Thesis (M.P.H.)--University of Hong Kong, 2008. / Includes bibliographical references (p. 82-88).

Thesis (Ph. D.)--Case Western Reserve University, 2006. / Frances Payne Bolton School of Nursing. Includes bibliographical references. Available online via OhioLINK's ETD Center.

Over 7 million participants play rugby union throughout over 120 countries. Despite this global status, very little is known about the longer-term health outcomes of players, or how health and health-related quality of life are influenced by participation in rugby union. The aim of this thesis was to design and undertake an epidemiological study to assess overall health, the presence of morbidity, and development of osteoarthritis within former elite rugby players. In addition to establishing a study, and assessing health and morbidity, secondary aims were to compare the prevalence of morbidity in this population with age-matched representative population-based survey participants, and to examine risk factors associated with the development of osteoarthritis in this population. A cross-sectional questionnaire study was designed to assess physician-diagnosed morbidity, playing exposure, injury history and current health status. Former rugby players for Oxford and Cambridge Universities, and members of the England Rugby Internationals Club, were invited to participate in this study. Data from the English Longitudinal Study of Ageing (ELSA) and the Health Survey for England (HSE) were used as population-based representative comparator groups. These four studies examine the feasibility of involving rugby players in sport-related healthcare research, the prevalence of morbidity and health-related quality of life relative to the general population, the prevalence and risk factors for osteoarthritis-related outcomes, and finally develop a prediction model of end-stage hip failure in this population. Involving players throughout the research cycle as experts of their own experience was seen to influence the research process and questionnaire development, and ensured this process was grounded in players' beliefs and experiences. In terms of physician-diagnosed morbidity, former players were seen to demonstrate less diabetes than ELSA participants, but more osteoporosis, anxiety, osteoarthritis (OA) and joint replacement. Risk factors for osteoarthritis-related outcomes were seen to vary between the knee, hip and shoulder, and between the definitions of osteoarthritis used (NHANES pain, physician-diagnosed OA or joint replacement). Joint-specific injury was most highly associated with osteoarthritis across all joints and definitions used. The prediction model for hip replacement was strong (AUC 0.88), despite the relatively small development dataset, and again emphasised injury, in addition to Slipped Upper Femoral Epiphysis, age, family history, and playing in the second row, as predictive of hip replacement. This was not externally validated, however internal validation was undertaken. This work has not only established health outcomes in this population, and developed the methodology and survey tools to replicate this work in other cohorts, but also assesses risk factors and strongly predicts poor OA outcome in this population. This work presents potential intervention opportunities for the sport to begin to address the now quantified health deficits; and also presents benefits of elite contact sports participation. These findings should support efforts to ensure healthy participation and adequate proactive management of health at the elite level, for all players.

Abstract This work engaged Finnish females affected with osteoarthritis (OA) of the hand to define the role of common sequence variations within the genes of the important structural protein of cartilage, aggrecan (AGC1), and the genes of inflammatory mediators, the interleukin 1 gene cluster and interleukin 6 (IL6), as possible risk factors for the disease. Also, a genome-wide linkage analysis was performed in a sample consisting of Finnish families with multiple individuals affected with hip and knee OA in order to reveal new chromosomal areas that are likely to contain disease associated variations. OA is a chronic disease that leads to the degeneration of articular cartilage in synovial joints. The etiology of the disease is for the most part unknown. Joints of the hand, hip and knee are most commonly affected, and obesity, trauma and excess mechanical stress are known risk factors for the disease. OA also has a significant genetic component. AGC1 carries a variable number of tandem repeats (VNTR) polymorphism, which may be significant for the biomechanical properties of cartilage. It was shown that the most common allele with 27 tandem repeats is protective against hand OA (HOA) (odds ratio 0.46, 95% confidence interval 0.27–0.78). Also, carrying two copies of any of the shorter or longer alleles increased the risk of the disease. Inflammation seems to play a role in the etiology of OA and certain polymorphisms within the interleukin 1 gene cluster and IL6 have been previously shown to increase the transcription of these molecules and to associate with OA. In this study it was shown that the G alleles in three common IL6 promoter single nucleotide polymorphism (SNP) sites are associated with the risk of more severe forms of HOA (p =  0.001 for GGG haplotype). A SNP in IL1B associated with the bilateral form of the disease (p =  0.006) and two IL1B-IL1RN extended haplotype alleles were associated with the same phenotype. Genome-wide and fine mapping linkage analyses recognized chromosomal locus 2q21 with a multipoint LOD score of 3.96. Despite the association analyses of several candidate genes within the locus, no disease-associating sequence variants were identified.

Abstract The role of sequence variations in genes encoding cartilage extracellular matrix (ECM) proteins were studied in osteoarthritis (OA) and multiple epiphyseal dysplasia (MED). The cartilage collagen genes COL2A1, COL9A1, COL9A2, COL9A3, COL11A1, and COL11A2 were screened for sequence variations in 72 Finnish probands and one US family with primary early-onset hip and/or knee OA. Altogether 239 sequence variations were found, of which 16 were not present in the controls. Seven of the unique variations — four in COL11A1, two in COL11A2, and one in COL2A1 — were studied further, because they resulted in the substitution of conserved amino acids or were predicted to affect mRNA splicing. Association analysis was performed by genotyping 6–12 common polymorphisms from each gene in 72 OA patients and 103 controls; no common predisposing alleles were identified. The results, however, suggest that mutations in the minor cartilage collagen genes can be the cause of OA in a subgroup of OA patients. Two MED families with clinical and radiographic features suggestive of a collagen IX mutation were studied. Mutation screening of COL9A1, COL9A2, and COL9A3 yielded negative results. Instead, an R718W mutation in COMP was identified in both families. Clinical and radiographic overlap between patients with collagen IX mutations and patients with COMP mutations points to a common supramolecular complex pathogenesis. Clinical, radiological and molecular analyses of known MED genes were performed on a cohort of 29 consecutive MED patients. The DTDST mutation was identified in four patients (14%), the COMP mutation in three (10%), and the MATN3 mutation in three (10%). Two new distinct phenotypic entities were identified in patients in whom no mutation was found. The findings suggest that mutations in the above mentioned known MED genes are not the major cause of MED and are responsible for less than half of the cases. The existence of additional MED loci is supported by the exclusion of known loci and finding of the specific subgroups among these patients. The results suggest that genetic defects in ECM genes can predispose to OA and cause MED, even though the major genes involved in both disorders remain to be found.

Introduction: Osteoarthritis (OA), a degenerative musculoskeletal disease affecting joints, is characterised by pain and poor physical functioning, resulting in poor health related quality of life (HRQoL), emotional well-being and quality of sleep. There are few studies in this area in Taiwan. Aim and objectives: The aim of the study was to investigate how quality of sleep impacts on quality of life in individuals with OA in Taiwan. Specific objectives were to measure quality of sleep; to measure pain, physical function, emotional health and quality of life, and investigate their associations with quality of sleep; to investigate predictors of quality of sleep; and to investigate the association between subjective sleep perceptions and objective sleep outcomes. Methods: In a cross-sectional study, 192 OA patients aged over 40, diagnosed by radiology, fluent in Mandarin or Taiwanese, and residing in the community were recruited from musculoskeletal or rehabilitation outpatient departments in a university hospital in Taiwan from October 2010 to March 2011. A supervised self-completion questionnaire was used to collect data. Four validated Mandarin Chinese versions of questionnaires were used: the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) to measure pain and physical functioning; the Short Form-36 Health Survey (SF-36) to measure HRQoL; the Hospital Anxiety and Depression Scale (HADS) to measure emotional health; and the Pittsburgh Sleep Quality Index (PSQI) to measure subjective quality of sleep. A sub-sample of 30 individuals was recruited to measure objective sleep quality using an Actigraph wrist monitor. Data were encoded, entered onto computer and analysed with SPSS 16.0 software. Results: Most participants had poor subjective quality of sleep (70.3%), but only 19.8% were taking sleep medication. Global quality of sleep was poorer in participants who were older, female, had a low educational level and had more severe OA. Pain was mild-to-moderate but 47.4% and 25.5% of participants reported no or poor self-management of OA symptoms respectively, and 66.7% never used a walking aid. Poor quality of sleep was associated with pain, poor physical function, anxiety, depression and low scores on the physical and mental components of HRQoL (Pearson correlations 0.27 to 0.87), although most participants did not present problems with anxiety or depression. Regression showed that taking sleep medication, SF-36 role physical and social functioning, high HADS anxiety, a lack of secondary education, high WOMAC pain and taking analgesics significantly contributed to poor global quality of sleep. Path analysis identified four components potentially causing poor quality of sleep: an OA component (pain and physical function), a sleep medication component, a psychological component (anxiety) and a sociodemographic component (low education and poor social functioning), where being female was causally related to the last two. From the objective measurements, participants overestimated the actual time to fall asleep and underestimated their sleep duration and efficiency. Those with poor subjective quality of sleep were woken more often during the night and awake for longer during the night (both p < 0.027). Conclusion: Global quality of sleep was poor in individuals with OA in Taiwan; pain, physical function and emotional health negatively influenced quality of sleep and HRQoL. A hypothesised causal model for quality of sleep had components related not only to OA but also to psychological distress, socio-demographics and taking sleep medication. Objective measurements indicated that sleep disturbance was associated with poor perceived quality of sleep. The study suggests that better support and guidance on self-management of OA in Taiwan is required to allow patients more control over their health, well being and quality of sleep.

Magister Scientiae (Physiotherapy) - MSc(Physio) / Reduced adherence levels have been demonstrated by some patients affected with Osteoarthritis. Therefore, this study aimed at exploring the barriers and facilitators regarding patient adherence towards physiotherapy rehabilitation programs in the management of osteoarthritis in Nairobi, Kenya. The objectives of the study were to determine the clinical profile of patients with osteoarthritis on physiotherapy rehabilitation programs, to explore the patient-reported barriers and facilitators towards physiotherapy rehabilitation programs and exploring physiotherapists’ perceptions of patient adherence towards physiotherapy rehabilitation programs. The study setting was at the Kenyatta National Hospital physiotherapy clinic in Nairobi, Kenya.

Osteoarthritis (OA) is a degenerative joint disease that affects an estimated 9.6 % of men and 18 % of women over 60 years of age. However, there is no chondroprotective agent that is approved for clinical application. We showed that LOXL2 is elevated in the regenerative response during fracture healing in mice and has a critical role in chondrogenic differentiation. Indeed, LOXL2 is an anabolic effector that attenuates pro-inflammatory signaling in OA cartilage of the TMJ and knee joint, induces chondroprotective and regenerative responses. The goal of the present study was to evaluate if LOXL2 adenovirus in vivo promotes protective and anabolic responses in the knee and TMJ-OA cartilage. We employed (Cho/+) OA mouse model to assess knee and TMJ-OA, which is a genetic model that develops progressive TMJ-OA due to a mutation in the Col11a1 gene. Intraperitoneal injection every 2 weeks of Adv-RFP-LOXL2 in four-month-old Cho/+ male and female mice for 16 weeks upregulated Sox9, aggrecan (Acan) and other anabolic genes in the knee and TMJ. Next, to evaluate if LOXL2 expression occurred in degenerative lesions in human clinical TMJ-OA, immunofluorescence and confocal image analysis were performed. LOXL2 has the potential to induce anabolic gene expression in the progressive knee and TMJ-OA mouse model. We showed for the first time that LOXL2-related functions could be useful for anabolic therapies for Cho/+ mice progressive knee and TMJ-OA. Thus, these data show that LOXL2 could have clinical translational applications in the future for OA-related anabolic therapies.

Varus knee thrust is an abnormal frontal-plane movement (i.e., an out-bowing) of the knee that occurs during the weight-acceptance phase of gait. Varus thrust is of clinical interest, as it is a potentially-modifiable biomechanical risk factor for knee osteoarthritis (OA) progression and has been associated with knee pain. The overall aim of this dissertation is to identify the structural and symptomatic consequences of varus thrust at the knee and along the lower limb, and the possible anatomical and sensorimotor causes of varus thrust in older adults with or at risk for OA. Varus thrust was assessed in Multicenter Osteoarthritis (MOST) Study participants using high-speed videos of self-paced walking. Varus thrust was observed in 31.3% of 3730 knees. We investigated the longitudinal relation of varus thrust to MRI lesions and found that thrust was associated with increased odds of incident and worsening bone marrow lesions and worsening cartilage loss. We then investigated the longitudinal association of varus thrust with WOMAC knee pain and found that thrust was associated with increased odds of incident and worsening total WOMAC knee pain and worsening pain during weight-bearing and non-weight bearing activities. In an ancillary quantitative gait analysis of a single subject with unilateral varus thrust, we found altered joint moments at the hip, knee, and ankle in the thrust limb compared to the non-thrust limb. We bolstered this pilot data with an investigation of low back and lower extremity pain in the presence of thrust in MOST participants: limbs with thrust had increased odds of incident frequent pain proximal (hip or low back) and distal (ankle and foot) to the knee compared to limbs without thrust. Finally, we investigated the cross-sectional relation of anatomical and sensorimotor impairments at the knee and lower extremity to the prevalence of varus thrust. Thrust was most prevalent in limbs with static varus malalignment and supinated feet during gait, while increasing static knee laxity had a protective effect against thrust. These results fill substantial gaps in the narrative regarding the role of varus thrust in OA development.

Intra-articular corticosteroid knee injections (ICIs) were used as a tool to determine the sensitivity of wearable inertial sensors and machine learning algorithms in identifying meaningful changes in gait patterns amidst day-to-day fluctuations in out-of-laboratory gait. Specifically, three overarching aims were proposed; I) Determine if three gait trials could define an everyday typical gait pattern, II) investigate if post-injection atypical strides are significantly different from pre-injection atypical strides and III) explore the relationship between changes in pain and atypical strides. Nine knee OA patients (7M/2F) were recruited from St. Joseph’s Healthcare Hamilton. Participants completed a total of four walking trials prior to the ICI and three following. Participants were fitted with two wearable sensors on each shank just below the knee, and one sensor on the lower back during every trial. Data from these sensors were processed to train and test a one-class support vector machine (OCSVM). Individual gait models were created based on three out of the four pre-injection trials. Each trained model was tested on a withheld pre-injection trial and three post-injection trials to determine the number of typical and atypical gait cycles. Self-reported pain was analyzed throughout the study and compared to the percent of atypical strides seen during each walk. It was found that three gait trials could not define a typical gait model and that post-injection atypical strides were not significantly different from with-held pre-injection atypical strides. Finally, large variations and fluctuations in self-reported pain were observed on a week-to-week basis, which were not significantly correlated to atypical strides observed. This study was the first to investigate the sensitivity of wearable inertial sensors and machine learning algorithms to detect changes in real-world gait patterns and provides foundational work for using wearable sensors to monitor and triage knee OA patients. / Thesis / Master of Science (MSc)