Foundation Funded Projects for 2011

 

October 1 to December 31, 2011

In the fourth quarter of 2011, the Foundation approved a total of $932,500 in new grants, for the following projects:

 

 

Dr. S.M. Bates
McMaster University

Evaluating Values and Preferences of Women for Thromboprophylaxis during Pregnancy

Venous blood clots (blood clots in the leg veins or in the lung) are an important cause of death and sickness in pregnant women. Women who have had blood clots are at risk of another episode when they become pregnant. Preventative blood thinning medications can reduce this risk. The blood thinner that is safe to take during pregnancy requires daily needles and has small risks of complications. Therefore, patient preferences need to be taken into account regarding the risk of recurrent clots versus these drawbacks when deciding who should be prescribed this medicine.

There are no data describing decisions women make about taking these preventative blood thinners during pregnancy. This study aims to improve our understanding of how women perceive the experiences of having a blood clot and of using preventative blood thinners during pregnancy.

100 women will be interviewed using different ways of presenting information to determine the risk of clots that women require to be willing to take preventative blood thinners during pregnancy. The factors that affect their decision will also be studied. Our results will help experts who write guidelines for doctors and patients about the best way to care for pregnant women with previous venous blood clots.

 

 

Dr. C. Chan
Dr. E. Greenblatt
Mount Sinai Hospital

Non-invasive genomic analysis of human endometrial receptivity

Infertility affects 15% of Canadian couples. In vitro fertilization (IVF) is the best treatment available. This procedure involves retrieving eggs from a woman’s ovaries, fertilizing them with a man’s sperm, and returning the resulting embryos back to the woman’s uterus in hopes of achieving a healthy pregnancy. Despite many technological advances, IVF success rates are still poor, with only 30% of couples achieving pregnancy per treatment cycle.

Failure of the embryo to attach to the uterus, known as failed implantation, is the major limiting factor to the success of IVF. Currently, there are no reliable clinical tests to predict whether or not a woman’s uterus is receptive to the embryo and capable of implantation. The goal of this research is to develop a non-invasive technique to obtain cells from the lining of the uterus in order to identify factors that are important in uterine receptivity.

Improved knowledge about these factors will help us design clinical tests to assess the implantation potential of a woman’s uterus. A better understanding of the molecular mechanisms involved in uterine receptivity and implantation will also lead to improved IVF outcomes and pregnancy rates, and increase the cost-effectiveness of this technology.

 

 

Dr. P.T. Church
Dr. V. Shah
Sunnybrook Health Sciences Centre

Academic Challenges for the Preterm Infant: Educators' Knowledge, Attitudes, and Identified Barriers to Providing Aid to this Population

The frequency of preterm births in Canada continues to rise. Despite advances in medical care, preterm birth is associated with long-term academic, attention difficulties and behavioral problems. These difficulties lead to potential academic underachievement, grade failures and need for remedial assistance during childhood and adolescence and difficulties in coping with adult life. Therefore, recognizing these difficulties earlier and providing educational interventional strategies to reduce the impacts is crucial.

Educators play a key role in: 1) early identification of children with such Impairments; and 2) providing parents guidance on how to manage such impairments. Despite the importance of this role, there are no data on educators‘ understanding of preterm birth and the long-term cognitive and academic outcomes of these survivors.

In this study, a focus group will be conducted and elementary educators in the Greater Toronto Area will be surveyed to document educators‘ level of knowledge of the impact of preterm birth on academic achievement, attention deficits and behavioral problems. Further, this study will explore attitudes towards these impairments/deficits; identify barriers regarding the availability/implementation of educational strategies and their willingness to advance their knowledge on these issues so that the child and the family can be assisted to achieve his/her potential.

 

 

Dr. A. Grewal
Dr. J. Lee
St. Michael’s Hospital

The Effect of Endoscopic Sinus Surgery on Nasal Nitric Oxide Levels in Patients with Chronic Sinusitis

Chronic Sinusitis (CS) affects an estimated 16% of the population, and has a surprisingly significant impact on quality-of-life (QoL). First-line therapy is primarily medical, and in treatment failure endoscopic sinus surgery (ESS) may be considered.

It has recently been discovered that Nitric Oxide (NO), a gas with potent vasoactive and antimicrobial properties, is produced in high concentrations in the paranasal sinuses. Researchers hypothesize that NO functions in host defense and that decreased production may predispose to sinus infections. Individuals with CS have been shown to produce lower levels of NO in the paranasal sinuses. However, the impact of surgical intervention on restoring NO production is not well understood.

This project aims to prospectively study 40 patients undergoing ESS for CS after failed medical therapy. Nasal NO studies will be performed pre-operatively, at 1- and 6-months post-operatively, in addition to a sinusitis-specific standardized QoL questionnaire. It is hypothesized that ESS will improve both NO production and QoL scores, and that the degree of NO increase will correlate to disease-specific QoL improvement.

Considering the substantial disease-burden and healthcare costs associated with CS, understanding the pathophysiology of NO in sinus disease is clinically important. It is hopeful that NO may play an important diagnostic and prognostic role in future management of CS.

 

 

Dr. S. Hota
University Health Network

A Randomized Controlled Trial of Oral Vancomycin Followed by Fecal Transplantation versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection

This study is a single-centre, unblinded, randomized controlled trial comparing oral vancomycin followed by fecal transplantation with oral vancomycin taper (standard of care) for the treatment of recurrent Clostridium difficile infection (CDI).

One hundred and forty-six adult patients with laboratory or pathology-confirmed recurrent CDI will be randomized in a 1:1 ratio to receive: (1) approximately 2 weeks of oral vancomycin followed by a single fecal transplant, delivered by enema; or (2) a 6-week taper of oral vancomycin. The 2 weeks of vancomycin pre-treatment in the fecal transplant group will allow for a fecal transplant donor to be screened for transmissible infectious diseases, to ensure appropriateness and safety of donation.

Participants will be followed for 120 days. The primary endpoint is recurrence of laboratory-confirmed CDI. Secondary endpoints include: safety profile; recurrence of symptoms compatible with CDI within 14 and 120 days; days of diarrhea; CDI requiring hospitalization, mortality attributable to CDI and allcause
mortality. Six follow-up visits will occur. If patients fail treatment during the follow-up period, they may cross over to the alternate treatment group. Those who cross over will be followed for an additional 120 days from the second intervention.

 

 

Dr. M. LeBel
Dr. S. Cristancho
University of Western Ontario

Observational learning strategies in simulation-based arthroscopic surgical training

Understanding what techniques help us learn new skills in the most effective way is crucial because we spend so much time learning how to do new things. Usually, when practicing a new task, we learn from our own mistakes. Learning by watching others’ performances is key for surgical training, where making mistakes could have dramatic consequences.

It has long been thought that, to learn a task, one should watch an expert. However, recent research indicates that watching perfect performance might not be optimal. Instead, watching errors that non-experts make gives the best chance of performing well, when one eventually gets to take part in the task. This surprising finding is what we will investigate in the context of learning arthroscopic surgery skills using virtual-reality simulation.

To investigate this ‘observational learning’, separate groups of subjects will watch either experts or non-experts performing a surgical task, before trying it themselves on a virtual-reality surgical simulator. It is expected that the group of subjects who watched non-experts before trying the task themselves on the simulator will outperform the group who watched experts. This counterintuitive finding would have dramatic impacts on surgical training methods, redefining the way in which motor skilled tasks should be taught.

 

 

Dr. C.M.J. McCabe
Dr. C.S. Bailey
University of Western Ontario

The importance of soft tissue restraints following type II odontoid fractures in the elderly - a biomechanical study

Odontoid fractures in the elderly are the most common cervical spine injury, and they will become more prevalent as the population demographic continues to increase in age. They are usually caused by an accident as simple as a slip and fall from a standing height, but the injury can be devastating. The treatment of this injury remains controversial, but the general goal is to produce rigid immobilization to protect the spinal cord and ensure healing of the fracture. However, rigid immobilization in the elderly population is associated with a high complication rate. Due to the low-energy nature of this injury, it is speculated that the soft tissue restraints (ligaments) supporting the spine at this level remain functioning. Thus, the need for surgery or rigid non-operative immobilization could be avoided.

Ten cadaveric spines will be loaded into a spine motion simulator. The “normal” motion will be compared to the “abnormal” motions created by the fracture and ligament resections. It is expected that the fracture will be stable until most of the ligament restraints have been released. Thus, a low-energy fracture produced in an elderly patient will not require rigid immobilization. This will decrease the treatment associated complication rate.

 

 

Dr. S.A. Morrow
University of Western Ontario

Recovery of demyelinating optic neuritis after treatment with equivalent high doses of oral vs. intravenous corticosteroids: a randomized single blinded clinical trial

Relapses in multiple sclerosis are due to a new demyelinating lesion and present as a worsening in neurological function (weakness, loss of sensation etc.) that recovers slowly over time. Optic neuritis - loss of vision due to demyelination in the nerve that carries visual information from the eye to the brain, the optic nerve - is a common relapse. Recovery from a relapse is hastened by treatment with high doses of steroids over several days. Traditionally, it has been given intravenously (IV), but oral treatment would be more convenient as it would not require coming into the hospital, is less expensive and less invasive. Although treatment with oral and IV steroids in equivalent doses results in similar blood levels of steroids, it is not known if the route of treatment affects the degree of recovery from the relapse.

This study compares the recovery of vision after an episode of optic neuritis when treated with IV or oral steroids using visual evoked potentials, an electrophysiological test that measures the response of the optic nerve to a visual stimulus, testing patients before treatment with steroids (randomly assigned to oral or IV), one month and 6 months after treatment.

 

 

Dr. Y. Pei
Dr. A. Paterson
University Health Network

Identifying Disease Genes for Immunoglobulin A (IgA) Nephropathy

IgA nephropathy (IgAN) is the most common cause of inflammation of the kidney filters (glomerulonephritis) worldwide and accounts for ~5% of end-stage kidney disease (ESKD) in Canada. Typically, patients with IgAN are asymptomatic and are only diagnosed by screening urine tests. Within 10-20 years from the time of diagnosis, up to 35% of patients will develop ESKD requiring dialysis or kidney transplantation.

Familial clustering of IgAN is very common and strong evidence implicates there are at least 5 disease genes that can cause this disease. However, none of these genes have been identified to date primarily due to the difficulty of screening many genes within the regions where the disease loci have been mapped.

Recent advances of a new technology called Next Generation Sequencing have provided a revolutionary tool for disease gene discovery that bypasses the bottleneck of gene-by-gene mutation screening. Using this powerful technology in a well-characterized set of families with multiple affected individuals, this study proposes to identify disease genes for familial IgAN as a means to gain critical insights into its pathobiology. Such knowledge will provide the essential foundation for developing better diagnostic tests and novel therapeutics for this important disease.

 

 

Dr. S. Riazi
University Health Network

Calsequestrin-1, a candidate gene for the diagnosis of malignant hyperthermia. Study of molecular genetics of Malignant Hyperthermia

Malignant Hyperthermia (MH) is a fatal pharmacogenetic disorder that occurs in susceptible patients (MHS) on exposure to volatile anesthetics, and/or succinylcholine. Current “gold standard” diagnostic testing is the caffeine-halothane contracture test (CHCT), which requires an invasive muscle biopsy, and therefore surgery, general anesthesia, and prolonged rehabilitation. Despite the genetic nature of this disease, genetic testing yields a low sensitivity of 50% as MH-associated mutations have been found in only two genes, the RYR1gene (MIM 180 901) and the CACNA1S gene (MIM 114 208).

Recently, creation of a knockout mouse lacking calsequestrin, a sarcoplasmic reticulum calcium-binding protein that modulates RYR1 function, showed an MH-like phenotype. It is imperative to explore if mutations in human calsequestrin 1 gene (CASQ1) contribute to MH susceptibility. This project intends to test MHS individuals without RYR1/CACNA1S mutations for presence of mutations in
CASQ1 gene or persistent alterations in its level of expression. Additionally, normal individuals, and MHS with known RYR1/CACNA1S mutations will be tested for the identified CASQ1 mutation(s).

By validating CASQ1 as a candidate gene in MH families, the sensitivity of genetic testing for diagnosis of MH can be improved, and genetic testing may replace CHCT in a higher proportion of cases, which could not only eliminate an unnecessary surgery, and disability for these at risk individuals, but can save lives, as it facilitates diagnosis and improves its accuracy.

 

 

Dr. P. Rumney
Holland Bloorview Kids Rehabilitation Hospital

Exploring The King’s Outcome Scale for Childhood Head Injury in Children Attending a Rehabilitation Hospital

Pediatric acquired brain injuries can severely impact the health and well-being of a child. It is important for the child to have access to appropriate and effective medical treatment and rehabilitation. In order to determine if treatment is effective and to determine levels of disability, there needs to be an accurate measure.

In this study, the King’s Outcome Scale for Childhood Head injury (KOSCHI) will be assessed in a clinical cohort of children 4 to 18 years of age who are seeking care at a pediatric rehabilitation hospital. A physician can score the KOSCHI after a clinical examination and/or after reviewing the medical notes. This study will determine if two physicians can rate the same child at the same level of the KOSCHI score. It will also determine if the different levels of the KOSCHI score are correlated with other outcome measures of overall health status. Lastly, it will determine if the KOSCHI score can detect changes in the child’s health status over time.

This project is especially relevant since a recent scientific panel recommended using the KOSCHI to assess levels of disability in pediatric patients with traumatic brain injury secondary to traffic collisions.

 

 

Dr. R. Sapir-Pichhadze
Dr. S.J. Kim
University Health Network

HLAMatchmaker Eplet Mismatches and Transplant Glomerulopathy

Kidney transplantation prolongs the lives of patients who have suffered kidney failure and require dialysis. Rejection occurs when transplant recipients develop antibodies towards the donor kidney and shortens the time patients can enjoy their transplant and not require dialysis.

In an attempt to decrease the risk of developing antibodies towards the donor kidney, transplant doctors try to ensure optimal donor and recipient compatibility. The HLAMatchmaker is a computer program that uses donor and recipient genetic information to identify the ideal match and thus minimize the risk of rejection.

This study will include patients who had their transplants at the University Health Network. From this group, patients whose transplant failed because of antibody related injury diagnosed on a biopsy will be identified. Using the HLAMatchmaker program, the degree of donor-recipient mismatch in patients who had antibody related injury will be compared with those who did not. We suspect that patients with evidence of antibody related injury on kidney biopsy will have a greater degree of donor-recipient mismatch compared with patients who did not.

A better understanding of the circumstances that cause antibody related injury in kidney transplants may improve provincial organ allocation processes, prolong transplant survival and decrease healthcare costs.