Spinal cord injuries can cause the catastrophic loss of motor and sensory function. The neurological deficits that result are the consequence of not only the primary injury to the spinal cord, but also a complex milieu of secondary pathological processes that are now beginning to be understood. The major mechanisms that underlie this secondary pathology include vascular disruption, ischemia, oxidative stress, excitotoxicity, and inflammation. In light of this, the fact that this secondary pathology occurs after the initial impact makes it potentially amenable to therapeutic intervention. Pharmacotherapies may attenuate some of these processes and minimize secondary damage. Some of the promising treatments that are emerging for acute spinal cord injury are drugs that are already used by physicians for the treatment of unrelated diseases. These drugs, which have already been established to be safe for humans, offer the unique advantage over other novel therapeutic interventions that have yet to be tested in humans. This would save a tremendous amount of time and money needed for human safety studies, if considered as a treatment for spinal cord injury. Examples of such drugs include minocycline (an antibiotic), erythropoietin (a recombinant hormone used to treat anemia), and statins (a popular class of blood cholesterol reducers), all of which have demonstrated the ability to attenuate the various pathophysiological processes initiated after trauma to the central nervous system. In a series of studies, erythropoietin, darbepoetin, atorvastatin, simvastatin, and minocycline were all evaluated for their ability to improve neurologic recovery in a clinically relevant model of spinal cord injury. My experiments revealed that erythropoietin, darbepoetin, atorvastatin and minocycline did not significantly improve neurological recovery. These negative results were in stark contrast to the positive findings which had been published in the literature suggesting that differences in experimental models and methodology influence the neuroprotective efficacy of these drugs. Simvastatin, on the other hand, demonstrated significant improvements in locomotor and histological outcomes. Although this is indeed exciting, the results were modest at best. My results highlight the need for further preclinical work on the above treatments to refine and optimize them prior to proposing them for human testing. / Science, Faculty of / Zoology, Department of / Graduate

Parental perspectives on risk and danger are important to consider in children’s injury prevention research, as they influence children’s adoption of safety strategies and influence how children approach risk and danger (Brussoni & Olsen, 2011). Despite single, stay-at-home, and gay fathers’ increasing numbers and the important roles they play in their children’s development, there has been a lack of research on their perspectives on children’s engagement in outdoor risky play until now. This thesis is written in the publishable paper format and is comprised of two papers, which were informed by poststructural feminist theory. In the first paper, I used semi-structured and photo-elicitation interviews and critical discourse analysis to explore single, stay-at-home, and gay fathers’ perspectives of their 4-12 year old children’s engagement in outdoor risky play and how they relate to tension-filled discourses of “good” fathering. In the second paper, I also used semi-structured and photo-elicitation interviews, but I explored single, stay-at-home, and gay fathers’ perspectives of masculinity and its influence on their understanding of their children’s outdoor risky play. Taken together, the findings from both papers showcase the important roles that single, stay-at-home, and gay fathers play in their children’s outdoor risky play.

Introduction: An injury surveillance system was piloted in 2011 to monitor injuries in Canadian Forces. This evaluation of the key system attributes examined system performance. Methods: A retrospective chart review, a coding reliability study, a completeness of forms study and a key informant interview. Results: Sensitivity was 0.36 (95% CI: 0.28, 0.46). The system was missing patients over age 35. Kappa coefficients over 0.80 demonstrated good agreement. Completeness of forms study demonstrated high percentages of response for most questions and lower rates for questions related to using protective equipment, and consent for information sharing. Interviews proved acceptability to stakeholders, usefulness for identifying clusters and trends, simple and complete data collection, and flexibility. Conclusion: The injury surveillance system had good potential for several reasons: data collection did not require additional work in clinics; the system was well accepted and partially proved usefulness and timeliness in identifying unusual injury events.

Wii Fit U games utilize a Wii Balance Board™ (WBB) in a manner that can provide precise feedback contingencies similarly to some forms of balance rehabilitation, thereby potentially increasing the dose of quality therapy with or without the presence of a therapist during post-brain injury rehabilitation. Additionally, an engaging video-game could improve treatment adherence, a critical aspect of making positive functional gains, by potentially increasing the rate and quality of reinforcement embedded in therapy. The present study had three aims: (1) develop a rigorous behavioral therapy for improving balance in individuals living with chronic brain injury using a Wii Fit U game and the WBB; (2) evaluate the program's effects on balance measures using a within-subject experimental design; and (3) assess social validity of behavioral gains by evaluating the program's effects on participant's "subjective balance confidence" (i.e., their Activities-Specific Balance Confidence (ABC) scores). A reversal design is proposed for use with primary study participants, wherein the experimental gameplay condition and no intervention condition are alternated for 6 to 10 weeks. A similar design was used in a truncated fashion with pilot participants, and a multiple baseline design was used with follow-up pilot participants. It was expected that participants would exhibit greater performance in the game as well as better balance score improvement when the Wii Fit U game was administered at a high therapeutic dose, and that increased ABC scores would correlate with directly measured balance scores.

Background: There is growing participation in soccer at all levels of sport. Soccer increases the physical and psychological demands on players, which subsequently increase the risk of injuries. There are limited prospective epidemiological studies in Africa, and studies that have been conducted to date often fail to incorporate standardised injury definitions or reporting methods. Therefore, there is an urgent need to conduct epidemiological studies within the context of low to middle-income countries, where resources may be limited, and taking into consideration exposure times to design appropriate preventive measures. Aim: The purpose of the study was to explore the nature and incidence of soccer-related injuries in first division players in Rwanda, and to establish intrinsic risk factors for injuries. Methods: A prospective cohort study was conducted for two seasons. Eleven teams (326 players) and 13 teams (391 players) were followed for the seasons 2014-2015 and 2015-2016. Anthropometric and musculoskeletal screening composed of flexibility tests, strength and endurance, balance and proprioception tests, and lower limb function tests were conducted as well as training and match exposure were recorded. Team medical personnel recorded the location, type, duration and mechanism of time-loss injuries following the suggestion of the International Federation of Football Associations (FIFA). The primary outcome was the incidence of overall, training and match injury as well as body part, type, patterns and severity of injuries. Multivariate model using the Chi-squared Automatic Interaction Detection (CHAID) was used to assess intrinsic predictors of injury. Significance was accepted as p<0.05. Results: There were 455 injuries and approximately 46% of the players were injured in each of the two seasons. The team weighted mean incidence of match injuries was significantly lower during season one (14.2 injuries/ 1000 hours) compared to season two (21.9 injuries/ 1000 hours) (t(22)= -2.092, p=0.048). No difference was observed in the team-weighted incidence for overall and training injuries between the two seasons. There was increased injury incidence with increased acute: chronic training and match workload ratios. Lower extremities were the most frequently affected over the two seasons (80% of all injuries), with the knee joint most commonly injured (28% off all injuries) followed by the ankle joint (25% of all injuries). Ligament strains were the most common form of injury followed by muscle strains and contusions. The most common mechanisms of injury were collisions between players and receiving a tackle. About three quarters of the reported injuries were mild or moderate in severity and injuries to the Achilles tendon lead to the longest median lay-off time. The greatest incidence of injuries was sustained between the 46thand 60thminute of match play. A score of 11cm or less on the Sit and Reach test, more than one year in the current club and a timed hop of more than 2.5 seconds were all associated with injury. Conclusions: The rate of injuries found in this study is lower compared to the studies that reported injuries in adult male at either professional or amateur level. The patterns of training and match injuries, location, type and severity of injuries are similar to previous studies. Flexibility and balance, and coordination emerged as being significant predictors of increased risk of injury. More studies with emphasis on intrinsic and extrinsic factors are needed to attain wider knowledge concerning injuries among soccer players in Africa. Prevention intervention is necessary to minimise the of lower limb injuries.

A research report submitted to the Faculty of Health Sciences, University of Witwatersrand, Johannesburg, in partial fulfillment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine Johannesburg, 2017 / Objective: There is limited data describing acute kidney injury (AKI) in HIV-infected adult patients in resource-limited settings where increasingly, tenofovir (TDF), which is potentially nephrotoxic, is prescribed. We describe risk factors for, and prognosis of AKI in HIV-infected individuals receiving and naïve to TDF. Methods: This was a prospective case cohort study of hospitalized HIV-infected adults with AKI (as defined by the 2012 KDIGO Clinical Practice Guideline for AKI) stratified by TDF exposure. Adults (≥18 years) were recruited: clinical and biochemical data was collected at admission; their renal recovery, discharge or mortality was ascertained as an in-patient and, subsequently, to a scheduled 3-month follow-up. Results: Amongst this predominantly female (61%), almost exclusively black African cohort of 175 patients with AKI, 93 (53%) were TDF exposed; median age was 41 years (IQR 35-50). Median CD4 count and VL and creatinine at baseline was 116 cells/mm3 and 110159 copies/ml, respectively. A greater proportion of the TDF group had severe AKI on admission (61% v 43% p=0.014); however, both groups had similar rates of newly diagnosed tuberculosis (TB) (52%) and NSAID (32%) use. Intravenous fluid was the therapeutic mainstay; only 7 were dialyzed. Discharge median serum creatinine (SCr) was higher in the TDF group (p=0.032) and fewer in the TDF group recovered renal function after 3-months (p=0.043). 3-month mortality was 27% in both groups but 55% of deaths occurred in hospital. Those that died had a higher SCr and more severe AKI than survivors; TB was diagnosed in 33 (70%) of those who died. Conclusions: AKI was more severe and renal recovery slower in the TDF group; comorbidities, risk factors and prognosis were similar regardless of TDF exposure. Because TB is linked to higher mortality, TB co-infection in HIV-infected patients with AKI warrants more intensive monitoring. In all those with poor renal recovery, our data suggests that a lower threshold for dialysis is needed. / MT2017

The vagus nerve is the principal pathway by which autonomic sensory information is carried from the periphery to the CNS where it influences the activity of a numerous structures including the locus coeruleus. Electrical stimulation of the vagus nerve has been demonstrated to enhance performance in a variety of memory tasks in both rats and humans and is used clinically for the control of epilepsy in humans. Electrical stimulation of the vagus nerve has also been shown to improve functional recovery following experimental brain injury in rats. The central hypothesis in these experiments is that vagus nerve stimulation exerts its beneficial effects by mediating the release of norepinephrine in the CNS. The results from Experiment I indicate that VNS results in increased extracellular NE concentration in the hippocampus at both the 0.5 and 1.0 mA stimulus intensities, and in the cortex at the 1.0 mA intensity. Increased concentrations of extracellular NE induced by VNS, regardless of structure, were transient, dissipating before the subsequent baseline recording period. Further, VNS-induced alterations in extracellular NE concentrations were observed bilaterally. Insult to the CNS by means of FPI resulted in long lasting depression of extracellular NE concentrations in the cortex of the injured controls and 1.0 mA VNS group that was partially attenuated 1.0 mA VNS. In the 0.5 mA VNS group NE concentrations remained above pre-injury levels for the majority of the post-FPI measurement period. In the hippocampus, mean NE concentrations in the period immediately following FPI were decreased in comparison to pre-FPI concentrations. Concentrations of hippocampal NE remained depressed in the injured control group throughout the 48 hr sample period. Hippocampal NE concentrations in both the 0.5 mA VNS and 1.0 mA VNS group recovered to above pre-injury levels by 14-20 hrs post-FPI and were significantly higher than that of the injured controls in the 20-26 and 26-32 hr post-FPI sampling periods. Further, hippocampal NE concentrations remained significantly higher in 0.5 mA VNS group in comparison to injured controls in the 32-38 and 38-44 hr sampling periods.

Myocardial injury after noncardiac surgery (MINS) is common in patients undergoing inpatient noncardiac surgery and has been shown to adversely impact short- and long-term patient prognosis. Most MINS events are asymptomatic and systematic troponin measurement early after surgery is of paramount importance to detect these events. The largest study to determine thresholds and prognostic importance of MINS used troponin T and high-sensitivity troponin T. There is limited information on how to diagnose MINS using high-sensitivity troponin I (hsTnI). How to predict who is at higher risk of MINS and would benefit the most from troponin monitoring, and how to manage patients who suffer a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps. Chapter 2 describes the result of a large prospective cohort of patients undergoing noncardiac surgery which determined the utility of preoperative N-Terminal pro-B type Natriuretic Peptide to predict 30-day MINS and vascular death, in addition to clinical evaluation. Chapter 3 uses data collected as part of a large prospective cohort with a nested biobank to determine thresholds of hsTnI that can predict major cardiovascular events in patients who underwent noncardiac surgery and be used to diagnosis MINS using hsTnI. Chapter 4 details the methods of an international, multicentre, randomized placebo-controlled trial (MANAGE Trial) determining the impact of dabigatran, a blood thinner, and using a partial factorial design, of omeprazole, a gastric acid reducing drug, on the occurrence of major vascular and upper gastrointestinal events in patients who suffered a MINS and are followed for up to 2 years. Chapter 5 presents the results of the omeprazole component of the MANAGE Trial. Chapter 6 discusses the key findings of the thesis and future research directions. / Thesis / Doctor of Philosophy (PhD) / Damage to the heart muscle occurring after a noncardiac surgery, called myocardial injury after noncardiac surgery (MINS), occurs frequently and negatively impacts patient’s short- and long-term health and survival. Most patients who suffer a MINS do not present symptoms suggestive of heart problems. Blood tests obtained after surgery measuring troponins, a marker of heart damage, is necessary to detect which patients are having MINS. Different troponin tests are available, including a test called high-sensitivity troponin I, for which there is limited information on how to diagnose MINS using this test. How to predict who is at higher risk of MINS and how to treat patients who suffered a MINS are also areas that need further research. This thesis presents studies that inform on these knowledge gaps.

Background: Liver injury is the most common severe adverse effect of first-line anti-tuberculosis therapy (ATT). Nacetylcysteine (NAC) has efficacy in patients with paracetamol toxicity, and may be of benefit in liver injury due to other causes, such as ATT-induced liver injury (AT-DILI). Rechallenge of first line ATT after liver injury is usually attempted and may result in recurrence of liver injury. Alanine transaminase (ALT) is the biomarker currently used in AT-DILI diagnosis. MicroRNA-122 (miR-122) is a sensitive biomarker for liver injury due to paracetamol, but data on utility as a biomarker for ATDILI are limited. Methods: We conducted a randomized double-blind placebo-controlled trial of intravenous NAC in adult hospitalized participants with AT-DILI. Primary endpoint was time to ALT < 100 U/L; secondary endpoints included length of hospital stay and 8-week mortality. We described outcomes of ATT rechallenge following AT-DILI. We quantified miR-122 and ALT concentrations before and after infusion of NAC/placebo, and explored the effect of NAC on miR-122. Results We enrolled 102 participants with AT-DILI, 53 randomized to NAC and 49 to placebo. Mean age was 38 (SD±10) years, 58 (57%) were female and 89 (87%) were HIV positive. Median time to ALT

Background: Motor impairments are common sequelae of Acquired Brain Injuries (ABI). An estimated 55-75% of ABI survivors have on-going limitations in UL function. Objective measures of UL function that have established validity and reliability in the ABI population are not readily available in the literature. The Chedoke Arm and Hand Inventory (CAHAI) is an assessment used with the stroke population. There are 4 versions of this assessment; a 13 item version and 3 shortened ones. The main purpose is to assess how much the affected UL contributes to a bilateral task. The CAHAI has strong reliability and validity in this population; however, it is unknown whether this measure can be used with other clinical populations such as ABI. Purpose: The purpose of this study was to estimate the inter-rater reliability of the Chedoke Arm and Hand Activity Inventory (CAHAI) when used with persons with ABI including 3 shortened versions of the measure.   Methods: This is an observational parameter estimation study.   Participants were recruited from an in-patient ABI rehabilitation program.   The administration of the CAHAI was video recorded for 6 persons with ABI.  The videos were assessed by 6 clinicians to estimate inter-rater reliability.  A Latin square design was used to balance the order raters evaluated the videos.   Analysis:  A repeated measures ANOVA was performed and the variance components were used to calculate an intra-class correlation coefficient (ICC) and standard error of measurement (SEM) with 95% confidence intervals (CI).   Results: Inter-rater reliability was high for all versions: CAHAI-7 ICC= 0.96 (95% CL: 0.89-0.99, SEM 2.65); CAHAI-8 ICC= 0.96 (95% CL: 0.90-0.99, SEM 2.72); CAHAI-9 ICC= 0.95 (95% CL: 0.85-0.99, SEM 3.49); CAHAI -13 ICC=0.96 (95%CL: 0.88-0.99, SEM 3.35).   Conclusions: These results suggest the CAHAI is highly reliability in the ABI population. The shortened versions may be particularly useful when time constraints or patient tolerance are an issue. / Thesis / Master of Science (MSc) / It is important to measure change using reliable assessment tools. Outcome measures are designed for specific populations. If used in a different population, the reliability may be impacted. The Chedoke Arm and Hand Activity Inventory (CAHAI) is a measure of upper limb function that has been developed for use in the stroke population. It was unknown if the measure would still be reliable in the acquired brain injury (ABI) population. The goal of this thesis was to determine if the CAHAI is also reliable in ABI. Our results suggest that the CAHAI is highly reliable in this population.