Karim Miran-Khan

Sports injury aetiology is a process in which internal and external risk factors contribute to an inciting event. The last decade has seen a rapid growth in research that identified how training and competition workloads relate to sports injury risk. My literature review highlighted that existing aetiology models do not describe how workloads contribute to injury. Furthermore, injury risk fluctuates on a time-scale in parallel to these workloads (e.g. daily), which creates several methodological and statistical challenges that have largely been ignored. If researchers are to understand how athletes’ workloads relate to injury risk, their conceptual aetiological models must be updated to incorporate training and competition workloads, and they should use appropriate statistical analyses. After my literature review, I divide this dissertation into three parts. In Part 1 I discuss how workloads relate to injury. I present a novel workload—injury aetiology model, which expands on previous aetiological frameworks and details 3 ways that workloads contribute to injury: 1) exposing athletes to external risk factors and potential inciting events, 2) reducing injury risk through beneficial physiological changes, and 3) increasing injury risk through transient negative changes in athletes’ internal risk profiles. I then present mediation and moderation as potential causal approaches to understand how athlete risk factors interact with workload changes to alter injury risk. In Part 2 I tackle the methodological challenges of analysing workload—injury data. I reviewed prospective cohort studies that reported intensive longitudinal data to analyse workload—injury data in team sports. I identified that few studies utilised statistical approaches that align with theoretical aetiology models or addressed the methodological challenges associated with longitudinal data. My analysis leads me to recommend mixed modeling as one advance, and I exemplify how it can be used by studying how player unavailability affects player outputs. In Part 3 I integrate the conceptual and methodological considerations into two applied settings. First, I describe how a methodological/mathematical concern (mathematical coupling) may influence applied practice (multifaceted player load management) and research (explicitly reporting calculations). Finally, I use mixed modeling to examine pre-season workload and in-season injury risk, controlling for athletes’ weekly workloads.

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Patellofemoral osteoarthritis (OA) is an under-recognized medical condition that may progress to generalized knee OA. It is highly prevalent and is associated with knee pain and disability. Patellofemoral alignment, tibiofemoral alignment or trochlear morphology may influence the prevalence, onset or worsening of patellofemoral OA. Therefore, my main objective in this dissertation was to use magnetic resonance (MR) imaging to quantify the relationships between knee alignment or morphology and prevalent patellofemoral OA. This dissertation is comprised of four studies. First, I systematically reviewed the associations among knee alignment or morphology with patellofemoral OA presence, severity, onset or worsening. Lateral patellar tilt, lateral displacement, patellar height, frontal plane knee alignment, and a shallow sulcus were all associated with OA prevalence and severity. Second, I examined the relationship between key alignment and morphology measures and early patellofemoral OA, one year following anterior cruciate ligament reconstruction. Lateral displacement and a shallow sulcus were associated with early patellofemoral OA.Third, I evaluated alignment and morphology in the Framingham community cohort, a population-based cohort. I established reference values in knees without patellofemoral OA or pain. I then evaluated dose-response patterns of the full sample. The odds of prevalent patellofemoral OA rose monotonically with greater lateral patellar displacement and a shallower sulcus. Odds rose for patellar tilt in both directions, i.e. increased medial or lateral tilt.Fourth, using an upright, open-bore MR scanner, I developed reproducible methods to evaluate three dimensional knee alignment in standing. I then examined differences in alignment from supine to standing positions, and differences in alignment in supine and standing in individuals with patellofemoral OA and matched controls. Key measures of malalignment were greater in standing then supine. In knees with patellofemoral OA, the patella was more laterally tilted, laterally displaced, and proximally displaced compared to controls, and the tibia was more externally rotated. Taken together, these studies suggest that knee alignment and trochlear morphology may influence the risk of patellofemoral OA.

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As a field, health promotion has largely ignored how sex and gender contribute to one’s capacity to increase control over and improve one’s health—the very essence of health promotion. This dissertation urges health promoters to adopt an intersectional view of sex and gender as determinants of health and to develop interventions with explicit attention to improving gender equity. Doing so positions health promotion to improve social as well as health outcomes.To develop this argument, I use intersectional theory to inform: an historical account of the development of health promotion and documentary review of key health promotion charters; an overview of reviews of interventions to increase physical activity, reduce smoking, and limit alcohol consumption among women; and a qualitative study of older women’s involvement in physical activity.Using criteria for gender-sensitive interventions articulated by the World Health Organization, the overview of reviews suggests that, to date, programs to address women’s physical activity and substance use are more likely to be gender-specific—aimed at women—than to be gender-sensitive. Building on this limited range of health promotion programs, I outline a conceptual framework to illustrate that health promotion could reduce gender-related health inequities by transforming gender-related norms, roles, and relations. I illustrate the need for and possibilities of such a framework with examples of social marketing messages directed at women and girls.I then present the findings of a qualitative study of older women’s engagement in physical activity with a gender lens. Though aware of the importance of physical activity for health, the women were motivated to be active to maintain their indepedence and function, rather than by health concerns, which can be understood as reflecting gendered expressions of resistance to the stigma associated with aging and disability—and their challenges to femininity. Informed by the framework on gender-transformative health promotion, programs could increase older women’s involvement in physical activity by aligning with older women’s priorities—stressing how being flexible, strong, and fit can contribute to women’s ability to live independently and pursue personal priorities—and simultaneously working to fight ageism, sexism, and barriers to participation.

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Introduction: Falls in the elderly are a significant cause of morbidity. Prescriptionmedication use has been identified as an independent risk factor for falls. Among all Emergency Department (ED) presentations by elderly persons, 14-40% are due tofalls, placing considerable strain on ED resources. Aims: In my thesis I aimed to 1) Provide updated estimates of the association between the use of specific medications and falling, 2) Determine whether the careprovided to elderly fallers while patients in the ED follows published recommendations and was provided in a timely fashion, 3) Estimate the cost per fallresulting in an ED presentation, 4) Design a discrete event simulation (DES) modelsimulating care and then simulating other approaches to care including hypotheticalchanges. Methods: 1) A Bayesian meta-analysis of studies assessing the association between specific classes of medication use and risk of a fall. 2) A cohort study ofelderly fallers presenting to the ED. 3) DES of the ED care received by elderly fallers. Results: Use of anti-hypertensives, diuretics, sedatives and hypnotics, neuroleptics and anti-psychotics, antidepressants, benzodiazepines, and non-steroidal antiinflammatorydrugs are associated with an increased risk of falling.1) In a sample of 101 ED fall presentations, 38% of elderly fallers leave the ED without a geriatric assessment and 14% are assessed by a physiotherapist.Less than 8% of fallers received care which met the wait time benchmarks. The estimated cost per fall causing an ED presentation is $11,408 with the cost per fall-related hospitalization estimated to be $29,363.2) Providing care in a timely fashion could significantly reduce the time an elderly faller spends in the ED and the opportunity costs associated with waiting to be seen by physician or admission to hospital. Summary: Many commonly used medications are associated with falls. The careprovided by the elderly faller in the ED does not currently meet therecommendations of published guidelines, nor is it provided in a timely fashion. The economic burden of falls is significant. By not providing ED care that meetsrecommended wait time benchmarks significant opportunity costs are incurred by the ED.

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THE PROBLEM: Rest cramps (also known as nocturnal leg cramps) are painful muscle contractions, typically in the legs or feet, that occur during prolonged rest - most often while in bed at night. Although common in older adults, safe and effective treatment options are lacking.OPPORTUNITY AND METHOD #1: Magnesium supplements are readily available and widely marketed to consumers for cramp prophylaxis. However the efficacy of magnesium for this indication is unclear and existing clinical trials are limited by the well recognized poor bioavailability of oral magnesium. To better assess the potential efficacy of magnesium in cramp prophylaxis I conducted a (N=46) double-blind, placebo-controlled RCT on community-dwelling rest cramp sufferers to determine whether a more reliable delivery method (5 consecutive days intravenous infusion of 20 mmol magnesium sulfate) could reduce the frequency of rest cramps. I additionally determined whether the response to treatment varied with the extent to which infused magnesium was retained (as measured by 24-hr urinary magnesium excretion) and performed a Cochrane Systematic Literature Review to find and synthesize all relevant randomised trials.OPPORTUNITY AND METHOD #2: Anecdotal evidence suggested several medications might promote muscle cramping. If true, cramp sufferers using these drugs could potentially gain cramp relief through therapeutic substitution or reduction of these agents. To investigate this potential cramp link I searched BC Ministry of Health databases containing diagnostic and prescribing information on the 4.2 million residents of British Columbia to determine, using sequence symmetry methods, whether quinine starts (i.e. new cramp treatment) increased in the year following introduction of the three most commonly prescribed medications with a link to muscle cramps (diuretics, statins and inhaled long-acting beta2-agonists).CONCLUSION: Although its role in pregnancy-associated rest cramps remains unclear, magnesium supplementation does not meaningfully reduce the frequency of rest cramps in older adults. Alternatively, for some cramp sufferers, reduction or discontinuation of select cramp promoting medications (inhaled long-acting beta2-agonists, potassium-sparing diuretics and thiazides) may be a useful therapeutic maneuver. Over a 13 year period 60.3% of quinine users (cramp sufferers) received at least one of these medications. In contrast, statin and loop-diuretic cramp associations were clinically unimportant.

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Introduction: This thesis comprises six studies that address important economic issues related to falls prevention in community living seniors. Aims: 1) To ascertain the economic burden of falls in different countries and examine why these costs differ. 2) To determine which falls prevention strategies provide the best value for money. 3) and 4) To estimate the cost-effectiveness and cost-utility of once and twice weekly resistance training compared with balance and tone classes for one year and two years in terms of falls prevented and quality adjusted life years (QALYs) gained. 5) To: a) quantify the difference in the incremental cost-effectiveness ratio (ICER) when the QALYs are generated from the EuroQol 5D (EQ-5D) and from the Short Form 6D (SF-6D) over the 12-month intervention period of the Brain Power study, b) determine key predictors of changes in health related quality of life and health resource utilization. 6) To determine whether executive functions are independently associated with health related quality of life in older women. Methods: I conducted two systematic reviews, two comprehensive cost-effectiveness and cost-utility analyses, a comparison of two generic preference based utility instruments and an exploratory study of the association between QALYs and cognition. Results: 1) The mean cost of falls ranged from US $3476 per faller to US $26 483 per fall requiring hospitalization. 2) The best value for money in falls prevention comes from interventions targeting high-risk groups. 3) Once weekly and twice weekly resistance training were cost saving compared with balance and tone classes (comparator). 4) The benefits in the year after participating were not sustained for both resistance training groups. 5) ICERs estimated from the SF-6D and EQ-5D may result in different conclusions. 6) Executive function is an independent predictor of QALYs in older women.Summary: Falls prevention strategies can be cost saving and are related to quality of life and executive function in specific groups of community dwelling seniors. Establishing consistency in economic evaluation methods is a priority for comparison of costs, QALYs and value for money between countries and between effective falls prevention strategies.

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Background: Painful tendon overuse pathology (tendinosis) is poorly understood. Theobjectives were to identify major cell populations within clinical tendinosis lesions, andto examine factors involved in the regulation of tendon cell death, survival, orproliferation. The overarching hypothesis was that both cell death and cell proliferationplay roles in the development of tendinosis.Methods:1: Chronic patellar tendinosis tissue was compared with normal, pain-free patellar tendonusing Western blot, immunohistochemistry and in situ hybridization. A variety of celltypes were examined in relation to relevant features of soft tissue injury and repairincluding cellular proliferation and versican expression.2: In adult male rats, early tendinosis was induced in the supraspinatus tendon by 4-16weeks of mechanical loading (eccentric exercise). Tendons were analyzedmorphologically using polarized light and transmission electron microscopy, and byimmunolabeling for molecular markers of proliferation and survival.3: The influence of IGF-I on tenocyte survival was tested in response to chronic hypoxiain a cell-culture setting.Results1: Tendinosis was characterized by proliferation of tenocytes, endothelial cells, andsmooth muscle cells within a versican-enriched extracellular matrix. Mast cells were alsomore numerous in patient biopsies, whereas macrophages and lymphocytes were virtuallyabsent. VEGF expression was increased in endothelial cells from tendinosis tendons andwas more marked in patients with shorter symptom duration.2: Mechanical loading of the rat supraspinatus tendon by downhill running caused focaltendon lesions characterized by tenocyte proliferation, collagen disarray andglycosaminoglycan accumulation. Tenocytes in these areas of injury demonstrated aproliferative response which correlated with IGF-I expression and phosphorylation ofERK-l/2and IRS-1.3: Prolonged hypoxia of primary tenocyte cell cultures resulted in tenocyte apoptosis andcaspase activation. Apoptosis could be prevented dose-dependently by IGF-I, whichactivated the PKB survival pathwayConclusionsThe current studies outlined predominant cell populations present in tendinosis lesionsand identified factors which may be involved in regulating their death, survival andactivity. These experiments have opened up new avenues of research into thepathophysiology of tendinosis.

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