Publication bias (PB) makes the resources for meta-analysis (M-A) unreliable in the sense of completion and accuracy, so to investigate, identify and correct PB is a very important issue in M-A. The current study proposed an empirical comparison in both detection and correcting PB, using a Monte Carlo study. Conditions to be manipulated include the number of primary studies, number of missing studies and true effect size. RANNOR in SAS will be used to generate normally distributed random variables and, for each condition, 10,000 M-As will be simulated. Type I error rates are to be calculated for the conditions with no PB and powers were estimated for the conditions with PB and adequate type I error control. Finally, a demonstration of how M-A can and should be used as a part of program evaluations was given. / text

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Mindfulness-Based Therapies (MBT) are a current technology within the cognitive behavioural tradition, which can be grouped according to whether mindfulness is a major or a minor component. A mindful approach to psychological difficulties attempts to change the relationship with unwanted inner experience. The model suggests this may help reduce affective symptomatology. There has been a considerable growth of interest in these therapies with an accompanying increase in the evidence base. A number of reviews have been conducted however they have not comprehensively appraised these therapies. The primary aim of my study was to contribute to ongoing research determining the effectiveness of MBT for the treatment of affective symptomatology. Depending on these results, a secondary aim of the study was to make recommendations for the use of MBT in clinical practice. Methods I conducted a meta-analysis which looked separately at therapies considered to have mindfulness as a major component; therapies considered to have mindfulness as a minor component; and a comparison of these two groups. Of the 598 unique citations identified in the literature, 113 were assessed for eligibility and 40 included in the pool of studies for the meta-analysis. Results For the major component therapies, there was a significant mean reduction score in depressive symptomatology as measured by the BDI of 8.73 points (k = 11; 95% CI = 6.61, 10.86). Evidence of effectiveness was also found for the minor component therapies (k = 8) in reducing anxiety symptomatology with a significant standardised mean difference of 1.24 (95% CI = 0.81, 2.10). Discussion I found evidence for the effectiveness of mindfulness-based therapies in reducing levels of depression or anxiety mainly in patients diagnosed with depressive or anxiety disorders. The robustness of these findings is discussed alongside the implications for research and practice within the context of the current literature.

Ischaemic stroke is responsible for substantial death and disability and creates a huge financial burden for healthcare budgets worldwide. At present there are few effective treatments for acute stroke and these are urgently required. Increased understanding of the ischaemic cascade has generated interest in neuroprotection for focal cerebral ischaemia. However, treatment effects observed in of over 500 interventions in animal models have yet to be translated to the clinic. Systematic review and meta-analysis allows unbiased identification of all relevant data for a given intervention, gives a clearer view of its true efficacy and the limitations to its therapeutic potential. Understanding the reasons for this bench-to-bedside failure and providing quantitative explanations may help to address these discrepancies. Random effects weighted mean difference meta-analysis of six interventions (tirilazad, tPA, NXY-059, Hypothermia, Piracetam and IL1-RA) reported study quality to be consistently low. In some instances, potential sources of bias were associated with overestimations of efficacy. Likewise, clinical trials have tested interventions in conditions where efficacy was not observed in animals. Cumulative meta-analysis suggests that for tPA the estimate of efficacy is stable after the inclusion of data from 1500 animals; hypothermia and FK506 are the only other interventions to have been tested in at least 1500 animals. Meta-regression suggests biological rather methodical factors are better predictors of outcome; a major limitation of these data is the impact of publication bias, and this work suggests effect sizes from met-analyses are inflated by about 31% because 16% of studies remain unpublished. The systematic review and meta-analysis of hypothermia was used to plan experiments investigating the possible impact of pethidine, a drug used to prevent shivering. This in vivo experiment, in which potential sources of bias were minimised, suggests that pethidine does not influence the observed efficacy of hypothermia in an animal model of ischaemic stroke. This thesis reports that animal studies of ischaemic stroke are often not conducted with sufficient rigour. Both minimising potential sources of bias in individual experiments and using meta-analysis to summarise data from a number of experiments may be helpful in improving the translation of neuroprotective efficacy in ischaemic stroke.

This thesis is about what happens in the brain when people switch between tasks. Each task requires a particular assembly of cognitive processes, an orientation of attention and set of rules relating action to input — a "task-set". The research reported used a task-cueing paradigm to study preparatory control of task-set. On each trial a stimulus (a coloured shape) was preceded by a verbal task-cue specifying which task to do (judge the shape or the colour of the stimulus). Reaction time and error rate increase on trials when the task changes relative to trials on which it does not. When the cue stimulus interval (CSI) is increased, this "switch cost" is reduced, indexing a process of task-set reconfiguration in which top-down control is employed to reconfigure the task-set parameters. Effective reconfiguration may also be indicated by a reduction in the "response congruence effect" — poorer performance on stimuli mapped to different responses for the two tasks than for stimuli mapped to the same response. I present six experiments using transcranial magnetic stimulation (TMS), a technique for interfering briefly and harmlessly with neuronal activity in a small region of cortex, to address the question of which brain regions contribute to anticipatory control of task-set as indexed by these behavioural measures. To help guide the selection of candidate brain regions, I first present a review and meta-analysis of neuroimaging studies of task-switching in the literature. Many fMRI studies, comparing brain activation on task-switch and -repeat trials have been published. Some have also tried to isolate activations related specifically to pro-active control of task-set. The activations reported are quite inconsistent over studies. I used a quantitative meta-analysis technique to identify which brain regions are most consistently found by studies reporting switch minus repeat contrasts and which may be specifically important for preparation on switch trials. The experiments examined the effect of stimulating several regions during the long cue-stimulus interval of a task-cueing paradigm, relative to control conditions. A first pair of experiments suggests an important role in proactive task-set control for two regions in dorsal medial frontal cortex, the supplementary motor area (SMA) and an area known as pre-SMA, though the former region appeared to contribute to reducing the switch cost while the latter appeared to reduce the effects of response congruence. In a further three experiments, I examined the role of the right intra-parietal sulcus (rIPS); this appears to play a crucial role in preparation for a task-switch but not post-stimulus task-set reconfiguration. In a final experiment, I used TMS guided by fMRI activations in the same participants to study the effects of stimulation over the left inferior frontal junction (IFJ). The results indicate that a region just anterior to the left IFJ is specifically important for preparing for a switch trial. I discuss the roles that may be played by these three regions in task-set control.

uchinok@ccf.org / Background Randomized controlled trials (RCTs) of endovascular therapy for acute ischemic stroke have had inconsistent results. We evaluated the efficacy and safety of endovascular therapy in published RCTs. Methods We performed a systematic review of RCTs of endovascular therapy with thrombolytic or mechanical reperfusion compared with interventions without endovascular therapy. Primary outcome was the frequency of good functional outcome (modified Rankin scale (mRS) of 0-2 at 90 days) and secondary outcomes were mortality at 90 days and symptomatic intracranial hemorrhage (sICH). Random-effects meta-analysis was performed and the Cochrane risk of bias assessment was used to evaluate quality of evidence. Results Ten studies involving 1,612 subjects were included. Endovascular therapy was not significantly associated with good functional outcome (Relative Risk [RR] =1.17; 95% CI, 0.97 to 1.42; p=0.10 and Absolute Risk Difference [ARD] =7%; 95%CI -0.1% to 14%; p=0.05); heterogeneity was moderate among studies (I2=30%). Mortality was unchanged with endovascular therapy (RR=0.92; 95 % CI, 0.75 to 1.13; p=0.45) and there was no difference in sICH (RR=1.20; 95 % CI, 0.79 to 1.82; p=0.39). The quality of evidence was low for all outcomes and the recommendation is weak for the use of endovascular therapy as per GRADE methodology. Conclusions Intra-arterial therapy did not show significant increase in good outcomes and no changes in either mortality or sICH in patients with acute ischemic stroke. We need further RCTs with better design and quality to evaluate the true efficacy of endovascular therapy.

Abstract Aim: It has been suggested that chronic hyperinsulinemia from insulin resistance is involved in the etiology of endometrial cancer (EC). We performed a systematic review and meta-analysis to assess whether insulin resistance is associated with the risk of EC. Methods: We searched PubMed-Medline, Embase, Scopus, and Web of Science for articles published from database inception through 30th September 2014. We included all observational studies evaluating components defining insulin resistance in women with and without EC. Quality of the included studies was assessed by NewcastleeOttawa scale. Randomeffects models and inverse variance method were used to meta-analyze the association between insulin resistance components and EC. Results: Twenty-five studies satisfied our inclusion criteria. Fasting insulin levels (13 studies, n Z 4088) were higher in women with EC (mean difference [MD] 33.94 pmol/L, 95% confi- dence interval [CI] 15.04e52.85, p Z 0.0004). No differences were seen in postmenopausal versus pre- and postmenopausal subgroup analysis. Similarly, non-fasting/fasting C-peptide levels (five studies, n Z 1938) were also higher in women with EC (MD 0.14 nmol/L, 95% CI 0.08e0.21, p < 0.00001). Homeostatic model assessment - insulin resistance (HOMA-IR) values (six studies, n Z 1859) in EC patients were significantly higher than in women without EC (MD 1.13, 95% CI 0.20e2.06, p Z 0.02). There was moderate-to-high heterogeneity among the included studies. Conclusion: Currently available epidemiologic evidence is suggestive of significantly higher risk of EC in women with high fasting insulin, non-fasting/fasting C-peptide and HOMAIR values.

A metanálise tem sido amplamente utilizada em estudos médicos especialmente em revisões sistemáticas de ensaios clínicos aleatorizados. Para modelos de regressão a técnica ainda é muito escassa e limitada. Geralmente trata-se apenas de uma medida baseada nas médias de estimativas pontuais dos diferentes estudos, perdendo-se muita informação dos dados originais. Atualmente torna-se cada vez mais fundamental o uso da metanálise para sumarizar estudos de mesmo objetivo, em razão do avanço da ciência e o desejo de usar o menor número de seres humanos em ensaios clínicos. Utilizando uma medida metanalítica Bayesiana, o objetivo é propor um método genérico e eficiente para realizar metanálise em modelos de regressão. / Meta analysis has been widely used in medical studies especially in systematic reviews of randomized clinical trials. For regression models the technique is still very scarce and limited. Usually it is just a measure based on the average point estimates of dierent studies, losing a lot of information of the original data. Currently it becomes increasingly important to use the meta-analysis to summarize the same objective studies, due to the advancement of science and the desire to use the smallest number of human subjects in clinical trials. Using a meta-analytic Bayesian measure, the objective is to propose a generic and ecient method to perform meta-analysis in regression models.

Student Number : 0416598H - MSc research report - School of Public Health - Faculty of Health Sciences / Background Evidence shows that the efficacy of intravenous quinine, which is the mainstay for treating severe malaria in children, is decreasing. Artemisinin derivatives are the potential replacement for quinine. Their efficacy compared to quinine in treating severe malaria in children is not well known. Objective To assess the efficacy of parenteral artemisinin derivatives versus parenteral quinine in treating severe malaria in children. Search strategy The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2005), MEDLINE (1966 to October 2005), EMBASE (1980 to October 2005), and LILACS (1982 to October 2005) were searched. Malaria researchers and a pharmaceutical company were contacted. In addition, conference proceedings were also searched. Selection criteria Randomised controlled studies comparing parenteral artemisinin derivatives with parenteral quinine in treating severe malaria in children. All trials had to report mortality as an outcome. Data collection After data were extracted, two individuals independently assessed the trial quality. In addition, information on adverse effects from the studies was also collected. Main results Eleven trials were selected (1455 subjects), nine of them from Africa and the rest from Asia. Allocation concealment was adequate in seven trials (1238 subjects). Overall there was no difference in mortality between artemisinin derivatives and quinine (Risk Ratio= 0.89, 95% confidence interval 0.71 to 1.1). There was no difference in mortality between adequately concealed and inadequately concealed /unconcealed trials (Risk Ratio = 0.93, 95% confidence interval 0.74 to 1.16 and Risk Ratio=0.66, 95% confidence interval 0.36 to 1.22). In Parasite Clearance Time (PCT), though there was no statistical difference between the two groups there was a tendency towards favouring the artemisinin derivatives (weighted mean difference among studies which reported PCT as mean was -4.76 with 95% confidence interval -9.68 to 0.17 and all three studies which reported PCT as median showed that artemisinin derivatives cleared parasites faster than quinine, each had p<0.001). However; when only trials with adequate concealment were considered this potential advantage disappeared. In exploring heterogeneity for PCT, it was shown that study settings (Asia versus Africa) might have been a cause for heterogeneity. The artemisinin derivatives resolved coma faster than quinine (weighted mean difference=-5.32, 95%CI: -8.06 to -2.59), but when only trials with adequate concealment were considered this difference disappeared. Other secondary outcomes i.e. Fever clearance time, Incidence of neurological sequelae, and 28th day cure rate showed no significant difference between artemisinin derivatives and quinine. There was no enough data to make meaningful comparison of adverse effects between the two groups. Conclusions The available evidence suggests that parenteral artemisinin derivatives are as efficacious as quinine in preventing mortality from severe malaria in children.

Fragility fractures caused by loss of bone mass due to postmenopausal osteoporosis represent a growing morbidity worldwide. Bisphosphonates are first-line medications for fracture treatment and prevention. In the first phase, we updated a Cochrane systematic review of randomized controlled trials on alendronate, assessing its efficacy for five types of fracture prevention, quality of life, and various safety outcomes. In the second phase, we combined indirect and direct evidence to perform a network meta-analysis including alendronate and nine other bisphosphonates evaluating the comparative efficacy and safety of these treatments. Overall, 58 studies were included in the review and 83 studies in the network. Most evidence was of moderate to high quality. Alendronate and zoledronic acid were effective for preventing the most types of fractures, while off-label and unapproved bisphosphonates showed poor efficacy. More evidence is required to evaluate long-term treatment and rare adverse events.