Background and Objectives: Mesothelin, identified as a tumor-associated biomarker, is more often overexpressed in triple receptor-negative breast cancer (TNBC) than in common luminal breast tumor subtype or normal tissues. The objective of this systematic review is to determine the association between the expressions of mesothelin with survival outcomes in patients with TNBC. Methods We searched the following electronic databases: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, PubMed, and Web of Science with no time or language restriction till May 19, 2016. Any prospective or retrospective longitudinal studies that investigate the prognosis of TNBC with mesothelin baseline measurement were selected. Two reviewers independently assessed every article for inclusion, extracted data, and assessed the methodological quality of every eligible trial. Pooled measures of associations were summarized with meta-analyses. Results and conclusions Among the 592 patients with TNBC included in the four eligible studies, 269 patients (45.4%) demonstrated mesothelin expression. For the primary outcome OS, we found the trend toward decreased survival for patients with mesothelin-positive TNBC than those without mesothelin expression. We also found that for long-term OS, the association was statistically significant (OR = 0.46; 95% CI= 0.30 to 0.73; P< 0.001). For the secondary outcomes, we found that mesothelin expression in patients with TNBC was associated with lower DFS and higher overall mortality than those without mesothelin expression. Despite the limitations of sample size, this present study shows a significant association between mesothelin expressions and survival outcomes in patients with TNBC. Patients with mesothelin-positive TNBC could benefit from mesothelin-targeted immunotherapies recently in the development. / Thesis / Master of Science (MSc) / It is unclear whether mesothelin expression in triple-negative breast cancer (TNBC) is an independent prognostic marker for survival. To the best of our knowledge, no systematic review or meta-analysis has ever been done on this topic. The present systematic review aims to evaluate the role of mesothelin as a prognostic marker for TNBC. The primary objective of this review is to synthesize available evidence on the association between the expression of mesothelin and overall survival (OS) of patients with TNBC. The secondary objectives include determining the relationship between the expression of mesothelin and disease-free survival (DFS), distant metastases, and mortality. Despite some limitations, this study shows a significant association between mesothelin expressions and long-term OS rate as well as DFS rate and mortality rate in patients with TNBC. Mesothelin has a prognostic significance for patients with mesothelin based on our findings. Patients with mesothelin-positive TNBC could benefit from mesothelin-targeted immunotherapies in development.

Hip fractures are common injuries with devastating consequences, including high rates of morbidity and mortality. The purpose of my thesis was to lay the foundation for further research which can fully explore: i) the epidemiology of morbidity and mortality following hip fracture; ii) risk factors for poor outcomes following hip fracture; iii) causes and pathways to mortality following hip fracture; iv) secondary prevention of morbidity and mortality following hip fracture; and v) potential interventions to improve outcomes following hip fracture. To this end, I will first detail the design, execution, results, and ‘lessons learned’ of a prospective observational pilot cohort study that recruited 100 consecutive patients aged ≥18 years presenting with a hip fracture to the Juravinski Hospital and Cancer Centre of the Hamilton Health Sciences. The primary aim of this pilot study was to assess the feasibility of a larger prospective international cohort study. Second, I will present a systematic review and meta-analysis of a promising intervention that consisted of multi-disciplinary (specifically geriatrician-led) co-management of hip fracture patients. This intervention has previously been shown to reduce mortality and length of stay following hip fracture. The meta-analysis presented will determine the effectiveness of this intervention in reducing the incidence, duration, and severity of delirium—a common condition following hip fracture. / Thesis / Master of Science (MSc)

Background: Cannabis is increasingly used for management of chronic pain; however, the benefits and harms of this therapy remain uncertain. We conducted a systematic review to inform harms associated with inhaled cannabis for chronic pain. Methods: We searched MEDLINE, EMBASE, PsychInfo, and Web of Science for non-randomized studies reporting on harms associated with inhaled cannabis use, from inception to October 6, 2021. We used random-effects models for meta-analyses and assessed the certainty of evidence using the GRADE approach. Results: We identified 29 eligible studies enrolling 174,562 participants that reported 145 adverse events. Moderate certainty evidence suggests inhaled cannabis use is probably associated with dry mouth (prevalence: 56%; 95%CI 49 to 64), thirst (prevalence: 44%; 95% CI 33 to 55), fatigue (prevalence: 38%; 95%CI 31 to 45), nausea (prevalence: 17%; 95%CI 8 to 27), increased appetite (prevalence: 13%; 95%CI 9 to 18), dizziness (prevalence: 10%; 95%CI 6 to 14), diarrhea (prevalence: 9%; 95%CI 3 to 18), confusion (prevalence: 9%; 95%CI 5 to 13), mood changes (prevalence: 8%; 95%CI 4 to 15), hallucinations (prevalence: 7%; 95%CI 4 to 10), amnesia (prevalence: 6%; 95%CI 3 to 11), impaired coordination (prevalence: 5%; 95%CI 4 to 6), and disorientation (prevalence: 3%; 95%CI 1 to 7). Moderate certainty evidence shows that, compared to non-users, inhaling cannabis is probably associated with increased risk of shortness of breath (risk difference [RD]: 7%; 95%CI 4 to 10). Conclusions: Our review found moderate certainty evidence that dry mouth, thirst, and fatigue are probably frequently experienced with inhaled cannabis use. Several other adverse events are also probable associated with inhaled cannabis use but were less common. Rigorously conducted cohort studies are needed to inform harms associated with inhaled medical cannabis for chronic pain. / Thesis / Master of Science (MSc) / Increasing recognition of harms associated with long-term opioid therapy for management of chronic pain has generated enthusiasm for alternatives, including medical cannabis which is often consumed through inhalation. This review assesses the harms associated with the use of inhaled cannabis for management of chronic pain. Among serious adverse events, we found that inhaled cannabis is likely associated with amnesia, disorientation, impaired coordination, hallucinations, confusion, dizziness, chronic wheeze, and shortness of breath. Inhaled cannabis may be associated with palpitations, paranoia, anxiety, and cannabis dependence. The effects of inhaled cannabis on lung cancer, depression, and psychosis were uncertain. Among less serious adverse events, we found that inhaled cannabis is likely associated with thirst, fatigue, increased appetite, nausea, mood changes, diarrhea, and dry mouth. Inhaled cannabis may be associated with red eyes, vomiting, phlegm, asthma, and cough. The effects of inhaled cannabis on euphoria and irritability were uncertain.

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OBJECTIVES: The objective of this thesis is to explore the effectiveness and safety of common pharmacotherapeutic options used for the management of patent ductus arteriosus (PDA) in preterm infants. METHODS: Following the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidance, article 1 develops the protocol to conduct the systematic review and network meta-analysis to answer the research question. Article 2 details the actual methods implemented to conduct the network meta-analysis and presents the results in the form of network plots, league tables, rank heat maps, rankograms and forest plots. RESULTS: Article 1 suggests the need to conduct a Bayesian random-effects network meta-analysis of randomized controlled trials (RCTs) as the analysis would involve multiple treatments with potentially both direct and indirect comparisons. Article 1 also a priori defines potential effect modifiers and statistical strategies to control for the same. In article 2, the results of the meta-analysis show that in 68 RCTs that included 4802 infants, 14 different variations of indomethacin, ibuprofen or acetaminophen were used. Oral high-dose ibuprofen was associated with a significantly higher odds of PDA closure compared with standard-dose intravenous ibuprofen (Odds Ratio [OR], 3.59; 95% Credible Interval [CrI],1.64-8.17) and intravenous indomethacin (OR, 2.35; 95% CrI,1.08-5.31). Oral high-dose ibuprofen ranked the best option for PDA closure (SUCRA [surface under the cumulative ranking curve],0.89 [SD, 0.12]) and to prevent surgical PDA ligation (SUCRA,0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis or intra-ventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. CONCLUSION: This thesis suggests that oral high-dose ibuprofen could be the best treatment option for closure of a hemodynamically significant PDA. Placebo or no treatment for a hemodynamically significant PDA may not increase morbidity and mortality. / Thesis / Master of Science (MSc) / The following thesis explores the effectiveness and safety of commonly used drugs for the treatment of a heart condition in premature infants called the patent ductus arteriosus (PDA). Article 1 outlines the protocol for the systematic review and network meta-analysis designed to evaluate the effectiveness and safety of indomethacin, ibuprofen and acetaminophen for the treatment of PDA in preterm infants. Article 2 provides in detail the results of the network meta-analysis that examined all eligible randomized controlled trials that compared intravenous or oral formulations of indomethacin, ibuprofen or acetaminophen compared against to other or placebo for the treatment of a PDA that may be harmful for a premature infant based on certain clinical and echocardiographic criteria set by the clinicians and researchers. Overall, this body of work suggests that a higher dose of oral ibuprofen is the best treatment for PDA in premature infants.

Background: Carpal Tunnel Syndrome (CTS) is a condition affecting wrists and hands, causing pain, tingling, and numbness. Despite the high prevalence of CTS and the existence of several diagnostic tools, there is no consensus over a diagnostic gold standard test. Thesis Objectives: To conduct a systematic review of diagnostic test accuracy of clinical scales, questionnaires and hand symptom diagrams/maps for the diagnosis of CTS in people suspected with this condition; and to do a cognitive interviewing qualitative study of the Kamath and Stothard questionnaire, a diagnostic tool for CTS, to identify and resolve potential sources of error. Methods: In the first study, we searched MEDLINE, CINAHL, and Embase databases keywords related to diagnostic accuracy and clinical tests of CTS. In the second study, we interviewed clinicians and people diagnosed with CTS and other upper extremity conditions. We recorded, and content analyzed their opinion on comprehensiveness and comprehensibility of Kamath and Stothard questionnaire. Results: Twenty-one articles met the eligibility criteria of the systematic review, of which nine were on the diagnostic accuracy of hand symptom diagrams and twelve assessed the diagnostic accuracy of clinical scales and questionnaires for the diagnosis of CTS. Positive likelihood ratios (LRs) to diagnose or rule in CTS ranged from 0.94 for Boston carpal tunnel questionnaire to 10.5 for CTS-6 scale, and negative LRs to rule out CTS ranged from 1.05 to 0.05 for the same diagnostic tools. In the cognitive interviewing study, we categorized the areas of uncertainty in the participants’ responses into five themes: clarity and comprehension (51%), relativeness (38%), inadequate response definition (3.75%), perspective modifiers (3.75%), and a reference point (2.5%). Conclusions: Very few high-quality studies exist on the diagnostic accuracy of CTS-6, Kamath and Stothard questionnaire, Bland questionnaire, and Katz and Stirrat’s hand symptom diagram. By doing cognitive interviews, we identified options for potential improvement in the wording of the Kamath and Stothard questionnaire. Future studies should assess the diagnostic properties of the proposed modified questionnaire, and high-quality studies are warranted to assist in deciding on ruling in or out CTS. / Thesis / Master of Science (MSc) / Carpal tunnel syndrome is a condition affecting the hands, causing feelings of burning pain, pins and needles, heaviness and/or lack of sensation. This condition is very common among people who do manual work and can make them unable to do their jobs and daily living tasks. Early diagnosis of carpal tunnel syndrome is very important in starting an appropriate plan of treatment. The best diagnostic test for carpal tunnel syndrome is still uncertain. In the first study, we collected studies of the questionnaires and hand maps that exist for the diagnosis of carpal tunnel syndrome. We then tried to summarize the information that assists clinicians in making a diagnostic decision. In the second study, we interviewed people about their opinion of a questionnaire that is used in hand clinics to diagnose carpal tunnel syndrome. We concluded that more studies with high quality are needed to confidently decide which diagnostic test is best. Also, we revised a questionnaire that is currently used, and we hope that these revisions make the questionnaire more relecant and understandable for people.

No / Reactivity to assessment has attracted recent attention in the brief alcohol intervention literature. This systematic review sought to examine the nature of change in alcohol consumption over time in control groups in brief intervention studies. Primary studies were identified from existing reviews published in English language, peer-reviewed journals between 1995 and 2005. Change in alcohol consumption and selected study-level characteristics for each primary study were extracted. Consumption change data were pooled in random effects models and meta-regression was used to explore predictors of change. Eleven review papers reported the results of 44 individual studies. Twenty-six of these studies provided data suitable for quantitative study. Extreme heterogeneity was identified and the extent of observed reduction in consumption over time was greater in studies undertaken in Anglophone countries, with single gender study participants, and without special targeting by age. Heterogeneity was reduced but was still substantial in a sub-set of 15 general population studies undertaken in English language countries. The actual content of the control group procedure itself was not predictive of reduction in drinking, nor were a range of other candidate variables including setting, the exclusion of dependent drinkers, the collection of a biological sample at follow-up, and duration of study. Further investigations may yield novel insights into the nature of behaviour change with potential to inform brief interventions design.