Foundation Funded Projects for 2015
Dr. D. Bardana
Dr. S. Waldman
Development of human engineered cartilage suitable for joint resurfacing
Damage to articular cartilage by osteoarthritis or injury causes significant morbidity as this tissue has little reparative potential. While tissue engineered cartilage offers the prospect of joint resurfacing, there are several barriers to the clinical translation as only a limited number of cells can be obtained from an individual. To address this shortcoming, the investigators have developed a novel approach to create large-sized engineered cartilage constructs directly from a small population of cells. Previous pre-clinical studies have demonstrated excellent defect repair and near indistinguishable integration to the surrounding native tissue and underlying subchondral bone. To further the development of this approach and lay the foundation for potential future clinical trials, translation to human cartilage needs to be demonstrated.
The objective of the proposed study is to develop large-sized, functional human engineered cartilage implants as well as to establish the criteria to select suitable candidates for a potential clinical procedure. Ultimately, with this new approach, patients will benefit from better clinical outcomes resulting in a lower risk of implant failure and shorter hospitalization. We expect that our methods will allow for the correction of degenerative changes due to osteoarthritis, and potentially to delay or eliminate the need for joint replacement surgery.
Dr. J.G. Boyd
The CONFOCAL Study: cerebral oxygenation and neurological outcomes following critical illness
Nearly 150,000 people are admitted to intensive care units in Ontario every year. With aggressive life support, we are decreasing the number of people who die from critical illness; however people who survive often have neurological problems. These neurological problems can include difficulties with memory, concentration, and attention. These problems are associated with poor quality of life among survivors of severe sepsis/septic shock.
The aim of this study is to identify the factors that contribute to these neurological deficits. Specifically, the investigators are testing whether changes in oxygen delivery to the brain during critical illness are related to both short- and long-term neurological complications. The researchers will be the first group to use both classic testing of brain function (pen and paper tests) and a robotic device that provides detailed and precise information about brain functioning. If the investigators are able to identify a relationship between oxygen delivery to the brain and neurological outcomes, then the next phase of this research program would be to develop strategies to improve oxygen delivery, and thus neurological recovery.
Dr. S. Dhanani
Dr. A. Seely
Children's Hospital of Eastern Ontario
Continuous waveform analysis to improve prediction of time to death after withdrawal of life sustaining therapy in critically ill patients
Organ donation after circulatory death (DCD), first implemented in 2006, now provides almost 25% of all organs transplanted in Ontario. Because warm ischemia beyond a certain time point irreversibly damages organs and precludes donation, an accurate prediction of time to death after withdrawal of life sustaining therapy (WLST) is essential to identify appropriate DCD candidates and improve practice. Many tools have been developed for this purpose but all have significant limitations.
The principal objective of this multicenter, observational study is to use variability analysis to create a clinical decision tool to accurately and reliably predict which patients will die within 2 hours of the withdrawal of life-sustaining therapies (WLST). The investigators plan to employ continuous physiological waveform monitoring, and use advanced analytics of patterns of variation (variability analysis) on patients enrolled in the Death Prediction and Physiology after Removal of Therapy (DePPaRT) study in order to uncover the changes in physiologic state during the dying process.
This knowledge will be used to better predict whether death is likely to occur within the 2 hour time limit required for DCD. A systematic approach to organ donation research is fundamental to improving organ donation in Ontario.
Dr. R.P. Jankov
Hospital for Sick Children
Preclinical assessment of nitrite as therapy for chronic neonatal lung injury and pulmonary hypertension
Pulmonary hypertension (high blood pressure in the lung) is commonly associated with chronic lung disease (known as bronchopulmonary dysplasia or BPD) that arises in infants born prematurely. Pulmonary hypertension is caused by thickening of the walls of blood vessels (known as remodeling), which blocks the normal passage of blood through the lung and prevents vessels from properly relaxing. Blood vessel remodeling often gets worse with time, leading to heart failure and eventual death. There are currently no treatments that are effective in preventing BPD and treatments currently available to treat pulmonary hypertension, such as inhaled nitric oxide, have not been shown to improve outcome.
New medical therapies are urgently required. The investigator’s laboratory has developed several newborn rat models with many similarities to the human condition, which are ideal for testing of new drugs. The researchers wish to use these models to test a new way of giving nitric oxide, a molecule that is known to be deficient in newborns with lung injury. This drug is called sodium nitrite. In contrast to inhaled nitric oxide, sodium nitrite costs very little and appears to have less potential to cause toxic effects. Sodium nitrite has never previously been tested in newborns.
Dr. R.A. Joundi
Dr. M. Kapral
Sunnybrook Health Sciences Centre
Impact of dysphagia in patients with acute stroke: a large population-based study using the Ontario Stroke Registry
Stroke is a common and serious medical condition that can result in damage to the brain and its many functions. One of the most devastating complications of stroke is dysphagia, or swallowing impairment. Dysphagia can result in malnutrition, dehydration, weight loss, and severe pneumonia due to aspiration of oral contents into the lungs, all of which put patients at much higher risk of death. The most effective way to prevent aspiration pneumonia is to test swallowing in as many patients as possible and as early as possible after stroke; however for unknown reasons the rate of testing is only approximately 60%, and there is a lack of high quality studies that adequately address dysphagia and its many complications.
Using the Ontario Stroke Registry, the investigators plan to conduct a large population-based study of acute stroke patients to investigate the nature of dysphagia, with particular interest in the following questions: What kind of patients do not receive a swallowing test and why? What are the outcomes of patients with dysphagia after stroke, in terms of complications such as pneumonia and death? Which patients require a permanent feeding tube? Systematically addressing these questions will enrich our knowledge base on dysphagia and provide guidance for future clinical recommendations.
Dr. S. Mahant
Dr. B. Johnston
Hospital for Sick Children
Probiotics for the prevention of antibiotic-induced diarrhea in hospitalized children (PAID)
Antibiotic-associated diarrhea (AAD) occurs when antibiotics disturb the natural balance of “good” and “bad” bacteria in the intestinal tract (gut). It is thought that this disruption of the intestinal tract is associated with a weakened gut barrier (diminished bacterial milieu) and that “bad” bacteria may multiply beyond their normal numbers. The typical symptoms of AAD include frequent loose or watery bowel movements. Probiotics are found in dietary supplements or yogurts and contain potentially beneficial bacteria. Probiotics may restore the natural balance of bacteria in the intestinal tract.
In North America, one of the most common reasons for hospitalization in previously healthy children is for treatment of infections with antibiotics. This study will determine if, in previously healthy children hospitalized and prescribed antibiotics, the co-administration of a probiotic milk product containing good bacteria, is safe and effective for reducing AAD, as compared to a placebo (identical appearing milk product). This will be a two-centered, randomized, masked (blinding of investigators, participants, caregivers, outcome assessors, data analysts) placebo-controlled clinical trial.
The results of this study will help inform clinicians and families on the use of probiotics in the prevention of AAD, a common side effect of antibiotic use among hospitalized children.
Dr. J.D. Marhong
Dr. S. Mehta
Mount Sinai Hospital
Sedation & mobilization during venovenous extracorporeal membrane oxygenation (VV-ECMO) for acute respiratory failure: an international survey
Acute respiratory failure (ARF) is often accompanied by profound hypoxemia and carries a high degree of morbidity and mortality for patients admitted to the intensive care unit. Venovenous extracorporeal membrane oxygenation (VV-ECMO) is an artificial means by which to maintain oxygenation and carbon dioxide removal in patients with severe ARF, and permits lung healing. In patients supported on VV-ECMO, evidence-based guidelines for sedation, analgesia, neuromuscular blockade (NMB), and mobilization have not been delineated.
The objective of this study is to characterize these practices and identify patient and center variables associated with sedation depth and early mobilization during VV-ECMO. The investigators will conduct an international cross-sectional survey of all ECMO centers registered with the Extracorporeal Life Support Organization (ELSO). The researchers will collect information pertaining to the use of validated monitoring tools for pain, sedation and delirium, sedative and analgesic medications, pharmacologic and non-pharmacologic strategies used to manage delirium, the use of protocols to guide care, and center characteristics.
The results will be used to provide a description of current practice, will identify variables that enable clinicians to minimize sedation and facilitate mobilization, and provide directions for education and future research.
Dr. S. Mason
Dr. A. Nathens
Sunnybrook Health Sciences Centre
The association between burn injury and mental health: a population-based analysis
Burn injured patients experience high rates of mental illness following their injury, and the prevalence of pre-morbid mental illness among burn patients is also high. This might negatively affect a patient’s recovery and quality of life after injury.
Through this population-based analysis, the association between mental illness and burn injury will be characterized. The rates of mood disorders, anxiety disorders and substance abuse will be estimated before and after injury, and risk factors for post-injury mental illness will be identified. In addition, the investigators will characterize the rate and risk factors of posttraumatic stress disorder among burn-injured patients. Mental illness is associated with high levels of health care utilization. In order to facilitate future resource planning and allocation, the health care utilization attributable to mental illness after burn injury will be estimated.
Overall, this work will inform the design and implementation of interventions aimed at mitigating the impact of mental illness on burn survivors. Improved diagnosis and treatment of mental illness will ultimately lead to improvements in the long-term outcomes of burn-injured patients.
Dr. B. Safa
Dr. S. Choi
Sunnybrook Health Sciences Centre
Comparison of the analgesic duration of 0.5% Bupivacaine with 1:200,000 epinephrine versus 0.5% Ropivicaine versus 1% Ropivicaine for low volume ultrasound-guided interscalene brachial plexus block
Severe pain following shoulder surgery is common and remains a major challenge. Prior to the use of interscalene brachial plexus nerve block (ISB), patients required postoperative admission and treatment with strong intravenous opioids such as morphine. Opioids have a number of undesired side effects. ISB provides superior analgesia and reduces opioid consumption. The analgesic and opioid sparing effects of ISB facilitate ambulatory shoulder surgery that it is standard of care.
In the recent years the trend has been to use smaller volume of local anesthetic in order to improve the safety and reduce the risk of ISB. Based on the limited data available thus far the analgesic duration of the block does not appear to be compromised. The purpose of this study is to determine which local anesthetic (at low volumes) provides the best quality and longest duration of pain relief following shoulder surgery. The investigators will be testing the differences in the level of post-operative pain and duration of pain relief between patients who receive different long acting local anesthetics or different strength of long acting local anesthetics.
Dr. D.Y. Tam
Dr. S.E. Fremes
Sunnybrook Health Sciences Centre
A novel risk stratification score for readmission after discharge from cardiac surgery
6 - 18% of patients discharged from home from their cardiac surgery procedure find themselves back in the hospital within 30 days. Readmission to the hospital is expensive and is associated with worse outcomes compared to patients that were not readmitted.
The first objective of this study is to determine the risk factors associated with readmission to hospital after cardiac surgery procedures performed in Ontario. The second objective is to create a risk-scoring tool to predict which patients are likely to be readmitted to hospital after discharge from surgery. Using administrative databases, all patients that underwent cardiac surgery procedures between 1996 and 2014 in Ontario will be identified. Those that were readmitted to hospital after discharge will be compared to those that were not readmitted. Risk factors for readmission will be identified and will be used to create a clinical scoring tool to categorize patients into low, medium and high risk for readmission after discharge.
The development of a risk scoring tool will allow us to target high-risk patients with more aggressive interventions in order to prevent readmission to hospital in hopes of improving patient outcomes, improving healthcare efficiency and reducing overall costs to the healthcare system.
Dr. J. Woulfe
University of Ottawa
Skin biopsy in Parkinson's disease: novel approach to detect pathological alpha-synuclein
Currently, definitive diagnosis of Parkinson’s disease (PD) relies on post-mortem examination of the brain. The recent discovery that the pathological hallmark of PD, aggregates of the neuronal protein alpha-synuclein (a-syn), occurs not only in the brain, but also in several peripheral organs, including the skin in PD patients, has led to several studies investigating the utility of biopsies of these organs as an approach to diagnosis. Studies of the efficacy of skin biopsy to diagnose PD have been hampered by a number of factors, including lack of a tool to detect the specific disease-associated form of a-syn with sufficient sensitivity and specificity.
In the proposed studies, the investigators will apply a novel histological technique (proximity ligation assay; PLA) which stains tiny aggregates of a-syn at their earliest stages of formation. In skin biopsies from PD patients and controls, the researchers will compare the efficacy of PLA to that of the currently employed staining approach (to detect phosphorylated a-syn).
These studies could lead to the development of a highly specific, sensitive and, importantly, standardized approach to PD diagnosis at its earliest stages in living patients. This will allow them to take full advantage of the disease modifying therapies that are currently in development.
Dr. C. Yarnell
Dr. R. Fowler
Sunnybrook Health Sciences Centre
Level of training and end-of-life predictions: a prospective study of resident and attending physician prognosis agreement and accuracy
End-of-life care that preserves dignity and reduces suffering requires accurate predictions about when patients are nearing the end of life; however physician predictions of patient survival are variable, challenging, and rarely included in medical education.
This project will investigate disagreements between resident and attending physician predictions to reveal the underlying factors that make predictions difficult. This will help guide the development of formal and informal efforts to improve physician predictions and consequently improve our ability to care for patients at the end of life.
Dr. A.J. Anton
Dr. N. Dudek
University of Ottawa
Beyond walking: using the comprehensive high-level activity mobility predictor (CHAMP) in lower extremity amputees
A traditional goal of rehabilitation for lower limb amputee prosthesis users is ambulation. Currently, clinicians measure physical mobility using tests of walking speed, walking distance, transferring, and balance. These tests only capture short-distance, level ground walking at customary walking speed. A subset of amputees exist who are physically high functioning, and capable of activities beyond just level ground walking. For these people, rehabilitation goals should include return to more advanced-level activities that will be necessary for them to fully participate in their work and recreational pursuits.
The Comprehensive High-Level Activity Mobility Predictor (CHAMP) consists of four advanced tests, and was developed and validated as a performance-based outcome measure for high-level mobility amongst male military service members less than 40 years old. This study will test the CHAMP amongst civilian amputees to determine its validity, feasibility, and utility in this population. Participants from The Ottawa Hospital Rehabilitation Centre outpatient amputee clinic will complete the 6 minute walk test, Amputee mobility predictor with prosthesis, CHAMP, Houghton Scale, Locomotor Capability Index, and Activity-specific Balance Confidence Scale.
Analyses will determine whether the CHAMP is valid in the civilian population, feasible in an outpatient therapy setting, and useful in providing more information than standard mobility measures.
Dr. M.D. Bould
The Ottawa Hospital
Consolidating tools for outcomes in resuscitation (CONTOUR)
Although there are consensus guidelines to manage pediatric cardiac arrest, real world team performance often deviates from these guidelines due to poor teamwork, resulting in poor outcomes. A novel promising solution for successful management of crisis scenarios is called the Cognitive Aids for Role Definition (CARD) system. CARD is a new teamwork-based “cognitive aid” that uses role identification cards worn by each team member to decrease team members’ mental workload, clarify roles and tasks, reducing redundancy and task overload.
This study aims to integrate the CARD system with existing knowledge-based cognitive aids or “cheat sheets” to improve adherence to guidelines, and therefore improve outcomes in pediatric cardiac arrest care. This is a simulation-based, randomized controlled, factorial multicenter study. Subjects (physicians, nurses, respiratory therapists) will form 76 teams. All subjects will undertake a pre-test scenario, without access to either cognitive aid and then will be randomized to one of four study arms (control, knowledge-aid, CARD, integrated). After an e-Learning session on crisis resource management all subjects will undertake a post-test simulation scenario with access to the same cognitive aids used in training. Sessions will be video recorded and team performance will be measured by adherence to Pediatric Advanced Life Support guidelines.
Dr. D. El Rouby
Dr. D. Piquette
Sunnybrook Health Science Centre
Physicians’ lived experience of end of life discussions during acute hospitalizations: a phenomenological study
Good communication among physicians, patients and family members can facilitate the development of comprehensive and sound care plans that are concordant with patient's wishes and values. Health care providers identify many barriers preventing them from engaging in end of life discussions. In addition, medical trainees feel generally underprepared for initiating these discussions.
This qualitative study aims at exploring the lived experience of physicians involved in end of life discussions during patient acute hospitalization. The investigators will also explore the relationships between the cumulative clinical and life events encountered by physicians and their experience of end of life discussions. This study is based on a hermeneutic phenomenological methodology. The researchers will use in-depth, semi-structured individual interviews as the data collection strategy. The participants will include internal medicine physicians with various experience levels (junior and senior residents, and attending physicians) who have been involved in end of life discussions.
The qualitative analysis will be focused on describing end of life discussions from the perspective of the physicians, in order to understand this process as it is understood by those who are involved in it. These findings will inform future educational interventions aimed at helping medical trainees to feel better prepared to engage in end of life discussions.
Dr. J. Elliott
Dr. E. Greenblatt
Mount Sinai Hospital
Non-invasive genomic analysis of human endometrial receptivity in women with polycystic ovarian syndrome
Successful implantation of an embryo into the uterus to lead to a healthy pregnancy requires a complex interplay of both embryonic and uterine factors. Polycystic ovarian syndrome (PCOS) is a common metabolic/hormonal disorder with negative impacts on fertility, manifested through irregular ovulation and other mechanisms. The investigators believe that PCOS has a negative influence on the lining of the uterus (endometrium), affecting its “receptivity” to an embryo, thus lowering fertility.
The aim of this study is to use a minimally invasive uterine fluid aspiration approach to sample endometrial fluid at multiple time points in the menstrual cycle of women with PCOS and perform RNA microarray analysis on the samples to determine the change in endometrial gene expression at the different time points. Women with PCOS who are obese and non-obese are both included to differentiate the individual effects of obesity and PCOS on endometrial receptivity.
Comparison to historical results for non-obese women without PCOS allows confirmation that gene expression differences might explain the lower fertility in women with PCOS. This could lead to development of targeted genes or gene products for analysis of endometrial receptivity, which is useful in optimizing fertility treatment selection and timing, to maximize success and minimize cost.
Dr. I. Gilron
Innovations in the management of musculoskeletal pain with alpha-lipoic acid: The IMPALA Trial
Pain is a major problem affecting one-third of Canadians and costing $850 billion/year in North America alone. Fibromyalgia (FM), is a chronic disorder characterized by widespread pain, sleep disturbance, fatigue, depression and mental slowing, resulting in substantial disability. FM is also common in elderly patients emphasizing the urgent need to improve treatment as our population ages.
Current analgesics provide incomplete relief and disabling side effects that aggravate fatigue and mental slowing – already prominent in FM, and the elderly; thus, there is a growing need for new FM treatments with better efficacy and tolerability. Alpha-lipoic acid (ALA) is an antioxidant proven effective in neuropathic pain with minimal side effects. Evidence suggests benefit is likely in FM but there are no trials. Since ALA does not cause sedation, fatigue or mental slowing, it would not aggravate these other FM-related symptoms.
The investigators propose to compare ALA to pregabalin to placebo in a trial of FM patients that assesses pain, side effects and other outcomes. This trial will guide future improvements in FM treatment. Given the current lack of new improved pain treatments, this research is expected to provide high quality evidence for a safer, more effective treatment for FM.
Dr. D. Grynspan
Dr. S. Bainbridge
Children’s Hospital of Eastern Ontario
A novel histopathology diagnostic antibody panel capable of identifying distinct subclasses of placental disease in preeclampsia
Preeclampsia is a serious hypertensive disease that affects pregnant women. Women who have preeclampsia in pregnancy are also at risk for cardiovascular disease after pregnancy. Preeclampsia is caused by the placenta (afterbirth) but there are different problems in the placenta that cause preeclampsia.
The researchers have found four different types of preeclampsia by looking at genes in the placenta. Because these gene experiments are expensive and take time, a simple tool will be developed that will inform which type of preeclampsia a woman had in her pregnancy. The investigators will look at levels of proteins in the placenta and develop a mathematical model (tool) which can identify each type of preeclampsia. After, the model will be used to see which type of preeclampsia puts a woman at highest risk for future cardiovascular disease. It is imagined that a woman’s risk of future cardiovascular disease is related to what type of preeclampsia she had.
At the end of this project, the investigators will have a simple test doctors can use to determine what type of preeclampsia a woman had, and importantly, find women at highest risk of future cardiovascular disease. These women should be watched closely by doctors to improve their health after pregnancy.
Dr. F.G. Kouyoumdjian
Dr. S.W. Hwang
St. Michael’s Hospital
Elucidating the health care utilization of people who experience detention or incarceration in provincial facilities in Ontario: a population-based study
A large number of Canadians experience detention or incarceration each year, and data suggest that this population has poor health. Little is known about health care access and utilization in this population. This information could inform interventions in custody and at the time of release to optimize health and decrease unnecessary health care costs.
In this study, the researchers will link data from the Ontario Ministry of Community Safety and Correctional Services on persons who were in provincial custody in 2010 with data on ambulatory care use, emergency department use, and hospitalization. The investigators will determine health care utilization rates for this population and compare them with rates for the general population. The data will be used to develop evidence-based interventions to optimize health care utilization and to target conditions that are responsible for a large proportion of health care utilization and are preventable.
Dr. S.L. Liu
CLEAR SIGHT: A randomized trial of non-mydriatic ultra-widefield retinal imaging to screen for diabetic eye disease
Diabetic eye disease causes major vision loss in many Canadians and is costly. There are effective preventions and treatments for diabetic eye disease but they strongly depend upon regular screening in asymptomatic patients. The 2013 Canadian Diabetes Association (CDA) guidelines recommend annual screening by eye care professionals, either in-person or through interpretation of dilated pupil retinal photographs.
Despite the benefits of screening, adherence to these guidelines is poor. Reasons include patient barriers, i.e. need for eye drops, time off work, wait times, and transportation issues. An option to minimize these barriers is to screen using a camera called non-mydriatic ultra-widefield (UWF) retinal imaging. This can be quickly done without eye drops on the same day as patients’ regularly scheduled diabetes clinic visits.
In this study, the investigators will compare the UWF camera to the usual screening approach recommended by the CDA. 740 patients with diabetes due for eye screening will be invited to either be screened using the UWF camera on the day of their diabetes clinic visit or be screened by their usual eye care professional. It is predicted that same-day screening with UWF imaging will find more patients with diabetic eye disease who need treatment compared to usual screening.
Dr. R.A. Todd
Dr. M. Cusimano
St. Michael’s Hospital
A Dark Room: documentary film based education on the psychiatric effects of hockey concussion
The primary objective of this knowledge translation project is to create an educational documentary that uses culturally salient, evidence-based themes to share knowledge about psychiatric illness as it relates to ice hockey concussion. Ice hockey has the highest rate of concussion in both high school and professional level athletes compared to all other sports (Koh 2001) and every year in Canada, there are over 500,000 individuals under the age of 18 engaged in this sport (IIHF, 2014). Concussion has been consistently linked to Major Depressive Disorder, Generalized Anxiety disorder, and suicide (Busch 1998; Rimel et. Al 1981, Schoenhuber 1998). The combination of these factors creates a dangerous health complex that requires extensive improvements in educating the population, raising awareness and changing behaviors.
There will be three phases to this knowledge translation project. Phase one will consist of the qualitative analysis of semi-structured interviews with ice hockey stakeholders such as coaches, players, trainers, and hockey parents. Phase two will focus on the creation and distribution of the educational documentary called “A Dark Room”. Phase three of this project will be the evaluation of the film utilizing pre and post film standardized questionnaires. Providing an educational platform for twenty thousand students who are at high risk for concussion, and their peers, will serve to prevent many concussions and help those who do suffer a concussion to seek help.
Dr. A.J. Baker
Dr. C. Libarch
St. Michael’s Hospital
Human umbilical cord perivascular cell (HUCPVC) therapy for traumatic brain injury: targeting the neurovascular unit
Traumatic brain injury (TBI) is a leading cause of death and morbidity in North America with enormous associated healthcare, society and personal costs. Mesenchymal stem cells, also referred to as “adult stem cells”, are derived from the bone marrow and are currently being used in clinical trials for treatment of diseases and conditions that involve immune system modulation (e.g., organ transplants) or stresses to the cardiovascular system (e.g. heart disease and stroke). These cells provide therapeutic benefit through a number of biologic mechanisms and have proven to be safe in many clinical trials.
Recent compelling evidence suggests that neuroinflammation and neurovascular injury are components of TBI that have potential to be simultaneously addressed with stem cell therapy. Injury and treatment of the neurovascular unit after trauma poses a challenge since a single-targeted therapy is likely to have limited impact on outcome. Human umbilical cord-derived perivascular cells (HUCPVCs) are considered a less differentiated type of MSC with potentially greater therapeutic capacity. In this regard, HUCPVCs, which are more easily attainable than MSCs, have great potential as treatment for TBI by addressing the injury process on numerous fronts in a technically feasible and promising approach.
Dr. J.D. Bell
Dr. A.J. Baker
St. Michael’s Hospital
A pilot study of sub-anesthetic ketamine infusion for neuroprotection after aneurysmal subarachnoid hemorrhage: effects on white matter integrity, inflammatory biomarkers, and neurocognitive outcome
Subarachnoid hemorrhage (SAH, bleeding in the brain as a result of a ruptured aneurysm) is a particularly devastating type of stroke. Many patients who undergo emergent neurosurgery to repair the aneurysm and evacuate the bleeding suffer from complications in their subsequent hospital stay, the most frequent and morbid of which is delayed cerebral ischemia (DCI) – or small strokes resulting from impaired blood flow to certain vital brain centers. This occurs because, although the aneurysm is repaired, there are changes to the brain’s blood vessels that occur after the bleed. The arteries can spasm, or small clots can form within the vasculature that disrupt normal blood flow. Patients are left with profound neurologic deficits from these secondary complications.
Anesthesiologists, neurosurgeons, and intensive care physicians are in need of a way to protect the brain during this vulnerable period following aneurysm repair. One drug that may provide such protection is ketamine, a compound frequently used in operating rooms and intensive care units to provide anesthesia and analgesia. Ketamine works by blocking glutamate receptors, ion channels that play a pivotal role in perpetuating brain cell death during strokes by flooding the brain with too much calcium and other dangerous chemicals.
This project is designed to test the efficacy of ketamine in protecting the brain following aneurysm repair, by using a controlled infusion of the drug in the ICU when patients return from their operation.
Dr. E. Boot
Dr. A.S. Bassett
University Health Network
Moving beyond Parkinson’s disease in 22q11.2 deletion syndrome: a study on movement disorders in adults
22q11.2 deletion syndrome (22q11.2DS) is a common yet under-recognized condition with a substantial burden of illness to the patient, family and society. The associated loss from chromosome 22, detectable with a clinical blood test, occurs in about 1 in 2,000 live births. This genetic disorder can result in a variety of birth defects, developmental delays, and later onset conditions, including a one in four risk of developing schizophrenia. Adults with 22q11.2DS have an increased risk of early-onset Parkinson’s disease (<50 years) and may also be susceptible to other movement disorders, including those induced by medication. These may increase risk of falling, disturb communication, and reduce overall quality of life.
In this study the investigators will for the first time systematically assess the occurrence of movement disorders in adults with 22q11.2DS using 3D motion tracking technology and validated clinical rating scales, comparing results to control groups. The results of this study promise to assist with identifying, assessing and managing patients with 22q11.2DS, and may also help to identify patients at high risk for Parkinson’s disease and drug-induced movement disorders, both in the 22q11.2DS and in the general population. The results will be used to modify international clinical practice guidelines.
Dr. C.M. Nowik
Dr. G.N. Smith
Maternal cardiovascular health: Understanding perceptions of risk and improving post-partum follow-up
The term “pregnancy-related cardiovascular risk indicators” encompasses preeclampsia, gestational hypertension, gestational diabetes, gestational impaired glucose tolerance, placental abruption, intrauterine growth restriction, and preterm birth. These conditions are associated with an increased risk of developing cardiovascular disease. At Kingston General Hospital, women who develop these complications are referred to the Maternal Health Clinic (MHC), which offers post-partum cardiovascular risk screening and counselling.
The investigators will survey patients to examine how they perceive their risk for cardiovascular disease at three points: 1) at the first antenatal appointment; 2) immediately prior to the medical assessment in the MHC; 3) six weeks after patients receive their final counselling through the MHC. If patients rate their risk more accurately and also perceive themselves to be at higher risk after their MHC appointment than either during pregnancy or prior to the MHC assessment, this would suggest that the MHC is successful in improving patients’ understanding of cardiovascular disease risk.
The researchers will also hold focus groups with primary care providers to examine how the MHC can facilitate better continuity of care. Finally, the investigators will survey patients who do not attend the MHC to identify barriers to accessing follow-up.
Dr. P. Rochon
Women’s College Hospital
Optimizing prescribing of cholinesterase inhibitors for older women and men with dementia
Cholinesterase inhibitor therapy is used to manage the symptoms of dementia, a devastating condition that affects 500,000 Canadians and more than 35 million people globally. Cholinesterase inhibitor therapy is approved in Canada and widely used, despite an understanding that it provides only modest benefits. Recent evidence suggests that the side effects associated with these medications may be under recognized.
This proposed study is critical and timely, given the profound impact of dementia on patients and their families in Canada and around the world. This study will explore the side effects associated with cholinesterase inhibitor therapy use in older women and men with different levels of dementia severity in Ontario. The study is comprehensive in that the investigators explore the spectrum of side effects ranging from signs and symptoms to serious events, and are able to explore the benefit and potential harm of cholinesterase inhibitor discontinuation.
The findings will inform safer and more tailored prescribing of cholinesterase inhibitor therapies for the millions of older adults across Canada and internationally, mostly women, who are prescribed these therapies on a daily basis.
Dr. H. Chaudhry
Dr. B. Ristevski
Distractions on the road: injury evaluation in surgery and fracture clinics (DRIVSAFE)
Distracted driving is any activity that diverts drivers’ attention away from the primary task of driving. Previous research suggests that distracted driving is a factor in approximately 4 million road traffic collisions annually in North America; however the prevalence is likely underreported given that data are often obtained from police and hospital reports.
In order to assess the burden of distracted driving on musculoskeletal injuries, the DRIVSAFE study will administer questionnaires to 1315 patients who present to a local Ontario fracture clinic. Specifically, the DRIVSAFE study will determine: 1) the prevalence of patients who present to a local fracture clinic with an injury that is the direct or indirect result of distracted driving; and 2) the prevalence and severity of various types of musculoskeletal injuries sustained as a direct or indirect result of distracted driving.
Additionally, the questionnaire will explore reasons that participants are attending the fracture clinic (e.g. type(s), severity, and cause of injury). It will also collect information about participants’ opinions and experiences with distracted driving. For participants who are attending the fracture clinic due to an injury from a road traffic collision, the questionnaire also queries participants about whether distracted driving played a role in their injury.
Dr. M.A. Hussain
Dr. M. Al-Omran
St. Michael’s Hospital
Trends and outcomes of carotid artery revascularization in Ontario
Carotid artery stenosis, or atherosclerotic narrowing of arteries in the neck, is a common cause of stroke. There are two main ways to treat these narrowings to prevent stroke: surgery or stenting. Surgery to remove the plaque, called carotid endarterectomy (CEA), has been the mainstay of treatment for several decades. In the last 10 years, carotid artery stenting (CAS) has emerged as an alternative to surgery due to its less invasive nature.
The role of CAS is currently highly contentious in literature as large clinical trials comparing CEA with CAS have produced conflicting results; however there is currently no knowledge on how the introduction of CAS has changed clinical practice in Ontario, or Canada. The objective of this research is to study the utilization trends of CEA versus CAS in Ontario from 2002 to 2014, and compare outcomes of patients who underwent these procedures. Large healthcare administrative databases that record information on patient demographics, hospitalizations and procedures will be used to identify and analyze data of patients who underwent CEA and CAS in Ontario.
Better understanding about the utilization trends and outcomes of these procedures will help determine their true role in clinical practice, and in the Canadian healthcare system.
Dr. P. Kannu
Hospital for Sick Children
cMET signaling in OFD and fracture repair
The investigators identified a novel gene mutation in the cMET gene causing a bone condition called osteofibrous dysplasia. Affected individuals develop lower limb bowing and spontaneous fractures which do not heal. Preliminary work on patient samples indicates the cMET gene alteration makes a cell receptor missing a critical region controlling its down-regulation. The cMET receptor is found in bone forming and resorbing cells.
Fracture samples from patients reveal abnormalities in these bone cells. It is therefore believed that cMET is important for fracture healing. The researchers plan to study how the cMET mutation affects the body. To study how fracture healing is impaired by this mutation, an animal model is required; thus the investigators developed a genetic mouse mimicking the human mutation. The repair of fractures induced by surgery will be studied using a combination of standard techniques.
The researchers will also trial an approved drug, a cMET inhibitor, to improve fracture healing in these mice. This work on fracture repair is important for the many people who are in pain and unable to work due to poorly healed fractures. Additionally, our results may have broader implications for other health problems like osteoporosis, which is also due to abnormalities in bone cells.
Dr. K. Lam
Dr. P. Peng
University Health Network
Applied anatomy of hip and knee innervation relevant to ultrasound guided pain intervention
With the aging population and increase in obesity, the burden of osteoarthritis, especially for patients with advanced symptoms and disability, is anticipated to become a major problem for health systems globally. Given the limited role of conservative management in patients with advanced symptoms and barriers to surgical intervention for certain patient populations, there is increased interest in strategies that function as adjunctive modalities.
Radiofrequency ablation of the nerve supply to the joint (RFA) emerges as a promising modality. The success of this treatment is predicated on the clarity of nerve anatomical course and validated landmarks for imaging guidance, which require further investigation. This study is among the first to attempt to provide this pertinent information. Twenty-four hips and knees will be examined with dissection microscope for the fine nerve branches innervating the joints. The detailed course of the nerves from where they branch to where they enter the joint will be traced manually with the use of a digitizer. The digitized data will be imported into a computer program to construct 3D models of the innervation of hips and knees. Translation of the anatomy to sonoanatomy is further determined to explore certain reference landmarks as the target for RFA.
Dr. P.P.W. Luke
Dr. R. Bhattacharjee
Immunological impact of carbon monoxide releasing molecule in renal transplantation
Kidney disease strikes 2.6 million Canadians with an average of 16 people per day experiencing kidney failure. Despite improvements in immunosuppressive therapy, the long-term survival of kidney transplants has not increased over the past decade. With limited survival, the new kidney’s lifetime is mostly dependent upon damages as a result of the transplant process and immune-related injury.
In animal models, carbon monoxide (CO) inhalation has been shown to protect organs by decreasing inflammation and preventing cell death during the transplantation process; however carbon monoxide inhalation is difficult to regulate and may lead to serious consequences to patients by preventing oxygen delivery to vital organs. Recently several agents called carbon monoxide-releasing molecules or CORMs have been synthesized which can effectively and efficiently deliver CO without risk of oxygen deprivation. The investigators have shown that these agents, like CO, improve kidney transplant function and survival when given to the kidney donor or when added directly to the kidney storage solution.
Our goal is to optimize kidney transplant protection after the transplant as well by investigating the mechanism and function of CORMs. The researchers believe that this will lead to reduction of toxic immunosuppressive drug use and minimization of transplant damage leading to improvement in the long-term survival of kidney transplants.
Dr. C. Marras
Dr. A. Lang
University Health Network
Risk of parkinsonism after appendectomy
Aggregation of the protein alpha-synuclein in the brain is the pathological hallmark of Parkinson’s disease (PD) and a toxic form of alpha-synuclein may play a critical role in the neurodegenerative process. A leading hypothesis of the development of PD is that abnormal alpha-synuclein may spread to the brain from elsewhere in the body, possibly the nervous system of the bowel. Very early involvement of the nerves of the bowel is suggested by the high incidence of constipation that commonly predates the development of overt motor symptoms of PD (e.g., tremor).
A recent study showed that in healthy individuals the appendix contains the highest concentration of alpha-synuclein in the bowel. This observation raises the strong possibility that the appendix may be a site of entry of alpha-synuclein to the brain through the nervous system of the bowel. If this were to be the case, removal of the appendix (appendectomy) could be a protective procedure against future development of PD.
Using Ontario Health Administrative data the investigators will test this hypothesis by comparing the risk of parkinsonism in individuals having undergone prior appendectomy to the risk of parkinsonism in the general population and individuals having undergone gall bladder removal.
Dr. V.A. McPherson
Dr. J. Izawa
A window of opportunity study to evaluate the role of the combination of metformin and simvastatin as a neoadjuvant therapy in invasive bladder cancer
Invasive bladder cancer is treated with chemotherapy and the surgical resection of a patient’s bladder. Unfortunately, up to 50% of patients will recur, and most of these patients will die of their disease despite aggressive chemotherapy; therefore there is a strong need for new therapies.
This study will evaluate the use of Metformin and Simvastatin prior to cystectomy. These drugs are non-toxic and commonly used for diabetes and elevated cholesterol, respectively. Additionally, this drug combination has recently been shown to be highly effective in pre-clinical trials in prostate cancer, while there is a strong rationale for their potential effectiveness against bladder cancer. Patients will receive a combination of Metformin and Simvastatin, and their tumors will be assessed for the drug's effectiveness in shutting down a critical cancer pathway.
The results of this trial could create a rationale for the early clinical implementation of these drugs as anticancer agents in bladder cancer, while providing the initial evidence required to create larger trials studying their efficacy. The combination of Metformin and Simvastatin could find a role not only in chemoprevention of recurrence, but also in sensitizing tumors to chemo and radiotherapies, potentially changing the way clinicians manage and treat invasive bladder cancer.
Dr. B.A. Petrisor
Dr. S. Sprague
Prospective Abuse and Intimate Partner Violence Surgical Evaluation (PRAISE-2): an Ontario-based multi-centre prospective cohort study
Every six days a woman in Canada is killed by her intimate partner. Intimate partner violence (IPV), also known as domestic abuse, is a leading cause of non-fatal injury in women worldwide. The cost of IPV in Canada is estimated at $5 billion annually. This research team recently completed a large, cross-sectional study of 2945 women (PRAISE) identifying 1 in 6 women attending surgical fracture clinics as self-reporting a history of IPV in the past year (Lancet, 2013). Given the high prevalence and costs associated with IPV, there is a need to identify health outcomes associated with IPV, the incidence of new and worsening cases of IPV, and resource use among IPV victims.
Building upon the success of PRAISE and the importance of collecting follow up outcomes on injured women, the investigators propose to conduct a prospective cohort study of 100 women with musculoskeletal injuries to assess differences in injury related outcomes (time to fracture healing, injury-related complications, and return to pre-injury function) between abused and non-abused women. This study will also determine whether a musculoskeletal injury can lead to new or worsening abuse by an intimate partner and how patterns of IPV change over time following musculoskeletal injuries. The researchers will also examine changes and differences in quality of life and utilization of support services and associated costs between abused and non-abused women. Finally, the proposed study will also inform the feasibility of a larger multinational cohort study. The results from this Ontario cohort will be targeted for publication in a high impact journal.
Dr. O.D. Rotstein
Dr. S. Rizoli
St. Michael’s Hospital
Effect of remote ischemic conditioning on neutrophil function and the immune-inflammatory and coagulation profiles in trauma patients with hemorrhagic shock
Dysfunction of vital organs is one of the major reasons why trauma victims die after sustaining a major injury, even though the organs themselves may not have been directly injured. The inability to clot blood as a result of inflammation further contributes to complications in a majority of these patients.
One intervention proposed to protect against impaired organ function is called “Remote Ischemic Conditioning”, wherein application of intermittent occlusion and release of blood flow to the arm by sequentially inflating and deflating a blood pressure cuff can protect against the development of distant organ injury and inflammation following a severe traumatic event. In a pilot study, the investigators will investigate the effects of remote ischemic conditioning in trauma patients with hemorrhagic shock, with a view to evaluate its effects on the immune system and coagulation profiles, both of which are known to be deranged in these patients.
These studies will potentially benefit patients and will serve as a proof of principle for the use of remote ischemic conditioning in the trauma setting.
Dr. C.J.D. Wallis
Dr. R.K. Nam
University of Toronto
A population-based cohort study assessing cardiovascular and oncologic events associated with testosterone replacement therapy
Testosterone replacement therapy (TRT) is indicated for testosterone deficiency, defined as low serum testosterone along with a variety of symptoms attributed to low testosterone. Testosterone deficiency itself is known to have adverse cardiovascular effects. However, there is great controversy as to whether TRT increases or decreases rates of cardiovascular events due to conflicting reports in the literature; furthermore as prostate cancer is an androgen-dependent tumor and androgen deprivation has been well-established in its management, there is concern that TRT may increase the rate of clinically-diagnosed prostate cancer.
The investigators propose a population-based, retrospective cohort study to assess rates of overall mortality, cardiovascular events and prostate cancer diagnoses in men over the age of 65 in Ontario taking TRT, as compared to age- and comorbidity-matched controls. Testosterone exposure will be measured from prescription databases and cumulative daily duration will be calculated. The composite cardiovascular outcome comprises myocardial infarction, cerebrovascular accident and venous thromboembolism. Cumulative incidence of the composite outcome, as well as each component, will be calculated using Kaplan Meier survival analyses. Cox proportional hazards modelling will be employed to identify risk factors.
Dr. K. Wong
Dr. K. Saidi
Northern Ontario School of Medicine
An analysis of the functional benefit, narcotic use and time to discharge readiness following the implementation of a comprehensive pain management protocol for primary total knee arthroplasty
A single-centre, prospective, double blind randomized control trial in 220 patients using combinations of intrathecal opioid (IO), femoral nerve block (FB) and periarticular infiltration (PI) for total knee arthroplasty will be conducted to determine the ideal anesthetic combination for safe early discharge. Secondary outcomes will look at function (Timed Up and Go walking distance, range of motion, ability to transfer); pain control (patient reported, total opioid consumption); complications (postoperative nausea, vomiting, pruritis); and patient satisfaction.
Patients will receive all three interventions and be block randomized to one of five anesthetic groups: all three (PI + FB + IO); a combination of two (FB + IO, PI + IO, PI + FB); or IO. Normal saline will be substituted for anesthetics for blinding. Statistical analysis using MANOVA and regression analysis will be completed to determine significant differences between groups.
It is expected that the combination of three anesthetics (PI, FB, IO) will result in additive pain control effect, minimize side effects and optimize patient recovery, and lead to early discharge. Hopefully, the results will not only have a direct benefit to patients but also an indirect cost benefit to the health care system.
Dr. D. Yuen
Dr. A. Kirpalani
St. Michael’s Hospital
Novel noninvasive assessment of kidney transplant fibrosis with magnetic resonance elastography
Kidney transplantation has greatly improved the quality of life and survival of people living with kidney failure. Unfortunately, up to 60% of these people go on to have failure of their transplant within 10 years, in many cases requiring drugs and/or return to dialysis. This is a devastating outcome. The cause for transplant failure is almost always, at least in part, due to scarring of the transplanted kidney.
There is currently no good test to detect this scarring. The best test available is a needle biopsy, which is associated not only with significant bleeding risks, but also an inability to sample and analyze the entire kidney. A new type of MRI called “MR elastography” has been proven to accurately measure scarring in the liver, but not yet in the kidney. It does not need any injections, can be done in 30 minutes, and may be able to measure scar throughout the entire kidney without needles.
This project aims to compare this new MRI test with needle biopsy. We will determine if it can measure scar in the transplanted kidneys of people with both normal and abnormal transplant function. This could drastically change how a doctor treats transplant failure.