Evolution of viral myocarditis to dilated cardiomyopathy (DCM)represents a delicate balance between host innate immunity and T-cell acquired immunity. IRF-9 is a key member of a transcription factor family that regulates type I interferon (IFN) production, critical for innate antiviral protection. RESULTS: IRF9-/- mice showed dramatically increased mortality compared to the wildtype littermates (0% WT vs 72% IRF-9-/- on day 14, P<0.0001). On day 42, there was less cardiac hypertrophy and inflammation in IRF-9-/- mice compared to WT controls (p<0.05). Onn day 42 there was a dramatic increase in the number of cytotoxic and helper T-Cells in the wild-type mice that was not observed in the IRF-9-/- spleens (p<0.05). CONCLUSIONS: These data suggest a novel dual role of IRF-9 in not only regulating interferon in acute stage of viral infection in myocarditis, but also late acquired immunity activation, including CD4/8 populations, contributing to the development of chronic cardiomyopathy.

Master of Science / Department of Kinesiology / Craig A. Harms / High-intensity interval training (HIT) has been utilized as a time-efficient strategy to induce numerous physiological adaptations and improve performance usually associated with “traditional” endurance training (ET). It is not known however, if HIT might lead to improvements in pulmonary function. Therefore we hypothesized that HIT would increase respiratory muscle strength and expiratory flow rates. Fifteen healthy subjects were randomly assigned to an ET group (n = 7) and a HIT group (n = 8). All subjects performed an incremental test to exhaustion (VO2 max) on a cycle ergometer prior to and after training. Standard pulmonary function tests, maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax), and maximal flow volume loops, were performed pre training and after each week of training. HIT subjects performed a four week training program on a cycle ergometer at 90% of their VO2 max final workload while the ET subjects performed exercise at 60-70% of their VO2 max final workload. All subjects trained three days/ week. The HIT group performed five one-minute bouts with three minute recovery periods and the ET group cycled for 45 minutes continuously at a constant workload. A five-mile time trial was performed prior to training, after two weeks of training, and after four weeks of training. Both groups showed similar (p<0.05) increases in VO2 max (~8-10%) and improvements in time trials following training (HIT 6.5 ± 1.3%, ET 4.4 ± 1.8%) with no difference (p>0.05) between groups. Both groups increased (p<0.05) PImax post training (ET ~25%, HIT ~43%) with values significantly higher for HIT than ET. There was no change (p>0.05) in expiratory flow rates with training in either group. These data suggest that whole body exercise training is effective in increasing inspiratory muscle strength with HIT leading to greater improvements than ET. Also, HIT offers a time-efficient alternative to ET in improving aerobic capacity and performance.

This research considers the treatment of malignant melanoma. Data were collected from patient records for 78 individuals treated within the Yale Cancer Center Melanoma Unit. The patients were diagnosed with malignant melanoma prior to 1994 and progressed to stage I11 or N disease before their deaths.Due to the rapid progression of malignant melanoma, treatments are initiated at the time of diagnosis. Results of experimental Extreme Drug Resistance (EDR) tests subsequently become available. Physicians are warned the test results are not intended to guide therapy; however, assay directed therapies arguably result in better outcomes with other cancers. Thus, the question arises of whether the use of these tests might benefit patients in this context.This study evaluates the treatment decisions made using a multi-disciplinary approach within the Yale Cancer Center Melanoma Unit regarding patients with malignant melanoma relative to information contained in EDR tests conducted by Oncotech Inc. Within this comparison, three specific outcomes consistent with hypotheses of the study were assessed: the utilization of test results, drug toxicity and cost effectiveness and survival.Results were found to suggest that the initial treatment decisions of the Yale Cancer Center Melanoma Unit were in accord with tests results that were received henceforth for 74 of 78 patients. Two of those patients were in terminal stages of the disease thus treatments were unchanged; however two patients received a change in therapy.It is suggested that physicians made use of the tests as they became available. However, only two patients with therapies altered by the test results were shown to face reduced costs, drug toxicity, or have the benefit of improved survival. From the patient data collected, four patients receiving drugs to which their tumors exhibited EDR were found to exhibit shorter survival times. Literature review studies conducted to evaluate physician treatment approach and patient preference rate favorably the consideration of quality of life issues. The principle finding of this observational study which focuses upon the development of the Yale Cancer Center Melanoma Unit, suggest that a multidisciplinary approach to the treatment of malignant melanoma may offer quality of life benefits to the patient.

A qualitative research study was conducted with people who had participated as healthy subjects in phase I drug trials at commercial research facilities, in order to develop a better understanding of their perspective regarding research participation. The participants were recruited using online advertisements posted on the University of Toronto student website (www.my.utoronto.ca) and NOW Magazine online. Thirty-one subjects were interviewed. The audiotaped interviews were transcribed and analyzed using grounded theory methods. A grounded theory was developed that describes the process of participation and the main factors affecting the experience of participation, from the perspective of healthy subjects. The theory, called Making Participation Work, explains how healthy subjects frame participation as an income earning opportunity, and how this framing shapes their behaviour with regard to participation. Participants expressed a range of attitudes about the experience of participation, from very positive to very negative. The main factor affecting the experience is the perceived net burden, which is in turn affected by the degree to which subjects find personal control over their participation. Net burden and finding personal control were both affected by the degree to which subjects felt valued by research staff, and by whether subjects had trust in the research enterprise. Although subjects framed participation as work, the relationship with the study doctors and nurses was viewed as clinical. Most subjects are generally trusting that participation in phase I drug trials is safe. These findings suggest that models of research participation assuming participation motivated by altruism or potential therapeutic benefit cannot accommodate the attitudes and behaviours of healthy subjects in phase I drug trials. New models must be developed which account for the framing of participation as work, while being sensitive to the trust that healthy subjects place in the research enterprise.

This thesis explores health technology innovation within indigenous enterprises in China, India, and Brazil. The main discussions are presented in five papers/manuscripts. The first is a case study of Brazil’s health biotechnology sector. It concludes that systemic tensions between the country’s public and private sectors may be detracting from its overall innovative success. The second paper gauges vaccine and medicinal innovation within enterprises in the stated countries by analyzing new technologies in their pipelines or on the market. It concludes that that a growing number of health enterprises in these countries are tackling more technologically challenging and costly innovations. The third paper explores how national institutions and industry globalization interact to shape commitments to new drug and vaccine innovations by enterprises in the three countries. It concludes that; a) the introduction of pharmaceutical product patent regimes has had a modest impact on entrepreneurial attempts to develop new technologies, b) key challenges that diminish patent incentives tend to be institutional in nature and, c) the increasingly globalized nature of health product innovation limits what countries can achieve independently. The fourth paper analyzes key issues and trends in health biotechnology firms’ transition to innovation in China, India, Brazil, and South Africa. It concludes that this transition often entails greater integration into the global system. The fifth paper ponders the implications for global health of the emerging market firms’ transition to innovation. It concludes that these enterprises have the potential to simultaneously address global health needs while exploiting global markets, provided support mechanisms are put in place to enable product development for the poorest market segments. This research suggests that to succeed in biopharmaceutical innovation, nations need to adjust scientifically, sectorally and globally all at the same time. Also, that national governments and the global health community need to enhance engagement of emerging market enterprises in related efforts.

Bone disease and fractures are common in men and women with chronic kidney disease (CKD). The etiology of fractures in CKD is multi-factorial; identifying risk factors for fracture is important in CKD, so that patients who are at high risk can be treated before they fracture. The majority of studies have focused on risk factors associated with fracture in patients with stage 5 CKD on dialysis–there is a need for studies in pre-dialysis CKD. Three novel, non-radiological factors were assessed in 211 men and women with stage 3-5 CKD: cytokines osteoprotegerin (OPG) and receptor activator of nuclear factor kappa beta ligand (RANKL); tests of neuromuscular function including the timed up and go (TUG), 6 minute walk (6MW), and grip strength; and daily activity levels by accelerometry. Fractures were defined as self-reported low-trauma fractures since the age of 40 and/or prevalent vertebral fractures identified by morphometry. Logistic regression and receiver operating characteristic curves (ROC) were performed using STATA version 11.0. Those with fractures had elevated OPG compared to those without fractures (9.37±4.23 vs. 8.13±3.04 pmol/L, p=0.03), however, after adjusting for age OPG did not differ by fracture status. After adjusting for age, weight, and sex, impairments in both the TUG and 6MW tests were associated with fractures (TUG odds ratio (OR): 1.68, 95% confidence interval (CI): 1.40-2.02; 6MW OR: 0.53, 95% CI: 0.52-0.54). The diagnostic tests characteristics of the TUG and 6MW tests were excellent; both could discriminate fracture status (TUG AUROC: 0.90, 95% CI: 0.84-0.95; 6MW AUROC: 0.87, 95% CI: 0.84-0.95). Overall, subjects were primarily sedentary. After adjusting for stage of CKD, increased sedentary activity and decreased light intensity activity could discriminate fracture status (sedentary AUROC: 0.72, 95% CI: 0.56 to 0.87; light activity AUROC: 0.71, 95% CI: 0.55 to 0.87). In conclusion, non-radiological, novel factors including the TUG, the 6MW, and daily activity, but not OPG or RANKL were able to discriminate fracture status in men and women with stage 3-5 CKD.

Pre-hypertension (pre-HT) (Blood Pressure (BP) ≥120/80mmHg to ≤ 140/90mmHg) increases the risk of developing hypertension (HT). BP reductions following acute exercise are known as post exercise hypotension (PEH). BP and perhaps PEH shows a daily circadian rhythm. Purpose: To compare the magnitude of PEH after morning and evening aerobic exercise in adults with pre-HT. Hypothesis: The magnitude of PEH will be larger after evening versus morning exercise. Participants: Pre-HT men and women 50-65 years old. Study Design: Participants engaged in cycling exercise (60% VO2max) on two occasions: 1.5 and 11 hours following waking. Cardiovascular function was assessed for 30 minutes pre and one hour post exercise. Results: 1) Systolic PEH responses affected by TOD differed by gender. 2) Baseline Heart Rate Variability and its response to exercise differed gender but not TOD. The inconsistent significant gender and TOD differences of PEH and its mechanisms suggest that this group.

The purpose of this thesis is to apply the Promoting Action on Research Implementation in Health Services (PARiHS) framework to a provincial osteoporosis management program to describe unit level factors that may have influenced implementation among participating inpatient rehabilitation units. A toolbox of measures was proposed to operationalize the frameworks elements of evidence, context and facilitation. A cross-sectional survey was completed with clinicians responsible for championing the program and their managers. Results demonstrated that leadership behaviours, organizational climate traits and champion behaviours varied among practice environments indicating that attention to unit level factors outlined by the PARiHS framework could increase the uptake of research evidence in practice. The proposed toolbox could be utilized as a diagnostic and prescriptive tool to identify potential implementation barriers, and guide the selection of appropriate tools/strategies to overcome them. Furthermore, it will enable future studies to provide further empirical support for the PARiHS framework

Background: Systematic reviews (SRs) should be kept up-to-date to maintain importance in informing health care policy and practice. However, updating policies and practices of health care organizations (HCOs) that fund or conduct SRs are either unclear or non-existent. Objective: To examine updating policies and practices of relevant HCOs. Primary Research Design: An exploratory Internet survey of 195 HCOs within the international SR community. Results: The completed response rate was 58% (n=114) across 26 countries. Although 57% of organizations reported to have a formal updating policy, 59% reported updating practices as irregular. Moreover, 54% estimated more than half of their respective SRs were likely out dated. Resource constraints were a prominent barrier. Most (70%) supported centralizing updating efforts across institutions or agencies. Significance: This research provides a baseline glimpse of the state of updating among HCOs globally involved in evidence synthesis and therefore adds to a limited body of knowledge.

Aerobic exercise is recommended as a lifestyle intervention to reduce blood pressure (BP) in individuals with elevated BP (SBP/DBP >120/80 mmHg). However, the BP response is highly variable after both acute (SBP/DBP: –27 to 9/-8 to 7mmHg) and chronic aerobic exercise (-20 to 9/ -11 to 11.3mmHg). We attempt to identify those who are resistant or responsive to training based on their responses to acute (one-bout) exercise. 17 prehypertensive (120 to 139/80 to 89mmHg) males and females (45-60yrs) underwent acute exercise assessments before and after an 8-week walking/jogging program. The magnitude of change in BP after acute exercise significantly correlated (r=.89, p < .01) with the magnitude of change in resting BP after the training. The antihypertensive mechanisms (total peripheral resistance, baroreflex sensitivity) for acute exercise were not correlated to those for chronic exercise. Central cardiovascular controls may link BP reductions after both acute and chronic exercise.