Orientadores: André Deeke Sasse, Carmen Silvia Passos Lima / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-20T01:24:11Z (GMT). No. of bitstreams: 1 Lima_JoaoPaulodaSilveiraNogueira_D.pdf: 5411736 bytes, checksum: d1c0f5a06bb4361a4b7416cd43d94af5 (MD5) Previous issue date: 2012 / Resumo: Introdução: a superioridade de regimes baseados em camptotecinas sobre os regimes baseados em etoposidio para câncer de pulmão de células pequenas, doença extensa, (CPCP-DE) e assunto amplamente debatido com achados contraditórios nos estudos randomizados que compararam estas combinações. Variações farmacogenomicas entre etnias surgiram como hipótese para justificar estas diferenças. Com objetivo de elucidar esta duvida e mensurar a extensão de um eventual beneficio, realizamos uma revisão sistemática e metalize. Métodos: Revisão sistemática da literatura com metanalise. Foram elegíveis estudos randomizados controlados que comparassem o uso de análogo de platina associado ou a camptotecina (irinotecano ou topotecana) ou ao etoposidio como tratamento de primeira linha para CPCP-DE. Buscamos estes estudos nas bases PubMed, EMBASE, CENTRAL, LILACS e nos sítios eletrônicos dos congressos da ASCO, ESMO, ECCO e IASLC. As avaliações de sobrevida global (SG) e sobrevida livre de progressão mediana (SLP) foram apresentadas como hazard ratio (HR) enquanto a taxa de resposta tumoral (RT), toxicidades graves e sobrevida global em um e dois anos foram expressas através de odds ratio (OR). Os intervalos de confiança de 95% foram calculados para cada desfecho. A metalize utilizou método de efeitos randomicos, sendo a heterogeneidade entre estudos expressa através do índice de heterogeneidade I². Avaliação de subgrupos conforme origem geográfica dos estudos foi realizada e o teste de interação foi utilizado para identificar eventuais diferenças. Irinotecano-platina (IP) e topotecana-platina (TP) foram avaliados separadamente. Resultados: 615 referencias foram avaliadas, sendo selecionados nove estudos (3527 pacientes). Dois estudos compararam TP versus EP enquanto sete compararam IP versus EP. A metanalise demonstrou que IP e capaz de aumentar a sobrevida global (1965 pacientes, HR = 0,87; 95% CI 0,80-0,95; P=0,002; I²=0%) e sobrevida global em um ano (HR = 0,74; IC95% 0,60-0,91; P = 0,004; I² = 14%), sem contudo, aumentar claramente a sobrevida livre de progressão, ou resposta tumoral. IP levou a maior incidência de toxicidades gastrointestinais e menos hematológicas. A avaliação de subgrupos conforme origem geográfica não identificou diferença na extensão de beneficio em sobrevida global e em um ano (interação ocidente versus oriente P = 0,34 e P = 0,08 respectivamente) com IP. Na analise de sobrevida global em dois anos, IP e superior a EP em pacientes europeus e asiáticos, sem contudo trazer ganho para pacientes da América do Norte (OR 1,05; IC95% 0,65-1,69; P = 0,85; interação América do Norte versus Europa, P = 0,009; interação América do Norte versus Ásia, P = 0,02). IP aumenta a sobrevida livre de progressão para pacientes orientais (HR = 0,61; IC95% 0,45 - 0,84; P = 0,01) sem ter impacto nos pacientes ocidentais (HR = 0,96; IC95% 0,82 - 1,13; P = 0,65%) com diferença estatisticamente significativa entre estes dois grupos (interação ocidente versus oriente, P = 0,03). O teste de interação não identificou impacto em taxa de resposta tumoral ao esquema IP conforme a origem geográfica (interação ocidente versus oriente P = 0,07). Nas diversas toxicidades avaliadas, não houve diferença entre pacientes ocidentais e orientais. A metanalise de TP versus EP não foi possível devido a heterogeneidade em todos os desfechos avaliados. Conclusão: O presente estudo confirma que IP aumenta sobrevida global tanto para pacientes ocidentais quanto orientais. A sobrevida livre de progressão sob o regime IP e a sobrevida global em dois anos parecem diferir conforme a origem geográfica, enquanto a taxa de resposta e tolerância não. IP pode ser considerado um novo padrão terapêutico para CPCP-DE em todo o globo, com diferenças regionais que merecem avaliação mais profunda / Abstract: Background: Superiority of camptothecin regimens over etoposide - both combined with platinum analogs - in extensive disease small cell lung cancer (ED-SCLC) has been extensively debated, with contradictory results in randomized trials worldwide. Ethnic and pharmacogenomical issues were hypothesized as major causes for these divergent findings. A systematic review was sought to elucidate this confounding scenario. Methods: Randomized controlled trials comparing first-line camptothecin (either irinotecan or topotecan)-platinum doublets (CP) versus etoposide-platinum doublets (EP) in ED-SCLC patients were searched in PubMed, EMBASE, and CENTRAL databases, ESMO, ASCO, and IASLC meeting proceedings. Meta-analyses were performed using random-effects model. Overall survival (OS) and Progression Free survival (PFS) were pooled as hazard ratio (HR), whereas response rate and toxicity were computed as odds ratio (OR). Pertinent 95% confidence intervals (CI) were calculated for all outcomes. Heterogeneity was measured by I². Subgroup analyses were undertaken comparing the geographical area of study and interaction tests were used to evaluate any existing differences found among subgroups. Irinotecanplatinum (IP) and topotecan-platinum (TP) trials were evaluated separately. Results: Nine studies (3527 patients) were included. IP improved median OS (1965 patients; HR = 0.87; 95% CI 0.80- 0.95; P=0.002; I²=0%) and one year OS (HR = 0.74; IC95% 0.60-0.91; P = 0.004; I² = 14%). PFS meta-analysis of IP versus EP was not feasible due to impending heterogeneity (I²=80%), as response rate meta-analysis (I²=56%; absolute response rates: IP = 52%, EP = 50%). There was more severe gastrointestinal toxicity with IP than EP, but less hematological toxicity. The median, and the one year OS analyses according to geographical area demonstrated that eastern and western patients experienced similar benefit from IP (interaction test Western trials versus Eastern trial, P=0.34 and P=0.08 respectively); however the two year OS analysis according to continental origin stated that European and Asian patients derived benefit from IP, whereas North Americans did not (interaction North America versus Europe, P = 0.009; North America versus Asia, P = 0.02). IP improved progression free survival in the Eastern trial (HR = 0.61; CI95% 0.45 - 0.84; P = 0.01), while it had no impact in Western trials (HR = 0.90; CI95% 0.78 - 1.03; P = 0.13; I² = 24%) with difference according to geographical origin (interaction test Western versus Eastern trials, P = 0.03). There was no identifiable difference in response rate to IP due to trial origin (interaction test, P = 0.07). In all toxicity sought, there was no suggestion of different toxicity according to trial origin. The metaanalysis of TP was not reliable due to impending heterogeneity in all outcomes. Conclusion: The present meta-analysis demonstrated that IP improved median and one year OS for both Western and Eastern patients. The activity of IP in terms of PFS and two year OS may be subject of geographical origin of patients ,while IP tolerance seemed to be stable. The present findings corroborate the role of IP as a new standard of care for SCLC-ED worldwide, with regional differences that merit further appraisal / Doutorado / Clinica Medica / Doutor em Clínica Médica

There is a big number of people dying every year from car accidents and not solving this problem is a big issue. Communication protocols have been created in mobile ad-hoc network (MANET) to be able to solve this issue. AODV and DSR are two protocols that are used in this communication. The fact that there is mobile nodes makes it hard to keep track of the efficiency of this communication. This study has for objective giving a better understanding as to which protocol performs better and answering four important questions to know to be able to evaluate what protocol is better according to those parameters or criteria. The implemented method to solve this problem is through a meta-analysis and this meta-analysis is done through a qualitative research, literature review for critical literature reading and data collection to select the appropriate studies and exclud- ing the irrelevant studies based on other criteria. The evaluation of these param- eters are based on others’ work and reading the work from critical eyes. This study compares AODV and DSR from the criteria that are chosen. The study has a critical analysis of the results collected through the different papers show that AODV has outperformed DSR in most of the cases and answering the proposed questions in the study. Finally concluding that AODV is more effective in the case of high congestion compared to DSR but making a bit hard to have a clear cut answer when it comes to the criteria but AODV performed better in all the cases in high congestion.

A third of youth in the United States are currently classified as overweight, which is impacted by the low rates of youth that meet daily physical activity recommendations. Engaging in physical activity contributes to healthy body weight and physical fitness, both of which have positive health consequences. Participating in physical activity not only aids in positive health outcomes, but research indicates that it also has a positive relationship with and effect on youths’ cognitive, academic, and behavioral outcomes. The majority of researchers conducting meta-analyses examining the effect of physical activity on youths’ cognitive, academic, and behavioral outcomes have excluded single-case design research from the data analyses. Excluding these types of designs from syntheses of the research may create an inaccurate account of the effect of physical activity on youths’ cognitive, academic, and behavioral outcomes. The current study addressed these issues by conducting a meta-analysis of single-case design studies over approximately the past 50 years to add to the current understanding of the effect of physical activity on youths’ cognitive, academic, and behavioral outcomes. Additionally, moderator analyses were conducted on numerous participant, intervention, and study characteristics that were deemed important, as indicated in the literature review. The effect size of physical activity on youths’ academic and behavioral outcomes was determined by utilizing hierarchical linear modeling of the included 81 time series from 15 single-case design studies. There were not enough data to calculate the effect size on youths’ cognitive outcomes. Significant effect sizes were found that indicate physical activity has an effect on increasing youths’ desirable behaviors (e.g.on task behavior and social skills) and decreasing youths’ undesirable behaviors (e.g. self stimulation, self-injurious behaviors, and off task behavior; ES = 1.83), as well as, increasing work completion, (ES = 2.01). No moderating effects were found other than the type of single case design moderated the effect on youths’ behavioral outcomes. The current study is important for decision makers in schools when deciding whether to increase or decrease particular students’ time spent in physical activity. Additionally, the results of the study are pertinent to other practitioners who work with youth, parents, and for youth themselves so that they can utilize physical activity interventions to help with appropriate behaviors and work completion.

Public policy analysts are often tasked with reviewing research or other forms of evidence in order to provide advice for policy decisions. Many have argued that systematic reviews that include meta-analyses (SRMAs) are the most rigorous forms of evidence, and thus, when possible, should form the basis of policy decisions. However, it is not yet clear to what extent policy analysts are aware of systematic reviews and meta-analyses, or to what extend they use them to inform policy work. Moreover, given the importance of evaluating the quality of research before using it for policy, it is not clear to what extent policy analysts feel able to judge the quality of systematic reviews and meta-analyses. An online survey was used to provide initial estimates of the extent to which policy analysts a) are familiar with SRMAs; b) use these reviews to inform their policy work; and c) are able to evaluate them. It further sought to explore other correlates of use, barriers to use, methods to increase use, and knowledge of factors that influence quality. Thirty-nine Ministerial policy analysts responded to the survey, 18 from the Ministry of Health, 9 from the Ministry of Environment, and 12 from other ministries. Policy analysts reported being fairly familiar with both systematic reviews and meta-analyses, although they were more familiar with systematic reviews than with meta-analyses. There were no differences between the Health, Environment, or Other groups with respect to familiarity. Respondents reported moderate scores on most indicators of use, with results suggesting the Health group having the highest rates of use, followed by the Environment group and then the Other group. Finally, there were relatively high self-ratings on ability to judge the quality of SRMAs, with no differences found between groups. The results of other exploratory analyses are also presented, and implications and recommendations are discussed. / Graduate

The goal of this thesis is to present a meta-analysis of studies that are focused on the relation between the international trade flow and the trade costs. The effect of trade costshasbecomeoneofthekeyelementstoresolvethesixmajor puzzles in the bilateral trade flow. I examine 1,090 estimates of the trade cost effect reported in 58 studies, codify 51 aspects of study design that may influencetheestimates.Iuse meta-regression analysis to investigate why trade costs effects vary. The results suggest that different methods and mainly data characteristics systematically affect the estimated trade costs effects. I find evidence for publication selection bias by using the appropriate tests. The authors of primary studies tend to report preferentially large estimates of the elasticity of trade with respect to trade costs. The evidence for publication selection bias is stronger for studies reported in peer-reviewed journals thanfor unpublished studies.

Master of Science / Department of Diagnostic Medicine/Pathobiology / Natalia Cernicchiaro / Japanese encephalitis virus (JEV) is a virus of the Flavivirus genus that may result in encephalitis in vertebrate hosts. This vector-borne zoonosis occurs in Eastern and Southeastern Asia and an intentional or inadvertent introduction into the United States (US) would lead to important public health and economic consequences. The objective of this study was to gather, appraise, and synthesize primary research literature to identify and quantify vector and host competence for JEV, using a systematic review-metaanalysis (SR-MA) approach. After defining the research question, we performed a search in selected electronic databases. The title and abstract of the identified articles were screened for relevance using a defined set of exclusion and inclusion criteria, and relevant articles were subjected to a risk of bias assessment followed by data extraction. Random-effects subgroup meta-analysis models were fitted by species (mosquito or vertebrate host species) to estimate pooled summary measures as well as to compute the variance between studies. Meta-regression models were fitted to assess the association between different predictors and the outcomes of interest and to identify sources of heterogeneity among studies. Data were extracted from 171 peer-reviewed articles. Most studies were observational (59.06%) and reported vector competence (60.2%). The outcome measures reported pertained to transmission efficiency, host preference, and vector susceptibility to infection within vector competence; and susceptibility to infection within host competence. All outcome measures (JEV proportion of infection in vectors and hosts from observational studies; and JEV infection, dissemination, and transmission rates in vectors from experimental studies) had high heterogeneity. Mosquito species, diagnostic method, country, and capture method represented important sources of heterogeneity associated with the proportion of JEV infection in vectors; host species and region were considered sources of heterogeneity associated with the proportion of JEV infection in hosts; and diagnostic and mosquito capture methods were deemed important contributors of heterogeneity for the minimum infection rate (MIR) outcome. Mosquito species and administration route represented the main sources of heterogeneity associated with JEV infection rate in vectors. Quantitative estimates resulting from this SR-MA will be inputted into risk assessment models to evaluate risks associated with the introduction of JEV in the US.

The etiology of central nervous system tumors (CNSTs) is mainly unknown. Aside from extremely rare genetic conditions, such as neurofibromatosis and tuberous sclerosis, the only unequivocally identified risk factor is exposure to ionizing radiation, and this explains only a very small fraction of cases. Using meta-analysis, gene networking and bioinformatics methods, this dissertation explored the hypothesis that environmental exposures produce genetic and epigenetic alterations that may be involved in the etiology of CNSTs. A meta-analysis of epidemiological studies of pesticides and pediatric brain tumors revealed a significantly increased risk of brain tumors among children whose mothers had farm-related exposures during pregnancy. A dose response was recognized when this risk estimate was compared to those for risk of brain tumors from maternal exposure to non-agricultural pesticides during pregnancy, and risk of brain tumors among children exposed to agricultural activities. Through meta-analysis of several microarray studies which compared normal tissue to astrocytomas, we were able to identify a list of 554 genes which were differentially expressed in the majority of astrocytomas. Many of these genes have in fact been implicated in development of astrocytoma, including EGFR, HIF-1α, c-Myc, WNT5A, and IDH3A. Reverse engineering of these 554 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme (GBM) were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. Lastly, bioinformatics analysis of environmental databases and curated published results on GBM was able to identify numerous potential pathways and gene-environment interactions that may play key roles in astrocytoma development. Findings from this research have strong potential to advance our understanding of the etiology and susceptibility to CNSTs. Validation of our 'key genes' and pathways could potentially lead to useful tools for early detection and novel therapeutic options for these tumors.

Mendelian randomization is an epidemiological method for using genetic variationto estimate the causal effect of the change in a modifiable phenotype onan outcome from observational data. A genetic variant satisfying the assumptionsof an instrumental variable for the phenotype of interest can be usedto divide a population into subgroups which differ systematically only in thephenotype. This gives a causal estimate which is asymptotically free of biasfrom confounding and reverse causation. However, the variance of the causalestimate is large compared to traditional regression methods, requiring largeamounts of data and necessitating methods for efficient data synthesis. Additionally,if the association between the genetic variant and the phenotype is notstrong, then the causal estimates will be biased due to the “weak instrument”in finite samples in the direction of the observational association. This biasmay convince a researcher that an observed association is causal. If the causalparameter estimated is an odds ratio, then the parameter of association willdiffer depending on whether viewed as a population-averaged causal effect ora personal causal effect conditional on covariates. We introduce a Bayesian framework for instrumental variable analysis, whichis less susceptible to weak instrument bias than traditional two-stage methods,has correct coverage with weak instruments, and is able to efficiently combinegene–phenotype–outcome data from multiple heterogeneous sources. Methodsfor imputing missing genetic data are developed, allowing multiple genetic variantsto be used without reduction in sample size. We focus on the question ofa binary outcome, illustrating how the collapsing of the odds ratio over heterogeneousstrata in the population means that the two-stage and the Bayesianmethods estimate a population-averaged marginal causal effect similar to thatestimated by a randomized trial, but which typically differs from the conditionaleffect estimated by standard regression methods. We show how thesemethods can be adjusted to give an estimate closer to the conditional effect. We apply the methods and techniques discussed to data on the causal effect ofC-reactive protein on fibrinogen and coronary heart disease, concluding withan overall estimate of causal association based on the totality of available datafrom 42 studies.

A recent systematic literature and meta-analysis reported relative efficacy of trimethoprim-sulfamethoxazole (TMP-SMX) for the treatment of toxoplasmic encephalitis (TE) in HIV-infected adults. Here, we estimated relapse rates during secondary prophylaxis with TMP-SMX, and further explored differences in relapse rates prior to introduction of highly active antiretroviral therapy (HAART) and the widespread adoption of HAART. A systematic search of PubMed, Embase, and Cochrane Central Register of Controlled Trials yielded 707 studies whereby 663 were excluded after abstract screening, and 38 were excluded after full review leaving 6 studies for extraction. We performed double data extraction with a third-party adjudicator. Study designs varied with only one randomized study, four prospective cohorts and one retrospective cohort. Relapse rates were transformed using the Freeman-Tukey method and pooled using both fixed-effect and random-effects meta-analysis models. The TMP-SMX relapse rate was 16.4% (95% CI = 6.2% to 30.3%) based on random-effects models. When the disaggregated pre-HAART studies (n = 4) were included, the relapse rate was 14.9% (random effects; 95% CI = 3.7% to 31.9%). Analysis of two post-HAART studies indicated a relapse rate of 19.2% (random effects; 95% CI = 2.8% to 45.6%). Comparing the relapse rates between pre- and post-HAART studies were contrary to what might be expected based on known benefits of HAART therapy in this population. Nevertheless, cautious interpretation is necessary considering the heterogeneity of the included studies and a limited number of subjects receiving TMP-SMX reported in the post-HAART era.

Economic evaluations and network meta-analyses (NMAs) are complex methodologies. Increasing their transparency and accessibility could enhance confidence in the legitimacy of policy decisions informed by these analyses. Four systematic reviews were conducted to understand policymakers’ informational needs and to determine what guidance researchers have on how to present economic evaluations and NMAs. Qualitative interviews were conducted with Canadian policymakers, i.e., knowledge users, to understand barriers and facilitators to using and communicating economic evaluations and NMAs and with individuals in international health technology assessment organizations, i.e. knowledge producers, to explore current approaches to communicating economic evaluations and NMAs. A toolkit for NMAs and economic evaluations was proposed based on an integrated review of these findings and guided by the Knowledge-to-Action framework. Examples of tools were developed and applied to an economic evaluation and NMA of osteoporosis therapies. Systematic reviews and qualitative interviews found that communication approaches that provide robust content, identify contextual factors relevant to policy decisions and enhance clarity were valued. Twelve tools were proposed that enhance communication, education and access to resources for policymakers. Two of these tools were developed: Economic Guidance for Researchers and NMA Guidance for Researchers.