Introdução: A estratégia de tratamento baseado em metas tem sido extensamente estudada em pacientes com AR inicial. No entanto, estudos sobre os benefícios de longo prazo do controle de atividade de doença em pacientes com AR estabelecida ainda são escassos. Objetivo: Avaliar a efetividade de longo prazo da estratégia de tratamento baseado em metas em pacientes com artrite reumatoide estabelecida na prática diária. Métodos: Pacientes com AR, previamente tratados de forma convencional, iniciaram estratégia de tratamento baseado em metas, sendo incluídos de março de 2005 a fevereiro de 2007 e acompanhados até dezembro de 2014. Os pacientes eram avaliados a cada 3 meses até remissão ou baixa atividade de doença serem alcançadas, e após a cada 6 meses. O tratamento seguiu um escalonamento de acordo com as recomendações vigentes. A atividade de doença foi mensurada através do DAS28 e do CDAI e a capacidade funcional, através do HAQ-DI. As informações foram extraídas pela revisão de formulários e de tabelas padronizadas. Variações na atividade de doença e na capacidade funcional foram comparadas pelo teste de Wilcoxon e Equações de Estimativas Generalizadas (GEE) A mortalidade foi avaliada através da curva de Kaplan-Meier. Resultados: Duzentos e vinte e nove pacientes foram incluídos, com duração média de doença 10,6±7,4 anos. Dentre os pacientes em moderada e alta atividade de doença no início da coorte, houve significativa redução do DAS28 (4,6±0,1 vs. 3,1±0,1; p<0,001) e do CDAI (21,2±1,0 vs. 7,9±0,7; p<0,001). Também houve redução do HAQ-DI (1,3±0,05 vs 1,0±0,1; p<0,001). A proporção de pacientes em remissão ou em baixa atividade de doença aumentou de 20% para 62% pelo DAS28. Com a estratégia de tratamento baseado em metas, houve um aumento na proporção de pacientes em uso de biológico para 30%. A taxa de mortalidade foi de 24,2 por 1000 pacientes-ano, discretamente superior à descrita na literatura. Conclusão: A estratégia de tratamento baseado em metas com objetivo de remissão e de baixa atividade de doença é efetivo em pacientes com AR estabelecida. / Introduction: Treating RA to a target has become a landmark strategy to be pursued in every patient. Nonetheless, few studies have addressed the true long-term impact of a T2T strategy in a real-world setting with established RA patients. Objective. To examine the long-term effectiveness of a treat-to-target (T2T) strategy in patients with established rheumatoid arthritis (RA) in daily practice. Methods. Patients with RA who were previously given the standard of care were started on a T2T strategy between March 2005 and February 2007 and followed through December 2014. Participants were seen every 3 months until remission/low disease activity was achieved and every 6 months thereafter. Treatment escalation followed a step-up strategy, according to national recommendations. Disease activity was measured by the DAS28 score and Clinical Disease Activity Index (CDAI), and physical function by the Health Assessment Questionnaire (HAQ). Data were extracted with standardized forms and a chart review. Changes in disease activity and physical function were compared using Wilcoxon’s test and generalized estimating equations. Mortality was analyzed using a Kaplan–Meier survival curve. Results. Two hundred and twenty-nine patients were included, with a mean (S.D.) disease duration of 10.6 (7.4) years. Significant reductions were observed in DAS28 (4.6±0.1 vs. 3.1±0.1; p<0.001), CDAI (21.2±1.0 vs. 7.9±0.7; p<0.001), and HAQ (1.3±0.05 vs 1.0±0.1; p<0.001) scores. The proportion of participants in remission/with low disease activity according to DAS28 increased from 20% to 62%. During implementation of the T2T strategy, a gradual increase in the proportion of participants using biologics was observed, to nearly 30%. The mortality rate was 24.2 per 1000 patient-years, slightly higher than that reported in other cohorts. Conclusion. A treat-to-target strategy aiming for remission or low disease activity is effective in patients with established RA.

Introdução: O prognóstico dos carcinomas epidermóides de laringe é limitado e a taxa de sobrevida em cinco anos é menor que 70%. A relação de características clínicas e epidemiológicas tem sido investigada na sobrevida de pacientes com tumores de laringe, mas pouco se conhece sobre o efeito dos polimorfismos genéticos no prognóstico da doença. Objetivo: Estudar o papel dos polimorfismos genéticos de genes relacionados aos processos de invasão e metástase (MMP1 e MMP3), de inflamação (Interleucina 2, Interleucina 6, LTA) e reparo de DNA(XRCC1) no prognóstico do carcinoma epidermóide de laringe. Material e métodos: Coorte com 170 pacientes com carcinoma epidermóide de laringe,confirmados por exame anátomo-patológico. Os casos tiveram origem em estudo caso-controle conduzido em cinco hospitais de São Paulo, um hospital em Porto Alegre e outro em Goiânia. As informações sobre o status vital dos pacientes foram levantadas dos prontuários médicos e dos bancos de óbitos municipais e estaduais. A extração do DNA das amostras de sangue dos pacientes foi realizada pelo Instituto de Medicina Tropical da USP e a genotipagem dos polimorfismos genéticos pela Fundação Hemocentro de Ribeirão Preto da Faculdade de Medicina da USP. Resultados: Os polimorfismos genéticos estudados (MMP1 1607, MMP1 -519,MMP3 -1171, IL2 -384, IL2 114, IL6 -174, LTA 252 e XRCC1) não apresentaram efeitos com significância estatística na sobrevida global ou específica pela doença quando analisados isoladamente. Para a sobrevida global, o consumo excessivo de álcool, em g/L/dia, reduziu a sobrevida dos pacientes (80-119 g/L/dia: hazard ratio(HR)=4,0 intervalos com 95% de confiança (IC95%)=1,10-14,53; _120 g/L/dia: HR=5,6 IC95%=1,71-18,24). No modelo de Cox múltiplo, quando ajustados pelo polimorfismo genético MMP3 -1171, a sobrevida piorou para esses pacientes (80-119 g/L/dia: HR=4,9 IC95%=1,07-22,91; _120 g/L/dia: HR=6,3 IC95%=1,49-26,84). Para a sobrevida específica pela doença, o estadiamento clínico IV reduziu a sobrevida dos pacientes (HR=3,5 IC95%=1,67-7,28). No modelo de Cox múltiplo,com ajuste pelos polimorfismos genéticos IL6 -174 e MMP1 1607, a sobrevidaespecífica pela doença piorou para esses pacientes (HR=4,7 IC95%=1,38-16,25).Conclusões: Na coorte examinada, somente três dos oito polimorfismos genéticos estudados relacionaram-se com a sobrevida global e específica pela doença, porém apenas alterando o efeito dos valores dos HR brutos dos fatores consumo de álcool e estadiamento clínico, respectivamente na sobrevida global e sobrevida específica pela doença. Isoladamente, nenhum polimorfismo genético estudado interferiu na sobrevida dos pacientes com câncer de laringe. / Introduction: The prognosis of laryngeal squamous cell carcinoma is limited and survival rate is lower than 70%. The relationships between clinical and epidemiological characteristics have been fully investigated on the survival of patients with laryngeal tumors, but the effect of genetics polymorphisms on squamous cell carcinoma of larynx is not well-known. Objective: To study the role of genetic polymorphisms of genes related to the processes of invasion and metastasis (MMP1 and MMP3), inflammation (Interleukin 2, Interleukin 6, and LTA) and repair of DNA (XRCC1) in the prognosis of laryngeal squamous cell carcinoma. Material and methods: Cohort with 170 laryngeal squamous cell carcinoma patients with histological confirmation. The cases have their origin in a case-control study carried out in hospitals of Sao Paulo, Porto Alegre and Goiania. The information about vital status of patients had been raised from medical records. The extraction of DNA was carried out by Institute of Tropical Medicine of USP and genotyping was carried out by the Center of Cellular Therapy of the Hemocentro of Ribeirao Preto of Medical School of USP. Results: The studied genetic polymorphisms (MMP1 1607, MMP1 -519, MMP3 -1171, IL2 -384, IL2 114, IL6 -174, LTA 252 and XRCC1), separately analyzed, did not have any statistical significant effect on the overall and cause-specific survival. High levels of alcohol consumption (g/L/day) reduced the overall survival (80-119 g/L/day: hazard ratio(HR)=4.0 intervals with 95% of confidence (95%CI)=1.10-14.53; _120 g/L/day:HR=5.6 95%CI=1.71-18.24). Multiple Cox model revealed, when adjusted for MMP3 -1171 genetic polymorphism, lower survival for those patients (80-119g/L/day: HR=4.9 95%CI=1.07-22.91; _120 g/L/day: HR=6.3 95%CI=1.49-26.84). The clinical staging (CS) IV was a factor for low cause-specific survival (CS IV:HR=3.5 95%CI 1.67-7.28). In the multiple Cox model, adjusted for genetic polymorphism IL6 -174 and MMP1 1607, the survival of those patients droppe(HR=4.7 95%CI=1.38-16.25). Conclusions: In this cohort, only three of eight genetic polymorphisms studied were showed to be related with overall and causespecific survival, however only modifying the effect of unadjusted HR of alcohol consumption and tumor clinical staging in the overall and cause-specific survival respectively. None of the studied genetic polymorphisms, when analyzed separately,affected the survival of laryngeal cancer patients.

My PhD work aimed to assess intergenerational transmission and life-course change of attitudes towards authority. Intergenerational transmission is hypothesised as the mechanism through which parents' authoritarian attitudes affect their children's attitudes towards authority in adulthood. In the assessment of this transmission mechanism, this analysis accounts for individual-level theoretically relevant factors such as gender, education, social class, offspring's cognitive ability in childhood, as well as family background, in a longitudinal, single-cohort perspective. The research used the British Cohort Study 1970 (BCS70), which allows for the analysis of change at both the intra- and inter-individual levels. The sweeps analysed are those in years 1975 for the parents, and 1980, 1996, 2000 and 2012 for the cohort members. The analytical chapters of the thesis are made of three papers: The first assessed change (or stability) in attitudes to authority in the BCS70 from 1996 to 2012; the second looked at how parental authoritarian worldviews affect their children's attitudes towards authority when the children are adults; finally, the third paper aimed to evaluate the effect of parental attitudes on cohort members' attitudes towards authority in adulthood, after controlling for the latter's cognitive ability in childhood. I found that attitudes had a reasonably high level of stability across the life course. Despite moderately strong correlations across attitudes within waves, the different attitudes showed different patterns of longitudinal evolution, suggesting different causal influences. The evidence for direct transmission of attitudes from parents to children was surprisingly weak; the social statuses of the parents and cohort members, and especially the members' childhood cognitive ability, were the strongest predictors of authoritarian attitudes in adulthood.

Background: Posttraumatic-Stress Disorder (PTSD) is less common in older adults than in younger adults, and little is known about specific risk factors for PTSD in older adults. We investigated the association between self-esteem in late adolescence and PTSD in older adults. Method: Using a cohort design, 1,436 individuals who had been assessed approximately 40 years earlier in their junior and senior year of high school with the Rosenberg Self-Esteem Scale (RSES) were evaluated for PTSD using the PTSD Checklist (PCL-17). Results: Fully controlled logistic regression models indicated that lower self-esteem in late adolescence predicted PTSD in the overall sample of older adults but not in the veterans-only subgroup. Limitations: The main limitations include self-completed measures to estimate PTSD diagnosis and lack of specific information on traumatic events. Conclusions: Our findings suggest that lower self-esteem from a young age may be a risk factor for PTSD in older age.

The purpose of this thesis was to assess the possible risk of myocardial infarction in work entailing exposure to vibration, and to study whether there is any relation between short-term exposure to vibration and cardiac regulation. Epidemiological methods were applied to investigate a possible association between occupational exposure to vibration and myocardial infarction. Two study populations were used; one case-control study (n=475) and one cohort of iron-ore miners in Kiruna and Malmberget, Sweden (n=13621). In the former, the cases were first-time myocardial infarction patients and the controls were selected to match for sex, age and hospital catchment area. Job-exposure matrixes for vibration were established for both the case-control study and the cohort study. In order to study acute effects on cardiac regulation, an experimental study was conducted on healthy subjects (n=20) who were exposed to hand-arm vibration exclusively and in combination with exposure to noise. The effect on the autonomic balance was measured by heart rate-variability. In the case-control study, an increased risk of contracting myocardial infarction was found among occupations entailing vibration exposure. The results from the cohort show an increased risk of myocardial infarction mortality compared to a reference population. The increment was higher for those younger than 60 years. Relative risks for myocardial infarction mortality increased with increasing exposure to vibration in the group at working-age and the increased risk remained after adjusting for exposure to dust. In the experimental study, exposure to hand-arm vibration was found to acutely affect the autonomic nervous system as the total heart-rate variability decreased during exposure to hand-arm vibration. To conclude: work entailing exposure to vibration is a risk factor for myocardial infarction, increased myocardial infarction mortality attributed to exposure to vibration seems to be mainly observed at working-age, and exposure to hand-arm vibration acutely decreases heart-rate variability and thus affects heart-rate regulation.

Objective: Although associations between testosterone and cardiovascular (CV) morbidity in women have been proposed, no large prospective study has evaluated potential associations between testosterone and mortality in women. The objective was to determine whether baseline testosterone levels in women are associated with future overall or CV morbidity and mortality. Design: Prospective cohort study with a 4.5-year follow-up period. Methods: From a representative sample of German primary care practices, 2914 female patients between 18 and 75 years were analyzed for the main outcome measures: CV risk factors, CV diseases, and all-cause mortality. Results: At baseline, the study population was aged 57.96±14.37 years with a mean body mass index of 26.71±5.17 kg/m2. No predictive value of total testosterone for incident CV risk factors or CV diseases was observed in logistic regressions. Patients with total testosterone levels in the lowest quintile Q1, however, had a higher risk to die of any cause or to develop a CV event within the follow-up period compared to patients in the collapsed quintiles Q2–Q5 in crude and adjusted Cox regression models (all-cause mortality: Q2–Q5 versus Q1: crude hazard ratios (HR) 0.49, 95% confidence interval (CI) 0.33–0.74; adjusted HR 0.62, 95% CI 0.42–0.939; CV events: Q2–Q5 versus Q1: crude HR 0.54, 95% CI 0.38–0.77; adjusted HR 0.68, 95% CI 0.48–0.97). Kaplan–Meier curves revealed similar data. Conclusions: Low baseline testosterone in women is associated with increased all-cause mortality and incident CV events independent of traditional risk factors.

Growing up in an urban area has been shown to be associated with an increased risk of psychotic disorder in later life. While it is commonly held that a only a tiny fraction of exposed individuals will develop schizophrenia, recent evidence suggests that expression of psychosis in exposed individuals may be much more common, albeit at attenuated levels. Findings are based on a population sample of 2548 adolescents and young adults aged originally 14–24 years, and followed up over almost 5 years up to ages 17–28 years. Trained psychologists assessed all these subjects with the core psychosis sections on delusions and hallucinations of the Munich-Composite International Diagnostic Interview. Growing up in an urban area was associated with an increased risk of expression of psychosis in the adolescents and young adults (adjusted OR 1.31, 95% CI 1.03–1.66). The proxy environmental risk factor that urbanicity represents may shift a relatively large section of the adolescent population along a continuum of expression of psychosis. Other causal influences may be required to make the transition to schizophrenia in adult life.

I assessed the accuracy of two clinical prediction rules, the d-dimer blood test and point of care ultrasound for diagnosing lower limb deep vein thrombosis. Emergency physicians were trained in ultrasound and prospectively scanned emergency department patients with suspected deep vein thrombosis. Accuracy of the Wells and AMUSE rules and the ultrasound result was compared to radiology-performed ultrasound and a 90-day clinical outcome. Univariate and multivariate analyses were performed assessing which factors were associated with the outcome. The sensitivity and specificity of the Wells score for the clinical outcome was 85.7% and 68.5%; the AMUSE score 85.7% and 54.4%. Ultrasound had a sensitivity of 91.7% and specificity of 91.7% for radiology-diagnosed thrombus and 78.6% and 95.0% for clinical outcome. The odds ratio of a positive outcome with a positive ultrasound was 65.1. After receiving the ultrasound training program, emergency physicians were unable to demonstrate sufficient accuracy to replace current diagnostic strategies.

Prevalence of childhood asthma in Taiwan has increased 9 times from 1.3% to 10-14% in the past 4 decades. Many studies worldwide have demonstrated that many genes in different chromosomes are implicated in childhood asthma in different ethnic populations. A growing body of evidence suggests that allergic sensitization could occur in perinatal stage and correlate to the development of childhood asthma. Epidemiological studies, however, indicate that prevalence of childhood asthma is much higher in developed countries than that in developing countries; and prevalence of childhood asthma in metropolitan area is higher than that in country sites. This suggests that certain genes can interact with the environmental factors in developed countries to promote the development of childhood atopic disorders. Interests are now increasing on what is (are) the real pathogenic gene-gene interaction(s) for childhood atopic disorders under influence of age, gender and environmental factors? In a large perinatal cohort study with 1,211 pregnant women and their offspring from the obstetrics and pediatrics of Kaohsiung Chang Gung Memorial Hospital, we analyzed 159 allergy candidate genes with 384 single nucleotide polymorphisms and showed that 14 genes over 22 somatic and X chromosomes risk to or protective from cord blood immunoglobulin E (CBIgE) elevation are different from those genes associated with IgE elevation in children under 1.5, 3 and 6 years of age (12, 15 and 12 genes, respectively). CX3CL1, IL13, PDGFRA and FGF1 polymorphisms were associated with elevated IgE at earlier ages (newborn, 1.5 and 3 years); HLA-DPA1, HLA-DQA1, CCR5 and IL5RA polymorphisms were associated with IgE production at 6 years of age. Further analysis by multifactor dimensionality reduction (MDR) developed from data reduction strategy, we found that there are interactions among innate immunity, adaptive immunity, and response and remodeling genes on IgE production begin in prenatal stage. For example, The gene-gene interaction among IL13, rs1800925, CYFIP2, rs767007 and PDE2A, rs755933 was significantly associated with IgE production at 3 years of age. This suggests that different genotypes of genes interact one another on the IgE production contributing to the development of allergic diseases. Since the concentration of IgE is an important indicator of atopic disorders and allergic sensitization, we believe after clarifying the natural course of the genomic profiles on IgE elevation, certain early predictor(s) and preventive regimens for allergic sensitization or atopic disorders may be made possible.

No description available.