Prevention and treatment of type 2 diabetes mellitus (T2DM), relies heavily on self-care behaviours such as dietary modification, physical activity, and medication adherence. Ability to perform these self-care behaviours depends, at least in part, on executive function (EF). Recent evidence suggests a correlation between T2DM and impaired cognitive function, including EF. Given the importance of EF for regulation of behaviours, and the importance of self-care in diabetes management, attenuated EF would represent a potential barrier to proper disease management. Thus the objective of Study 1 was to examine the association between T2DM and EF through meta-analytic techniques. Medline, PsychoInfo, and Scopus, as well as article references, were used to identify studies comparing individuals with T2DM to a control population. Effect size was calculated using cohen’s d and random effects modeling, and the potential impact of moderators (age, sex, and T2DM duration) were examined. Review of 60 studies (59 articles), revealed a significant, small-to-moderate effect size (d=-0.249, p<0.001) such that those with T2DM have lower EF. This finding was consistent across all aspects of EF examined (verbal fluency, mental flexibility, inhibition, working memory, and attention), and the association was stronger for those with shorter disease duration. The findings of study 1 illustrate that although individuals with T2DM have a great need for EF, as evidenced by the reliance of self-care behaviours on EF, this population has lower EF upon which to draw to perform these behaviours. Thus, strategies that improve EF, such as aerobic exercise, may be particularly relevant to this population. Acute aerobic exercise has been shown to improve EF in young and older adults; however this effect had not yet been examined in individuals with T2DM. Thus the objective of Study 2 was to examine the effects of acute aerobic exercise on EF in adults with T2DM. A within-subject design was used to compare the change in EF task performance following moderate and minimal intensity aerobic exercise, using Stroop and GNG to measure EF. Analysis revealed a significant effect of moderate exercise in women (but not men) and recently active (but not inactive) individuals, such that moderate exercise mitigated the self-regulatory fatigue effect observed following exercise. This study provides preliminary evidence of a significant beneficial effect of moderate aerobic exercise on EF in female and recently active adults with T2DM.

Objectives: The aim of this dissertation was to examine bias in randomized controlled trials (RCTs) and non-randomized studies (NRS) in surgery using the literature evaluating laparoscopy and conventional (i.e. open) surgery for the treatment of colon cancer as a case study. The objectives were 1) to develop a conceptual framework for bias in comparative NRS; 2) to compare effect estimates from NRS with those from RCTs at low risk of bias; 3) to explore the impact of NRS-design attributes on estimates of treatment effect. Methods: The methods included a modified framework synthesis, systematic review of the literature, random-effects meta-analyses, and frequentist and Bayesian meta-regression. The Cochrane Risk of Bias Tool was used to classify trials as Strong RCTs (i.e. low risk of bias) or Typical RCTs (i.e. unclear or high risk of bias). Results: A conceptual framework for bias in comparative NRS was developed and it contains 37 individual sources of bias or “items”. These items were organized within 6 overarching “domains”: selection bias, information bias, performance bias, detection bias, attrition bias, and selective reporting bias. Our analyses revealed that NRS were associated with more extreme estimates of benefit for laparoscopy than Strong RCTs when examining subjective outcomes. The odds ratios from NRS were 36% smaller (i.e. demonstrating more benefit for laparoscopy) than those from Strong RCTs for the outcome post-operative complications (Ratio of Odds Ratios, ROR 0.64, [0.42, 0.97], p=0.04). Similar exaggerated benefit was seen among NRS when assessing length of stay, (Difference in Mean Differences, -2.15 days, [-4.08, -0.21], p=0.03). This pattern was not observed with the objective outcomes peri-operative mortality and number of lymph nodes harvested. Analyses adjusted for period effects and between-study case-mix yielded similar findings. Finally, effect estimates in NRS did not consistently vary according to the presence or absence of nine design characteristics identified from the conceptual framework. Conclusions: We have demonstrated that the results of surgical NRS can be significantly biased as compared with those of low risk of bias RCTs when evaluating subjective outcomes. However, none of the nine NRS-design characteristics examined was consistently associated with biased effect estimates.

Objectives: The aim of this dissertation was to examine bias in randomized controlled trials (RCTs) and non-randomized studies (NRS) in surgery using the literature evaluating laparoscopy and conventional (i.e. open) surgery for the treatment of colon cancer as a case study. The objectives were 1) to develop a conceptual framework for bias in comparative NRS; 2) to compare effect estimates from NRS with those from RCTs at low risk of bias; 3) to explore the impact of NRS-design attributes on estimates of treatment effect. Methods: The methods included a modified framework synthesis, systematic review of the literature, random-effects meta-analyses, and frequentist and Bayesian meta-regression. The Cochrane Risk of Bias Tool was used to classify trials as Strong RCTs (i.e. low risk of bias) or Typical RCTs (i.e. unclear or high risk of bias). Results: A conceptual framework for bias in comparative NRS was developed and it contains 37 individual sources of bias or “items”. These items were organized within 6 overarching “domains”: selection bias, information bias, performance bias, detection bias, attrition bias, and selective reporting bias. Our analyses revealed that NRS were associated with more extreme estimates of benefit for laparoscopy than Strong RCTs when examining subjective outcomes. The odds ratios from NRS were 36% smaller (i.e. demonstrating more benefit for laparoscopy) than those from Strong RCTs for the outcome post-operative complications (Ratio of Odds Ratios, ROR 0.64, [0.42, 0.97], p=0.04). Similar exaggerated benefit was seen among NRS when assessing length of stay, (Difference in Mean Differences, -2.15 days, [-4.08, -0.21], p=0.03). This pattern was not observed with the objective outcomes peri-operative mortality and number of lymph nodes harvested. Analyses adjusted for period effects and between-study case-mix yielded similar findings. Finally, effect estimates in NRS did not consistently vary according to the presence or absence of nine design characteristics identified from the conceptual framework. Conclusions: We have demonstrated that the results of surgical NRS can be significantly biased as compared with those of low risk of bias RCTs when evaluating subjective outcomes. However, none of the nine NRS-design characteristics examined was consistently associated with biased effect estimates.

Background: A compilation of high quality systematic reviews (SRs) on lifestyle factors associated with adult glioma and meningioma was developed. Methods and Materials: Phase 1 consisted of a systematic overview of existing SRs. For Phase 2, high quality SRs were incorporated in an update. Moderate or low quality SRs which had not been considered in a high quality review were eligible for a de-novo synthesis. Results: Phase 1 resulted in seven moderate to low quality reviews. From this, in Phase 2, smoking, mobile phone and hair dye use were subjected to de-novo reviews. For smoking, it was suggestive that past smokers had an increased risk. For mobile phone use, there was no overall association, however it was suggestive that ipsilateral and high cumulative call time were associated with slight increased risk. No association was observed for personal hair dye use. Conclusions: Despite these null associations, rigorous SR methods were used providing confidence in conveying these results.

Nowell (1976) first proposed that unless cytotoxic cancer therapy eradicates all tumor cells, genetic or heritable variation within heterogeneous tumors will inevitably lead to the evolution of chemotherapeutic resistance through clonal selection. This evolutionary hypothesis was formalized by Goldie and Coldman (1979), who developed one of the earliest mathematical kinetic models of resistance evolution in neoplasms. Their model predicted that the likelihood of response and cure would be increased in combination vs single agent cytotoxic therapies. In a later study, Gardner (2002) developed a computational kinetic model to predict chemotherapeutic combinations, doses, and schedules most likely to result in patient response and prolonged life. This model predicts that combination therapy involving both cytotoxic and cytostatic drugs will be more effective than combination therapy involving only cytotoxic drugs. Thus far, no systematic evaluation of the Goldie and Coldman and Gardner hypotheses have been conducted in the metastatic clinical trial setting. Here I test these hypotheses using the results of over 700 phase II, III and II/III clinical trials. I show that, as predicted by Goldie and Coldman, both overall response rate and overall survival were greater in combination arms. Moreover, median duration of response – the key indicator of the rate of resistance evolution - was also greater in combination vs single agent arms. These results suggest that generally combination chemotherapy is more effective than single agent therapy for advanced solid tumors as predicted by Goldie and Coldman (1979) hypothesis and that, at least in the metastatic setting, the potential disadvantages of combination therapy with respect to accelerated resistance evolution are outweighed by the greater waiting times for resistance mutations to arise. By contrast, although combination cytotoxic and cytostatic therapy is associated with a greater average overall response rate than multi agent cytotoxic therapy, this is not the case for both median duration of response and overall survival. Hence, there is no evidence that, in contrast to the predictions of the Gardner (2002) model, combination cytotoxic and cytostatic therapy decreases the rate of resistance evolution relative to that obtaining under combination cytotoxic therapy.

Background and Purpose: In 2007, the WHO classification of brain tumors was extended by three new entities of glioneuronal tumors: papillary glioneuronal tumor (PGNT), rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) and glioneuronal tumor with neuropil-like islands (GNTNI). Focusing on clinical characteristics and outcome, the authors performed a comprehensive individual patient data (IPD) meta-analysis of the cases reported in literature until December 2012. Methods: PubMed, Embase and Web of Science were searched for peer-reviewed articles reporting on PGNT, RGNT, and GNTNI using predefined keywords. Results: 95 publications reported on 182 patients (PGNT, 71; GNTNI, 26; RGNT, 85). Median age at diagnosis was 23 years (range 4–75) for PGNT, 27 years (range 6–79) for RGNT, and 40 years (range 2–65) for GNTNI. Ninety-seven percent of PGNT and 69% of GNTNI were located in the supratentorial region, 23% of GNTNI were in the spinal cord, and 80% of RGNT were localized in the posterior fossa. Complete resection was reported in 52 PGNT (73%), 36 RGNT (42%), and 7 GNTNI (27%) patients. Eight PGNT, 3 RGNT, and 12 GNTNI patients were treated with chemo- and/or radiotherapy as the primary postoperative treatment. Follow-up data were available for 132 cases. After a median follow-up time of 1.5 years (range 0.2–25) across all patients, 1.5-year progression-free survival rates were 52±12% for GNTNI, 86±5% for PGNT, and 100% for RGNT. The 1.5-year overall-survival were 95±5%, 98±2%, and 100%, respectively. Conclusions: The clinical understanding of the three new entities of glioneuronal tumors, PGNT, RGNT and GNTNI, is currently emerging. The present meta-analysis will hopefully contribute to a delineation of their diagnostic, therapeutic, and prognostic profiles. However, the available data do not provide a solid basis to define the optimum treatment approach. Hence, a central register should be established.

京都大学 / 新制・課程博士 / 博士(地球環境学) / 甲第24061号 / 地環博第224号 / 新制||地環||43(附属図書館) / 京都大学大学院地球環境学舎地球環境学専攻 / (主査)教授 宇佐美 誠, 准教授 吉野 章, 教授 諸富 徹 / 学位規則第4条第1項該当 / Doctor of Global Environmental Studies / Kyoto University / DFAM

Thesis (PhD(Psychology))-University of Pretoria, 2007. / Abstract in English. Includes bibliographical references. Available on the Internet via the World Wide Web.

Univ., Habil.-Schr.--Zürich, 2005. / Literaturverz. S. 329 - 342.

Thesis (Ph. D.)--Carleton University, 2003. / Includes bibliographical references (p. 132-163). Also available in electronic format on the Internet.