussion, with applications.

Analyzing life-time data with long-term survivors is an important topic in medical application. Cure models are usually used to analyze survival data with the proportion of cure subjects or long-term survivors. In order to include the propor- tion of cure subjects, mixture and non-mixture cure models are considered. In this dissertation, we utilize both maximum likelihood and Bayesian methods to estimate model parameters. Simulation studies are carried out to verify the nite sample per- formance of the estimation methods. Real data analyses are reported to illustrate the goodness-of- t via Fr echet, Weibull and Exponentiated Exponential susceptible distributions. Among the three parametric susceptible distributions, Fr echet is the most promising. Next, we extend the non-mixture cure model to include a change point in a covariate for right censored data. The smoothed likelihood approach is used to address the problem of a log-likelihood function which is not di erentiable with respect to the change point. The simulation study is based on the non-mixture change point cure model with an exponential distribution for the susceptible subjects. The simulation results revealed a convincing performance of the proposed method of estimation. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

Personalised medicine is replacing the one-drug-fits-all approach with many prognostic models incorporating biomarkers available for risk stratifying patients. Evidence has been emerging that the effects of biomarkers change over time and therefore violate the assumption of proportional hazards when performing Cox regression. Analysis using the Cox model when the assumptions are invalid can result in misleading conclusions. This thesis reviews existing approaches for the analysis of non-proportional effects with respect to survival data. A number of well-developed approaches were identified but to date their uptake in practice has been limited. There is a need for more widespread use of flexible modelling to move away from standard analysis using a Cox model when the assumption of proportional hazards is violated. Two novel approaches were applied to investigate the impact of follow-up duration on two residual risk models, IHC4 and Mammostrat, for predicting risk in early breast cancers using two studies with different lengths of follow up; the Edinburgh Breast Conservation Series (BCS) and the Tamoxifen versus Exemestane Adjuvant Multinational (TEAM) trial. Similar results were observed between the two approaches that were considered, the multivariable fractional polynomial time (MFPT) approach and Royston-Parmer flexible parametric models, with their respective advantages and disadvantages being discussed. The analyses identified a strong time-varying effect of IHC4 score with the prognostic effect of IHC4 score on time-to distant recurrence decreasing with increasing follow-up time. Mammostrat score identified a group of patients with an increased risk of distant recurrence over full follow-up in the TEAM and Edinburgh BCS cohorts. The results suggest a combined IHC4 and Mammostrat risk score could provide information on the risk of recurrence and warrants further study.

Usualmente a análise de sobrevivência considera a modelagem da função da taxa de falha ou função de risco. Uma alternativa a essa visão é estudar a vida residual, que em alguns casos é mais intuitiva do que a função de risco. A vida residual é o tempo de sobrevida adicional de um indivíduo que sobreviveu até um dado instante t0. Este trabalho descreve técnicas semiparamétricas e não paramétricas para estimar a média e a mediana de vida residual em uma população, testes para igualdade dessas medidas em duas populações e também modelos de regressão. Tais técnicas já foram testadas anteriormente em dados com baixa presença de censura; aqui elas são aplicadas a um conjunto de dados de pacientes com insuficiência cardíaca que possui uma alta quantidade de observações censuradas. / Usually, survival analysis is based on the modeling of the hazard function. One alternative approach is to consider the residual life, which would be more intuitive than the hazard function. Residual lifetime is the remaining survival time of a person given he or she survived a given time point t0. We describe semiparametric and non-parametric techniques for mean and median residual life estimation in a one-sample population, as well as tests for two-sample cases and regression models. Such techniques were previously tested for moderate censored data; here we apply them to heart-failure patients data with a high rate of censoring.

Alzheimer's disease (AD) has multiple factors that contribute to the disease process. Among these is a state of chronic inflammation that is endured by the brain during the aging process. The use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the amount of neuroinflammation sustained by the brain, and greater levels of NSAID use have been demonstrated to be associated with decreased probability of developing AD. This study looked at whether greater rates of NSAID use were also associated with decreased rates of cognitive and funtional decline and survival in a population-based sample of persons with AD.

The purpose of this dissertation is to understand why individuals enrolled in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) fail to retrieve food vouchers, miss WIC appointments, and become inactive in program components. In Kentucky, mothers who fail to pick up food instruments for 60 days are automatically terminated from the program. The specific research questions that guided this study are: (1) Which segments of enrollees are at greatest and least risks of nonparticipation in the WIC program? (2) How do predisposing, enabling and need characteristics impact WIC nonparticipation among eligible mothers? (3) How do WIC enrollees describe their experiences using WIC? (4) What do WIC enrollees report as reasons for nonparticipation while still eligible? Addressing these research questions will inform the development of practical outreach solutions specifically tailored for the purpose of mitigating nonparticipation in WIC and contribute to our understanding of the factors that deter eligible families from using government assistance programs like WIC.

MPhilPH / Female tubal sterilisation, often referred to as "tubal ligation" but more often performed these days using laparoscopically-applied metal clips, remains a popular form of contraception in women who have completed their families. A review of the literature on the incidence of failure of tubal sterilisation found many reports of case-series and small clinic-based studies, but only a few larger studies with good epidemiological designs, most recently the US CREST study conducted during the 1980s and early 1990s. The CREST study reported a conditional (life-table) cumulative incidence of failure of 0.55, 0.84, 1.18 and 1.85 per 100 women at 1, 2, 4 and 10 years of follow-up respectively. The study described here estimated a lower bound for the incidence of tubal sterilisation failure in NSW by probabilistically linking routinely-collected hospital admission records for women undergoing sterilisation surgery to hospital admission records for the same women which were indicative of subsequent conception or which represented censoring events such as hysterectomy or death in hospital. Data for the period July 1992 to June 2000 were used. Kaplan-Meier and proportional-hazards survival analyses were performed on the resulting linked data set. The conditional cumulative incidence per 100 women at 1, 2 4 and 8 years of follow-up was estimated to be 0.74 (95% CI 0.68-0.81), 1.05 (0.97-1.13), 1.33 (1.23-1.42) and 1.51 (1.39-1.62) respectively. Forty percent of failures ended in abortion and 14% presented as ectopic pregnancies. Age, private health insurance status and sterilisation in a smaller hospital were all found to be associated with lower rates of failure. Strong evidence of time-limited excess numbers of failures in women undergoing surgery in particular hospitals was also found. The study demonstrates the feasibility of using linked, routinely-collected health data to evaluate relatively rare, long-term outcomes such as sterilisation failure on a population-wide basis.

The survival of motor neurons is controlled by multiple factors, which regulate different aspects of their physiology. The identification of these factors is important because of their relevance for motor neuron disease. This thesis began with a search for novel growth factors that naturally keep these neurons alive. Members of the TGF-β superfamily, including Mullerian inhibiting substance (MIS) and bone morphogenetic protein 6 (BMP6), were identified as putative survival factors following a cDNA microarray analysis of a mouse model of motor neuron disease. MIS is a gonad-derived hormone with a male bias. It induces the degeneration of the female reproductive tract during development and it was thought to have no physiological function outside of the reproductive system. In this thesis, multiple techniques were used to show that adult motor neurons produce MIS and its receptors. The copy number of MIS mRNA in motor neurons was comparable with that of the testis, whereas the mRNA of the MIS type II receptor (MISRII) in motor neurons appeared to be the most abundant receptor of the TGF-β superfamily. These results were confirmed using Western blot and immunohistochemistry. Thus, MIS may exert its function through an autocrine or a paracrine mechanism between neighbouring motor neurons. The function of MIS was examined using a culture system and a mouse null mutation of MISRII. The in vitro assays showed strong neurotrophic effects of MIS on embryonic motor neurons with the maximum extent of survival being similar to that achieved by the classical motor neuron survival factor, GDNF. MIS has a male bias in utero raising the issue of whether motor neurons are sexually dimorphic. Consistent with this, the number of motor neurons in the lumbar lateral motor column of neonatal male MISRII+/+ mice was 13 % greater than in female mice (P = 0.01). The nuclei of male motor neurons were approximately 20 % larger than their female counterparts (P = 0.000). MISRII-/- male mice had 18 % fewer motor neurons than wild-type males (P = 0.01) and the mean size of their motor neurons was 20 % smaller (P = 0.000). The number and size of motor neurons in the MISRII-/- males was not different to those of MISRII+/+ females. These results implicate MIS as being responsible for neuronal survival as well as producing sexual dimorphism of the limb innervating motor neurons. Since MIS does not appear to be expressed in the embryonic neuromuscular system, it is postulated that MIS is a gonad-derived neurotrophic factor for developing motor neurons. The BMP type II receptor (BMPRII) was the second most abundant receptor of the TGF-β superfamily expressed by motor neurons. One of its ligands, BMP6, was found to have a neurotrophic effect on motor neurons in culture but was slightly less potent than MIS. BMP6 mRNA was detected in nerve, skeletal muscle and spinal cord, but not in motor neurons. BMP6 immunoreactivity was mainly associated with the myelinated Schwann cells and satellite glia that surround motor neurons. In skeletal muscles, immunoreactivity was not detected in muscle fibers, nor the postsynaptic region of the neuromuscular junction (NMJ). BMP6 was, however, associated with the interstitial cells of skeletal muscles. Double nerve ligations were used to examine whether Schwann cell-derived BMP6 interacts with motor neurons. Consistent with this, BMP6 was retrogradely transported in motor axons. These observations collectively suggest that BMP6 is a glia-derived regulator of motor neurons. MIS and minority of BMP6 were anterogradely transported towards the NMJ. Their receptors, MISRII and BMPRII, were detected in the postsynaptic portions of the adult NMJ. These observations raised the possibility that MIS and BMP6 may be regulators of the adult NMJ. Since functional redundancy amongst the members of the TGF-β superfamily has been suggested, the function of MIS/BMP6 signaling at the NMJ was therefore examined in mice with muscle-specific deletion of Smad4, a central mediator of TGF-β superfamily pathways. More than 75% of animals lacking Smad4 in muscles died before embryonic day (E) 14 and none survived postnally. This was due to the loss of functional Smad4 in developing cardiac myocytes, which resulted in severe heart defects and early death of embryos. Thus, the function of MIS/BMP6 signaling at the adult NMJ could not be studied. Finally, this thesis briefly examined the phenotypes of mice carrying double null mutations of MISRII and TGF-β2. The animals died at an early stage and showed a more severe phenotype than either of the single null mutants. This suggests that functional redundancy among members of the TGF-β superfamily exists in many organs. In summary, motor neurons require multiple sources of growth factors for their survival. MIS and BMP6 were discovered as novel survival factors for motor neurons in this study. MIS was implicated as a regulator of sexual dimorphism in developing motor neurons, whereas both MIS and BMP6 appear to regulate mature motor neurons, and possibly the NMJ.