Conclusion. The missing data is a common problem in clinical trial. The methodology development is urgently needed to detect the difference of two treatments drug in patient quality of life. The modified pattern mixture model incorporating generalized estimating equation method or multiple imputation method provides a solution to tackle the non-ignorable missing data problem. Different clinical trials with various treatment schedules, missing data patterns will be formed. Further studies are needed to study the optimal choice of patterns under the methods. / Introduction. Health-related Quality of Life (HRQoL) has now been included as a major endpoint in many cancer clinical trials in addition to the traditional endpoints such as tumor response and survival. It refers to how illness or its treatment affects patients' ability to function and whether it induces symptoms. Toxicity, progression and death are common outcome affecting patient's QOL in cancer trial. Since this type of missing data are not occurred at random and are called non-ignorable missing data, conventional methods of analyses are not appropriate. It is important to develop general methods to deal with this problem so that treatment effectiveness for improving patient's QOL or those with serious side effect that is detrimental to patient's QOL can be identified. / Methods. The generalized estimating equation based on modified pattern mixture model is constructed to deal with non-ignorable missing data problem. We conducted a simulation study to examine performance of the model for different types of data. Two scenarios were examined. The first case assumes that two groups have quadratic trend but with different rates of change. The second case assumes that one group has linear trend with time while the other group has quadratic trend with time. Moreover, the second methodology is the multiple imputation based on modified pattern mixture model. The main idea is to resample the data within each pattern to create the full data set and use the standard method to analyze the data. Comparison between two methods was carried out in this study. / Recently, joint models for the QOL outcomes and the indicators of drop-outs are used in longitudinal studies to correct for non-ignorable missing. Two broad classes of joint models, selection model and pattern mixture model, were used. Most of the methodology has been developed in the selection model while the pattern mixture model has attracted less attention due to the identifiability problem. Although pattern mixture model has its own limitation, a modified version of this model incorporating Generalized Estimating Equation can be used in practice. / Result. The power of generalized estimating equation alone is higher than pattern mixture model when the missing data is missing at random. Moreover, the bias of generalized estimating equation is less than that of pattern mixture model when the missing data is missing at random. However, the pattern mixture model performs well when the missing data is missing not at random. On the other hand, the modified pattern mixture model has higher power than the standard pattern mixture model if one group has quadratic trend and other group has linear trend. However, the power of modified pattern mixture model is similar or worst than the standard when the data is both quadratic trends with different rates of change. On the other hand, the results of multiple imputation based on modified pattern mixture model were similar but the power was less than the generalized estimating equation model. / Mo Kwok Fai. / "August 2006." / Adviser: Benny Zee. / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 6051. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 91-93). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

Source: Dissertation Abstracts International, Volume: 70-03, Section: B, page: 1576. Advisers: Dejian Lai; Asha S. Kapadia. Includes bibliographical references.

Thesis (Ph. D.)--University of Alabama at Birmingham, 2007. / Title from first page of PDF file (viewed Oct. 13, 2008). Includes bibliographical references.

Objective. The Cochrane risk of bias tool (CRoB) is one of the most widely used tools for assessing the risk of bias of clinical trials. However, it was criticized for its poor inter-rater reliability, lack of clear and detailed guidelines for its application, and no clear distinguishing between reporting quality from real quality in implementation. This study aims to develop a framework (or improved CRoB, iCRoB) so as to improve the inter-rater reliability of the CRoB in its first 4 domains: sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment, through providing: i) a structured pathway for assessing risk of bias assessment; and ii) a comprehensive dictionary of scenarios for each domain. / Methods. The study is consisted of 4 steps: / i) Step 1: Develop a step-by-step structured pathway for assessing the risk of bias. / ii) Step 2: Identify and summarize possible scenarios that are used in literature to describe a domain in clinical trials by using a qualitative content analysis approach. A random sample of 100 Cochrane systematic reviews (SRs) was taken from the Cochrane Database of Systematic Reviews. Each review was carefully scrutinized for this purpose. / iii) Step 3: Merge the scenarios identified from the sample with those already provided in the CRoB. The combined list of scenarios extends the current coverage of the CRoB and forms a more comprehensive dictionary of scenarios for use in the future. The bias assessment pathway and the new dictionary of scenarios in combination are the new components added or contribution to the CRoB to form the iCRoB. / v) Step 4: Conduct a randomized controlled study that allocated at random 8 raters equally into either using the CRoB or our new iCRoB. 150 clinical trials were randomly selected from the fore-mentioned 100 SRs for the inter-rater reliability comparison. Both inter-rater reliability among individual raters (measured with Fleiss’ κ) and that across rater pairs (measured with weighted Cohen’s κ) were computed. Data analyses were conducted by using STATA version 13.0. / Results. A structured pathway for systematically assessing bias was designed, which helps classify a study into one of 5 categories for each risk of bias domain based on the information provided in the report of a trial: Category A: a trial reports in details how a bias reduction method was conducted and it is also deemed by the assessor to be conducted adequately; Category B: a trial reports in details how a bias reduction method was conducted but it is deemed by the assessor to be conducted inadequately; Category C: a trial reports that a bias reduction method was conducted but no detailed description was given which can be used to judge whether it was done adequately; Category D: a trial reports that a bias reduction method was not conducted; Category E: a trial does not mention at all whether or not a bias reduction method was conducted. / A total of 34, 36, 26 and 20 scenarios were generated for sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment, respectively. We extended the current CRoB list of scenarios by a number of 20, 23, 26 and 20 respectively for the 4 bias reduction domains. / Our trial results showed that the iCRoB had a higher inter-rater reliability across rater pairs than the original CRoB for every bias reduction domain. The weighted κ was 0.71 and 0.81 for sequence generation respectively for CRoB and iCRoB; 0.53 and 0.61 for allocation concealment respectively for CRoB and iCRoB; 0.56 for blinding of participants and personnel in CRoB, 0.68 for blinding of participants and 0.70 for blinding of personnel ini CRoB; and 0.19 and 0.43 for blinding of outcome assessment respectively for CRoB and iCRoB. / Conclusion. We developed the iCRoB including a standard pathway and extended substantively the dictionary of scenarios for making the judgement on risk of bias in the reports of clinical trials. Our iCRoB showed a higher reliability than the current CRoB in all the domains examined. The iCRoB can be recommended for improving the assessment of bias in clinical trials. / 目的：考柯藍偏倚風險評估工具(CRoB)是最廣泛應用的用於評價臨床試驗偏倚風險的工具之一。然而，CRoB 有以下三個缺陷：評價者間信度低，缺乏明確和詳細的應用說明和沒有明確區分報告質量和方法學質量。本研究擬制定一個新的工具iCRoB 用以提高CRoB 前4 項指標的評價者間信度。這4項指標分別為隨機序列生成，分配隱藏，對研究對象和研究者實施盲法，和對結局評估者實施盲法。本研究通過以下2 點實現這一目的：i) 提供一個結構化路徑用以評估偏倚風險；ii) 為每個研究指標提供一個廣泛包含偏倚風險評估相關描述場景的字典。 / 方法：本研究包含以下4 個步驟： / 第1 步：制定一個用以評估偏倚風險的結構化路徑。 / 第2 步：從考柯藍系統綜述數據庫中隨機抽取100 篇系統綜述，應用定性內容分析法從中確定並總結出臨床試驗中與偏倚風險相關的可能的描述場景。 / 第3 步：將從100 個樣本中總結的描述場景與CRoB 中已有的場景合併，從而擴大CRoB 的描述場景的覆蓋範圍，得到一個更廣泛包含偏倚風險評估相關描述場景字典。偏倚風險評估的結構化路徑和包含場景描述的字典共同形成了本研究中新制定的iCRoB，用以評估臨床試驗的偏倚風險。 / 第4 步：在一個隨機對照研究中，8 名評價者被隨機平均分配至CRoB 組或者iCRoB 組。在上述100個系統綜述所納入的臨床試驗中隨機抽取150 個臨床試驗用以比較CRoB 和iCRoB 的評價者間信度。評價者間信度的比較包括個體評價者間信度（用Fleiss’κ 測量）和配對評價者間信度(用加權Cohen’s κ 測量)的比較。數據採用Stata 13.0 進行統計分析。 / 結果：本研究成功的制定了一個用於系統評價偏倚風險的結構化路徑，在該結構化路徑中，每個偏倚風險相關的指標在一個臨床研究中將分為以下5 類： / A 類：臨床試驗詳細描述了預防偏倚的措施的實施，根據描述可以判定該措施的實施能預防偏倚的產生; B 類：臨床試驗詳細描述了預防偏倚的措施的實施，根據描述可以判定該措施的實施不能預防偏倚的產生; C 類：臨床試驗報告採取了預防偏倚的措施，但未描述這一過程如何實施，從而無法判斷其實施是否正確; D 類：臨床試驗報告沒有採取任何預防偏倚的措施; E 類：臨床試驗沒有報告是否採取了預防偏倚的措施。 / 本研究分別為隨機序列生成，分配隱藏，對研究對象和研究者實施盲法，和對結局評估者實施盲法收集了34，36，26 和20 個描述場景。與CRoB 提供的描述場景比較，iCRoB 分別為隨機序列生成，分配隱藏，對研究對象和研究者實施盲法，和對結局評估者實施盲法增加了20，23，26 和20 個新的描述場景。 / 隨機對照試驗結果顯示，iCRoB 中每個研究指標的配對評價者間信度均高於CRoB，其中，隨機序列生成加權κ 為0.71（CRoB）和0.81（iCRoB），分配隱藏加權κ 為0.53（CRoB）和0.61（iCRoB），對研究對象和研究者實施盲法加權κ 為0.56（CRoB），對研究對象實施盲法加權κ 為0.68（iCRoB），對研究者實施盲法加權κ 為0.70（iCRoB），對結局評估者實施盲法加權κ 為0.19（CRoB）和0.43（iCRoB）。 / 結論：本研究通過制定一個由偏倚風險評估的結構化路徑和包含場景描述的字典組成的iCRoB，用以改善CRoB 中對臨床試驗中隨機序列生成，分配隱藏，對研究對象和研究者實施盲法，和對結局評估者實施盲法偏倚風險評估過程。相比於CRoB，iCRoB 在每個研究指標中均顯示出更好的配對評價者間信度。這些結果證明評價者間信度可以通過提供結構化偏倚風險評估路徑和更全面的描述場景字典而提高。 / Wu, Xinyin. / Thesis Ph.D. Chinese University of Hong Kong 2014. / Includes bibliographical references (leaves 93-105). / Abstracts also in Chinese. / Title from PDF title page (viewed on 09, September, 2016). / Wu, Xinyin. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.y066 / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Thesis (Ph.D. in Biostatistics) -- University of Colorado Denver, 2008. / Typescript. Includes bibliographical references (leaves 117-119). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;

After adjusted for the effect of baseline MCE risk and reduction in SBP, the multivariate meta-regression showed baseline SBP was not significantly related to the RD for all the relevant outcomes examined (p>0.22) except MCE (p=0.0226). However, the baseline MCE risk remained significantly related to the RD for all the outcomes (p<0.01) except CHD (p=0.1011). The reduction in SBP remained significantly related to the RD for deaths due to CVD, MCE, CHF and stroke (p<0.01) but not to the RD for all-cause death (p=0.3788) and CHD (p=0.8755). / Conclusions. This study showed that baseline CVD risk and reduction in blood pressure were strongly and consistently related to the absolute effect of treatment and surprisingly the baseline blood pressure was not. The findings lend direct support to the overall risk approach to primary prevention and suggest that contrary to conventional wisdom and current practice, the overall CVD risk rather than blood pressure alone should be used to identify and treat people to prevent major CVD events through anti-hypertensive drugs. These findings suggest that anti-hypertensive drugs should be given to those who have a high future CVD risk rather than high blood pressure alone so as to achieve better cost-effectiveness of anti-hypertensive drugs for primary prevention. / Data extraction and analyses: Two reviewers independently abstracted data on baseline variables, variables that determine methodological quality, and outcomes. The following main outcomes were assessed: all-cause deaths, deaths due to cardiovascular disease, death due to causes other than CVD, major cardiovascular events (MCE), congestive heart failure (CHF), stroke, and coronary heart disease (CHD). / Key words. hypertension, antihypertensive drugs, cardiovascular disease, meta-analysis, systematic review, randomized controlled trial, primary prevention, baseline risk, evidence based medicine / Meta-analysis was used to obtain the overall odds ratio (OR) and risk difference (RD). Forest plots, bubble plots and funnel plots were used to show the results visually or to check biases. Meta-regression was used to identify factors that may independently determine the effect of antihypertensive drugs. The control CVD risk, initial mean blood pressure and reduction in blood pressure were examined. / Method. Identification of studies: The databases searched included ACP Journal Club, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, Cumulative Index to Nursing & Allied Health Literature, Chinese Medical Current Contents to identify relevant studies between 1966 and 2005. We also examined references from relevant trials, reviews and meta-analyses. For trials to be included in this review, they have to have the following characteristics: (1) essential hypertension in patients of any age, sex and race; (2) treatment intervention is antihypertensive drugs; (3) control intervention is a placebo or no treatment; (4) endpoint outcomes are all-cause death and major cardiovascular events; and (5) randomized controlled trials. / Objective. Although the overall risk approach to cardiovascular disease (CVD) primary prevention has been widely adopted, direct evidence that supports this policy is however weak and in some aspects lacking. Importantly, there is no direct evidence to show, between blood pressure and CVD risk, which is a better predictor of the absolute benefit from anti-hypertensive drugs. The evidence that the absolute benefit increases as the future CVD risk increases does not necessarily mean that treating high risk people will be more cost-effective than treating hypertensive people as blood pressure may also be positively related to treatment benefit. The high risk approach would be preferable only when we can show with strong evidence that blood pressure is not related to the absolute benefit of treatment or the CVD risk is much more strongly related to the benefit than blood pressure. We thus conducted this systematic review to examine the evidence from randomized controlled trials to directly show how blood pressure and CVD risk are related to the absolute benefit from anti-hypertensive drugs and compare the capability of the two factors in predicting the benefit. The stronger predictor should be a better indicator for identifying those who should be treated with anti-hypertensive drugs. / Results. Twenty-two eligible randomized controlled trials with a total of 55,448 participants were identified from 1967 to 2004. The average follow-up was 45.6 months ranging from 13 to 84 months. The combined RD and OR for all-cause deaths, deaths due to CVD, MCE, CHF, Stroke and CHD were all statistically significant, showing a consistent and considerable reduction in the risk of these outcomes due to the treatment of anti-hypertensive drugs (p<0.01). / Jiang, Yu. / "September 2007." / Adviser: Jin Ling Tang. / Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4657. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2007. / Includes bibliographical references (p. 107-115). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract in English and Chinese. / School code: 1307.

Made available in DSpace on 2015-07-22T20:49:27Z (GMT). No. of bitstreams: 0 Previous issue date: 2006-04-03 / Avaliação do uso terapêutico do extrato de Lafoensia pacari St. Hil. Mangava brava na erradicação do Helicobacter pylori: Ensaio Clínico Randomizado Duplo Cego. Objetivo: Avaliar a ação de uma planta usada popularmente como fitoterápico, conhecida cientificamente como Lafoensia pacari, na erradicação do Helicobacter pylori e verificar se a mesma é mais efetiva que o placebo para alívio da sintomatologia dispéptica. Analisar também sua ação sobre os processos inflamatórios e seus possíveis efeitos adversos. Método: Pacientes dispépticos, maiores de 18 anos, H. pylori positivos (teste rápido da urease), foram randomizados para receber 500mg do extrato metanólico de L. pacari duas vezes por dia (Grupo Intervenção) ou placebo (Grupo Controle), por duas semanas. A variável (“Erradicação do H.pylori”) foi analisada oito semanas após o fim da medicação por nova endoscopia com biópsia e realização do teste rápido da urease e histologia. As outras variáveis (“Melhora”, “Alívio completo dos sintomas” e “Efeitos adversos”) foram analisadas no fim da medicação (duas semanas). Resultados: Cem pacientes com idades entre 18 e 79 anos foram randomizados e alocados nos grupos Intervenção (n=55) e Controle (n=45). Os resultados dos exames (urease e histologia) mostraram que a situação relativa à positividade para o H. pylori se manteve inalterada em 100% dos participantes. Melhora da sintomatologia foi observada em 74% no grupo-intervenção (IC 95%: 62,4 a 85,8) e em 48% do controle (IC 95%: 33,9 a 63,8) com p= 0,007. Alívio completo de sintomatologia foi observado em 42,5% (IC 95%: 29,4 a 55,8) no grupo-intervenção e em 21%(I C 95%. 8,8 a 33,1) do grupo-controle, com p=0,020 (qui quadrado). Os efeitos colaterais foram mínimos e similares nos dois grupos. Conclusões: O extrato de L. pacari, como agente único, na dose e no tempo de uso estabelecidos neste ensaio, foi ineficaz para a erradicação do H. pylori na população analisada. Foi, porém, bem tolerado e conseguiu resolução sintomatológica significativa em grande parte dos participantes que dele fez uso. Futuros estudos poderão testá-lo, com a utilização de doses e períodos maiores, tanto em tratamento sintomatológico, como em associação com antibióticos no combate ao H. pylori. / Background: The eradication of Helicobacter pylori is easily achieved by combining antisecretory agents and antibiotics; however, the cost of these associations is very high for the population of Third World countries, where the prevalence of the infection is even higher and leads to markedly reduced treatment effectiveness. We tested a plant (Lafoensia pacari) that is used in the central region of Brazil. According to previous studies, this plant has high concentrations of ellagic acid, which presents gastric antisecretory and antibacterial actions. Material and Methods: 100 dyspeptic, urease-positive patients were randomized to receive 500mg of methanolic extract of L. pacari (n= 55) or placebo (n= 45), for 14 days, in a double-blind clinical trial. The main variables assessed were the eradication of H. pylori eight weeks after the intervention and complete symptom relief at the end of the treatment. Results: The exams (urease and histology) showed persistence of H. pylori in 100% of participants. Complete symptom relief was experienced by 42.5% of patients (95% CI: 29.4-55.8) in the intervention group and by 21% (95% CI: 8.8-33.1) in the control group, p=0.020. The side effects were minimum and similar in both groups. Conclusions: The extract of L. pacari as a single agent was not effective to eradicate H. pylori. However, it was well tolerated and many participants reported relief of symptoms. Future studies may test the agent using larger doses and longer periods, in monotherapy or in combination with antibiotics. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2015-07-22T20:50:46Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-04-28 / Objetivo: Avaliar, através de uma revisão sistemática da literatura, os efeitos antitumorais dos canabinóides em qualquer tipo de neoplasia, utilizando como amostra seres humanos e animais de laboratório com tumores, bem como culturas de células tumorais. Método: A pesquisa incluiu as seguintes bases eletrônicas de dados: PUBMED, EMBASE, LILACS e “The Cochrane Collaboration Controlled Trials Register”. Todos os estudos publicados que envolveram os efeitos antitumorais (mecanismos celulares e moleculares) dos canabinóides foram considerados para esta revisão. Desta forma, foram levados em conta não somente ensaios clínicos (randomizados ou não) como também estudos experimentais in vivo e in vitro. A estratégia de busca bibliográfica compreendeu todas as publicações de cada base de dados até 31 de dezembro de 2009. O exame minucioso de todas as referências bibliográficas dos artigos importantes para esta revisão (incluindo artigos de revisão) foi igualmente realizado com o objetivo de selecionar artigos que não tivessem sido capturados pela estratégia de busca eletrônica. Resultados: De 3.920 artigos inicialmente identificados, 117 preencheram os critérios de inclusão para esta revisão. Todos os estudos incluídos nesta revisão sistemática foram experimentais (in vivo e/ou in vitro), excetuando-se um estudo clinico piloto fase I/II em humanos. Em todos os estudos experimentais incluídos, os canabinóides exerceram atividade antitumoral in vitro e/ou evidência antitumoral in vivo em vários modelos de células tumorais e tumores, respectivamente. As atividades antitumorais incluíram: efeitos antiproliferativos (sequestro do ciclo celular), diminuição da viabilidade e morte celular por toxicidade, apoptose, necrose, autofagia, efeitos antiangiogênicos e antimigratórios. As evidências antitumorais incluíram: diminuição do tamanho tumoral, efeitos antiangiogênicos e antimetastáticos. Adicionalmente, a maioria dos estudos descreveu que os canabinóides apresentaram seletividade na ação antitumoral em vários modelos tumorais. Desta forma, as células normais usadas como controle não foram atingidas. O fator segurança na administração dos canabinóides também foi demonstrado in vivo, em ratos com tumores marcados com células tumorais. O único estudo realizado em humanos, por sua vez, demonstrou segurança na administração intratumoral do delta-9-THC em pacientes com glioblastoma multiforme recorrente. Conclusões: Os vários canabinóides testados em múltiplos modelos de tumores apresentaram efeitos antitumorais in vitro e in vivo. Estes achados indicam que os canabinóides são compostos promissores para o tratamento das neoplasias. No entanto, pesquisas em seres humanos através de ensaios clínicos randomizados, metodologicamente bem conduzidos, devem ser realizadas para a avaliação de eficácia dos mesmos antes que eles possam ser indicados para esta finalidade. Este é o caso do delta- 9-THC e do canabidiol, que já foram testados e aprovados para uso em humanos em outras condições clínicas. Outros canabinóides, no entanto, necessitam ainda de pesquisas farmacocinéticas, farmacodinâmicas e toxicológicas antes de poderem ser testados em seres humanos. / Objective: To evaluate, through a systematic review of the literature, the antitumoral effects of cannabinoids on any type of cancer, involving both human beings and animal samples, as well as cultured tumor cells. Method: Research included the following electronic databases: PUBMED, EMBASE, LILACS and "The Cochrane Collaboration Controlled Trials Register. All published studies involving the antitumoral effects (cellular and molecular mechanisms) of cannabinoids were considered for this review. Thus, not only clinical trials (randomized or not) but experimental studies (both in vivo and in vitro) were taken into account. The bibliography search strategy included all publications of each of these databases until December 31, 2009. The scrutiny of all the references from the relevant articles for this review (which included review articles) was also performed, in order to select items that could not have been captured by the chosen electronic search strategy. Results: From 3,920 initially identified articles, 117 fulfilled the inclusion criteria for this review. All the studies included in this systematic review were experimental (in vivo and/or in vitro), except for a pilot clinical trial phase I/II involving humans. In all experimental studies included, cannabinoids exerted antitumoral activity in vitro and/or antitumoral evidence in vivo in several models of tumor cells and tumors, respectively. The antitumor activity included: antiproliferative effects (cell cycle arrest), decreased viability and cell death by toxicity, apoptosis, necrosis, autophagy, as well as antiangiogenic and antimigratory effects. Antitumoral evidence included: reduction in tumor size, antiangiogenic, and antimetastatic effects. Additionally, most of the studies described that the canabinnoids exercised selective antitumoral action in several distinct tumor models. Furthermore, normal cells used as controls were not affected. The safety factor in the cannabinoids’ administration has also been demonstrated in vivo in rats with tumors which were marked with tumor cells. The sole study in humans demonstrated safety in intratumoral administration of delta-9- THC in patients with recurrent glioblastoma multiforme. Conclusions: The various cannabinoids tested in multiple tumor models showed antitumoral effects both in vitro and in vivo. These findings indicate that cannabinoids are promising compounds for the treatment of cancer. However, methodologically well conducted research on humans through clinical trials has yet to be performed in order to evaluate their effectiveness. This is the case of delta-9-THC and cannabidiol, which have been tested and approved for use in humans in other clinical conditions. In the case of other cannabinoids, however, further pharmacokinetic as well as pharmacodynamic and toxicological studies are required before their being tested in humans. / TEDE / BV UNIFESP: Teses e dissertações

INTRODUÇÃO: A alta prevalência da obesidade infantil em diferentes partes do planeta a posiciona como um dos principais focos de atenção da saúde pública, conhecida a associação dos seus agravos às doenças cardiovasculares e à morte prematura. O objetivo do presente trabalho foi avaliar as intervenções escolares que se utilizam das práticas em atividade física e educação nutricional na antropometria e na pressão arterial de crianças e adolescentes. MÉTODOS: Os artigos foram recuperados por buscas sistemáticas em quatorze bases de dados eletrônicas e por busca manual em listas de referências, com atualização até 30 de setembro de 2012. Dois revisores independentes avaliaram os trabalhos e extraíram os dados. Os trabalhos deveriam atender adequadamente aos seguintes critérios de elegibilidade: população dos 6 aos 18 anos de idade; intervenções comunitárias randomizadas no ambiente escolar, fundamentadas nas práticas em atividade física ou educação nutricional, ou nas duas formas combinadas; presença de grupo controle em paralelo, com seguimento concomitante; descrição de pelo menos um dos desfechos: índice de massa corporal, peso corporal e pressão arterial. A meta-análise foi desenvolvida pelo modelo de efeito randômico, com diferença padronizada entre médias pelo método de Hedges. Também foi realizada a meta-análise de regressão para identificação das fontes de heterogeneidade entre os ensaios, envolvendo as variáveis tempo e tipo de intervenção, faixa etária e qualidade. O grau de heterogeneidade entre os estudos foi verificado pelas estatísticas Q de Cochran e I2, e o viés de publicação foi avaliado subjetivamente por meio da distribuição no gráfico funnel plot. RESULTADOS: Dos 5.899 trabalhos inicialmente recuperados, 140 tiveram seus dados extraídos e 60 remanesceram para a composição das sínteses, assim subdivididas: 12 em atividade física, 8 em educação nutricional e 40 com intervenção combinada. A análise das intervenções combinadas apresentou significância estatística a favor do grupo de intervenção no índice de massa corporal, com a magnitude e variabilidade na medida do efeito em diferença padronizada de -0,14 (IC95%: -0,24 a -0,03; p=0,01; n=29471; I2= 94,4%), ao contrário dos resultados obtidos nas duas intervenções em separado, que não foram conclusivos. No desfecho peso corporal, os resultados foram significantes nas intervenções em atividade física (-0,14; IC95%: -0,27 a -0,02; I2= 7,84%) e nas combinadas (-0,65; IC95%: -1,17 a -0,13; I2= 99,3%). As análises da pressão arterial não obtiveram resultados com significância estatística. O conjunto de todas as intervenções com dados em índice de massa corporal, incluindo 55 estudos, mostrou o resultado de -0,02 (IC95%: -0,03 a 0,00; I2= 94,5%), e nenhuma das covariáveis incluídas na meta-regressão, tempo de intervenção, qualidade metodológica do estudo e faixa etária da população mostrou significância para explicar a heterogeneidade observada. A análise de subgrupos mostrou redução do efeito no estrato por tempo de intervenção curto, de até quatro meses, com estimativa de -0,04 (IC95%: -0,06 a -0,03; I2= 96,6%), e na faixa etária dos seis aos dez anos, com estimativa de -0,23 (IC95%: -0,27 a -0,19; I2= 97,9%). CONCLUSÕES: As intervenções escolares que combinaram atividade física e educação nutricional mostraram redução do índice de massa corporal, ao contrário das intervenções que se utilizaram destes elementos em separado. Os efeitos positivos estão associados aos estudos com menor tempo entre as avaliações iniciais e finais e com as faixas populacionais mais jovens. A alta heterogeneidade observada compromete a validade externa dos resultados e sugere cautela quanto à capacidade de generalização para outras populações. / INTRODUCTION: Because of its high prevalence of in different parts of the planet childhood obesity is one of the main public health issues, with obesity worsening known to be associated with cardiovascular diseases and premature death. The aim of this study was to evaluate school interventions that use physical activity and nutrition education practices in anthropometric measurements and blood pressure in children and teenagers. METHODS: The articles were retrieved via a systematic search of fourteen electronic databases and manual search through reference lists updated until September 30, 2012. Two independent reviewers assessed studies and extracted data. The papers should meet the following eligibility criteria: population aged 6 to 18 years old; randomized community interventions targeting the school environment based on physical activity or nutrition education practices, or a combination of the two approaches; placebo- controlled parallel group and concomitant monitoring; description of at least one of the outcomes: body mass index, body weight and blood pressure. Random-effects meta-analysis was used, with Hedges\'g standardized mean differences. Also, meta-analysis was performed to identify sources of heterogeneity between trials, involving the variables such as duration and type of intervention, age group and quality. The degree of heterogeneity between studies was assessed using Cochran\'s Q statistics and I2 tests, and publication bias was subjectively assessed by a funnel plot. RESULTS: Of the 5,899 papers initially retrieved, 140 were data-extracted and 60 were used in synthesis, as follows: 12 in physical activity, 8 in nutrition education and 40 in combined intervention. Analysis of the combined interventions showed that BMI was statistically more significant in the combined intervention group, with magnitude and variability in the measure of the effect size in standardized difference of (-0.14; CI95%: -0.24 to -0.03; p=0.01; n=29471; I2= 94.4%), unlike the results obtained in the two separate interventions, which were not conclusive. Regarding the body weight outcome, the results were significant for physical activity (-0.14; CI95%: -0.27 to -0.02; I2= 7.84%) and in the combined interventions (-0.65; CI95%: -1.17 to -0.13; I2= 99.3%). Blood pressure analyses did not obtain statistically significant results. The set of all interventions with BMI data (55 studies), showed the result of -0.02 (CI95%: -0.03 to 0.00; I2= 94.5%), and none of the covariates included in meta-analysis, intervention duration, methodological quality of the study and population age could explain the heterogeneity observed. Subgroup analysis showed a reduced effect in the short intervention duration stratum (up to four months), with an estimate of -0.04 (CI95%: -0.06 to -0.03; I2= 96.6%), and in the age group of 6-10 years old, with an estimate of -0.23 (CI95%: -0.27 to -0.19; I2= 97.9%). CONCLUSIONS: The school interventions that combined physical activity and nutrition education led to reduced body mass index, unlike the interventions that used these approaches separately. The positive effects are associated with studies with shorter periods of time between the initial and final evaluations and younger populations. The high heterogeneity observed jeopardizes the external validity of the results and suggests caution in generalizing these findings to other populations.

INTRODUÇÃO: A alta prevalência da obesidade infantil em diferentes partes do planeta a posiciona como um dos principais focos de atenção da saúde pública, conhecida a associação dos seus agravos às doenças cardiovasculares e à morte prematura. O objetivo do presente trabalho foi avaliar as intervenções escolares que se utilizam das práticas em atividade física e educação nutricional na antropometria e na pressão arterial de crianças e adolescentes. MÉTODOS: Os artigos foram recuperados por buscas sistemáticas em quatorze bases de dados eletrônicas e por busca manual em listas de referências, com atualização até 30 de setembro de 2012. Dois revisores independentes avaliaram os trabalhos e extraíram os dados. Os trabalhos deveriam atender adequadamente aos seguintes critérios de elegibilidade: população dos 6 aos 18 anos de idade; intervenções comunitárias randomizadas no ambiente escolar, fundamentadas nas práticas em atividade física ou educação nutricional, ou nas duas formas combinadas; presença de grupo controle em paralelo, com seguimento concomitante; descrição de pelo menos um dos desfechos: índice de massa corporal, peso corporal e pressão arterial. A meta-análise foi desenvolvida pelo modelo de efeito randômico, com diferença padronizada entre médias pelo método de Hedges. Também foi realizada a meta-análise de regressão para identificação das fontes de heterogeneidade entre os ensaios, envolvendo as variáveis tempo e tipo de intervenção, faixa etária e qualidade. O grau de heterogeneidade entre os estudos foi verificado pelas estatísticas Q de Cochran e I2, e o viés de publicação foi avaliado subjetivamente por meio da distribuição no gráfico funnel plot. RESULTADOS: Dos 5.899 trabalhos inicialmente recuperados, 140 tiveram seus dados extraídos e 60 remanesceram para a composição das sínteses, assim subdivididas: 12 em atividade física, 8 em educação nutricional e 40 com intervenção combinada. A análise das intervenções combinadas apresentou significância estatística a favor do grupo de intervenção no índice de massa corporal, com a magnitude e variabilidade na medida do efeito em diferença padronizada de -0,14 (IC95%: -0,24 a -0,03; p=0,01; n=29471; I2= 94,4%), ao contrário dos resultados obtidos nas duas intervenções em separado, que não foram conclusivos. No desfecho peso corporal, os resultados foram significantes nas intervenções em atividade física (-0,14; IC95%: -0,27 a -0,02; I2= 7,84%) e nas combinadas (-0,65; IC95%: -1,17 a -0,13; I2= 99,3%). As análises da pressão arterial não obtiveram resultados com significância estatística. O conjunto de todas as intervenções com dados em índice de massa corporal, incluindo 55 estudos, mostrou o resultado de -0,02 (IC95%: -0,03 a 0,00; I2= 94,5%), e nenhuma das covariáveis incluídas na meta-regressão, tempo de intervenção, qualidade metodológica do estudo e faixa etária da população mostrou significância para explicar a heterogeneidade observada. A análise de subgrupos mostrou redução do efeito no estrato por tempo de intervenção curto, de até quatro meses, com estimativa de -0,04 (IC95%: -0,06 a -0,03; I2= 96,6%), e na faixa etária dos seis aos dez anos, com estimativa de -0,23 (IC95%: -0,27 a -0,19; I2= 97,9%). CONCLUSÕES: As intervenções escolares que combinaram atividade física e educação nutricional mostraram redução do índice de massa corporal, ao contrário das intervenções que se utilizaram destes elementos em separado. Os efeitos positivos estão associados aos estudos com menor tempo entre as avaliações iniciais e finais e com as faixas populacionais mais jovens. A alta heterogeneidade observada compromete a validade externa dos resultados e sugere cautela quanto à capacidade de generalização para outras populações. / INTRODUCTION: Because of its high prevalence of in different parts of the planet childhood obesity is one of the main public health issues, with obesity worsening known to be associated with cardiovascular diseases and premature death. The aim of this study was to evaluate school interventions that use physical activity and nutrition education practices in anthropometric measurements and blood pressure in children and teenagers. METHODS: The articles were retrieved via a systematic search of fourteen electronic databases and manual search through reference lists updated until September 30, 2012. Two independent reviewers assessed studies and extracted data. The papers should meet the following eligibility criteria: population aged 6 to 18 years old; randomized community interventions targeting the school environment based on physical activity or nutrition education practices, or a combination of the two approaches; placebo- controlled parallel group and concomitant monitoring; description of at least one of the outcomes: body mass index, body weight and blood pressure. Random-effects meta-analysis was used, with Hedges\'g standardized mean differences. Also, meta-analysis was performed to identify sources of heterogeneity between trials, involving the variables such as duration and type of intervention, age group and quality. The degree of heterogeneity between studies was assessed using Cochran\'s Q statistics and I2 tests, and publication bias was subjectively assessed by a funnel plot. RESULTS: Of the 5,899 papers initially retrieved, 140 were data-extracted and 60 were used in synthesis, as follows: 12 in physical activity, 8 in nutrition education and 40 in combined intervention. Analysis of the combined interventions showed that BMI was statistically more significant in the combined intervention group, with magnitude and variability in the measure of the effect size in standardized difference of (-0.14; CI95%: -0.24 to -0.03; p=0.01; n=29471; I2= 94.4%), unlike the results obtained in the two separate interventions, which were not conclusive. Regarding the body weight outcome, the results were significant for physical activity (-0.14; CI95%: -0.27 to -0.02; I2= 7.84%) and in the combined interventions (-0.65; CI95%: -1.17 to -0.13; I2= 99.3%). Blood pressure analyses did not obtain statistically significant results. The set of all interventions with BMI data (55 studies), showed the result of -0.02 (CI95%: -0.03 to 0.00; I2= 94.5%), and none of the covariates included in meta-analysis, intervention duration, methodological quality of the study and population age could explain the heterogeneity observed. Subgroup analysis showed a reduced effect in the short intervention duration stratum (up to four months), with an estimate of -0.04 (CI95%: -0.06 to -0.03; I2= 96.6%), and in the age group of 6-10 years old, with an estimate of -0.23 (CI95%: -0.27 to -0.19; I2= 97.9%). CONCLUSIONS: The school interventions that combined physical activity and nutrition education led to reduced body mass index, unlike the interventions that used these approaches separately. The positive effects are associated with studies with shorter periods of time between the initial and final evaluations and younger populations. The high heterogeneity observed jeopardizes the external validity of the results and suggests caution in generalizing these findings to other populations.