Dr. Laureen Hachem has long been interested in neurosurgery and the potential of endogenous stem cells to repair spinal cord injuries. She started her research career in her last year of high school, volunteering in the lab of Dr. Charles Tator, a researcher and neurosurgeon at Toronto Western Hospital, and she continued working in Dr. Tator’s lab throughout her undergraduate and medical school education at the University of Toronto.

In 2017, she graduated from medical school and started the Toronto Neurosurgery Residency Program, which combines clinical and lab-based research training.

“When I’m on clinical service, I see questions or problems that I can critically analyze and think about how I would address them in a systematic, hypothesis-generating way,” says Dr. Hachem. “When I go back to the lab, I have an important perspective because I’ve seen what is relevant and feasible in the clinic, and the patient is always top of mind.”

In 2020, she started her PhD research, supervised by Dr. Tator and Dr. Michael Fehlings, continuing her studies of endogenous stem cell regeneration, with the aim of identifying therapies for spinal cord injury.

She had previously found that high levels of the neurotransmitter glutamate activate the AMPA receptor, which stimulates a response from endogenous stem cells. With a PSI Resident Research Grant, she began to look for clinically relevant methods to therapeutically activate AMPA receptors to stimulate endogenous stem cell regeneration, focusing on a class of drug called ampakines.

Ampakines bind to AMPA receptors to improve neuron signalling and have been used in neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease and in the setting of opioid-induced respiratory depression, and have been tested in clinical trials for some neuropsychiatric conditions. But until Dr. Hachem’s research, ampakines had not been examined for their potential in enhancing endogenous spinal cord stem cell regeneration.

Dr. Hachem says that PSI’s Resident Research Grant is a valuable tool for residents to develop their own research program and gain valuable skills early in their career.

“Because this grant funds residents as principal investigators who are asking the questions and leading the work, it gives residents ownership over the project,” she says. “It sets you up for the future in developing your career as a scientist and your own research program.”

Repurposed drug shows promise for neural stem cell regeneration

With PSI funding, Dr. Hachem used a clinically relevant rodent model of spinal cord injury to test whether an ampakine drug could stimulate the AMPA receptor to regenerate endogenous stem cells and restore function.

She found that the treatment increased the growth and division of endogenous neural stem cells and the production of beneficial growth factors, which was associated with increased neuron survival, reduced inflammation and improved functional recovery.

Dr. Hachem notes that other more invasive strategies – including stem cell transplantation – have been studied to repair spinal cord injuries, and while they show promise, her research is the first to show that ampakines have potential as a less invasive approach to regenerate neural stem cells.

“With this work, we’re trying to harness the body’s own regenerative potential with these stem cells. Since the discovery of these cells, it’s been a long-standing question of how we can actually use them to repair the spinal cord after injury, and this study is a critical step in answering that,” she says. “The relevance of the therapy and translation to the clinic is always top of mind, and ultimately the goal is to translate this drug and this approach of positively modulating these cells to patients in a clinical trial.”

With these first results, Dr. Hachem is continuing her research to understand the mechanisms at work, as well as examining the use of ampakines in chronic spinal cord injury. She plans to continue pursuing lab-based research along with clinical care to build a career that ultimately improves care for patients with spinal cord injury.

“Funding from PSI Foundation allowed me to do this first critical experiment to show the feasibility and efficacy of the drug, as well as optimize drug dosing, timing and duration, and this work paves the way for larger scale studies and ultimately clinical translation to patients,” says Dr. Hachem. “This line of research has really grown with me throughout my medical education. Looking forward in the future, I aim to have a career where I can integrate my research interests with my surgical practice.”

Screening women for intimate partner violence (IPV), which includes physical, sexual, and emotional violence, may not seem to fall under the scope of an orthopedic or fracture clinic. But orthopedic surgeons and researchers who recently led an international study on IPV prevalence among orthopedic patients explain that the fracture clinic can actually be a good setting to address this issue.

“In the fracture clinic, you often see patients with injuries frequently during the first few weeks to months. Follow-up often continues for months and sometimes longer,” says Dr. Brad Petrisor, an orthopedic surgeon and professor at McMaster’s Department of Surgery. “You get multiple snapshots over the course of the year after their injury, so this is a major opportunity to ask about and understand intimate partner violence in people’s lives.”

Dr. Petrisor, Dr. Sheila Sprague, Associate Professor in the Department of Surgery, Dr. Kim Madden, Assistant Professor in the Department of Surgery, Dr. Mohit Bhandari, Chair of the Department of Surgery, along with a large multi-disciplinary team, are leading a research program that is generating more awareness of IPV among orthopedic specialists and equipping them to address it with their patients.

As part of her PhD thesis, Dr. Sprague led one of the early studies of IPV among orthopedic patients, the PRAISE (Prevalence of abuse and intimate partner violence surgical evaluation) study. The research team examined the prevalence of IPV among 3,000 women attending orthopedic fracture clinics in Canada, the US, the Netherlands, Denmark and India. They found that one in six women had experienced IPV in the year before the injury, and one in three had experienced IPV in their lifetime. The study was published in The Lancet in 2013.

In 2015, Dr. Petrisor and Dr. Sprague received funding from PSI Foundation to expand on those results with the PRAISE-2 study, which examined reporting rates of IPV among orthopedic patients during the first year following the injury and how IPV affects outcomes such as return to function, complications from the injury and health-related quality of life.

The team assessed IPV disclosures and clinical outcomes of 250 women from Canada, the Netherlands, Spain and Finland at the first visit to the orthopedic fracture clinic and at one, three, six and 12 months after the first visit.
They found that 33% of the patients disclosed IPV during their first visit, and an additional 12.4% who did not disclose IPV at the first visit did disclose IPV at some point during the 12-month follow up.

The team also found that women who disclosed IPV were slower to return to their pre-injury level of function, experienced more complications from their injury and had lower health-related quality of life during the follow-up period. The results were published in the Journal of Bone and Joint Surgery, the field’s most prestigious journal.

“These kinds of statistics can help inform education so that surgeons know to ask about IPV, not just once but at each visit, because you could be missing a significant number of people who could be helped,” says Dr. Sprague. “And knowing that patients who experience IPV have a more difficult recovery is helpful so that the surgeon can intervene earlier with referrals to appropriate services.”

The research team’s work over the last decade has helped to change the perspective of orthopedic specialists from viewing IPV as outside their scope of practice to feeling better equipped to help patients experiencing IPV. They have published papers in top journals and delivered presentations at major orthopedic trauma meetings, and their work has led to positional statements by the Canadian Orthopedic Association recognizing IPV as a significant determinant of morbidity and mortality.

Importantly, Dr. Sprague, Dr. Bhandari, and their colleagues have used the results from the research program to develop a program called EDUCATE, an open access website for orthopedic surgeons and fracture clinic staff that provides knowledge and skills to assist women who are victims of IPV. By the end of 2021, the EDUCATE program had trained more than 150 health care professionals, and they hope to eventually broaden the program to include more health care fields.

“It teaches them how to optimize their fracture clinic and how to ask about IPV. And it also describes the resources that are available and referrals that health care providers can give,” says Dr. Sprague.

As a practising surgeon, Dr. Petrisor says that the research program has changed his own approach with patients.

“When we started this program of research, there was a lot of discomfort among orthopedic surgeons: how do you ask people about IPV, how can the environment in the fracture clinic be conducive to asking about it, and if a patient discloses, what do I do about it?” says Dr. Petrisor. “Knowing that more than one third of women in the clinic disclose IPV has definitely changed my approach in how I interact with patients. In the same way we ask about smoking, alcohol or drugs without judgment, we can ask about IPV and know what to do after a disclosure.”

“It can be hard for physicians who practice in the community to get research off the ground because they don’t have access to traditional funding streams… I look at the community setting as a real-life lab for doing research, and it’s so beneficial to have funding from PSI that supports physicians in this setting.” – Dr. Kamila Premji

Dr. Kamila Premji, a family physician practising in Ottawa, has been interested in research throughout medical school and residency—with a particular interest in health care policy and access to primary care. Now a PhD candidate in Family Medicine at Western University, she has had the opportunity during her training to lead research that has provided important information about challenges with Ontario’s current system of physician compensation.

“I have been able to use my clinical practice experience in the community, see what my patients were struggling with and look for answers to those problems,” she says. “Research was such a natural path to explore those interests and make a difference in health care policy to help improve access to care.”

Dr. Premji had been working at her community practice for a few years when she decided to pursue a master’s degree, which would give her the skills to undertake more rigorous research, and soon transitioned into the PhD stream.

Early in her graduate training, Dr. Premji was part of a team led by Dr. Richard Glazier that examined whether the physician access bonus led to better patient care.

Ontario introduced the access bonus in 2004 as part of several pay-for-performance incentives in primary care. The access bonus is meant to reward family physicians who organize their practices to be more accessible by providing higher bonuses to physicians whose patients seek less external care, such as walk-in or after-hours clinics. Emergency department visits and specialists are not counted as external care.

However, the access bonus has been a controversial incentive, particularly because patients in urban and rural communities have different access to external health care services. With patients in rural communities often relying on emergency departments, it results in bonuses that may not accurately reflect whether physicians are making their practices more accessible.

“The access bonus creates all kinds of unintended consequences for the way services are delivered, and it can even impact the patient-physician relationship at times,” she says. “It’s such a big part of the dominant payment model in Ontario, so it seemed like something that warranted further exploration.”

In 2019, the team including Dr. Premji published a study that linked administrative data about patients’ health care use with their physicians’ access bonuses. The study found that physicians who earned the highest access bonuses were more likely to practice in rural or small urban areas and have higher proportions of patients with less complex health care needs; but these physicians did not necessarily offer more after-hours care, and their patients had higher rates of emergency room use.

PSI Research Trainee Award project suggests access bonus is not working as intended

Dr. Premji wanted to examine the results in the urban setting more closely, as well as consider a different measure of patient access. With a PSI Research Trainee Award, Dr. Premji and the team examined the access bonus for physicians in large, medium and small urban centres from the perspective of whether it improved patients’ experiences and perceptions of access.

“This is such an important part of understanding what the access bonus payment does from a patient perspective,” she says. “From their perspective, are patients experiencing a better level of service and access with this bonus? Is the bonus doing what it is meant to do?”

The team used data from the Health Care Experiences Survey, a patient experience survey conducted quarterly and funded by the Ontario Ministry of Health, and health administrative data from ICES. They were able to link patients with their physicians and family health teams and find associations between patient perceptions of access and their physicians’ bonuses.

The team found that in large and medium urban centres, where walk-in clinics and after-hours care are easily accessed, patient-reported experiences of access were positively associated with their physician’s access bonus. But this association did not hold in small urban centres, and as in the previous study, higher bonuses did not actually mean that patients experienced better access to their physicians.

“In large and medium urban centres, the higher the bonus, the more satisfied patients were with their access, which suggests that the bonus may be motivating physicians and clinics to organize their services in a way that improves the patient’s experience of access,” she says. “But the availability of resources and patients’ choices are still driving the bonus and having more of an impact, and these are out of physicians’ control.”

The results of both studies suggest that the access bonus is not necessarily doing what it is meant to do and may need to be redesigned to account for the differences in geography and patient experience. The results were published in the Canadian Medical Association Journal in November 2021 and have been presented to stakeholders including the Ontario Medical Association and the Ontario Ministry of Health.

The PSI Research Trainee Award concluded in 2020, but Dr. Premji is continuing research in primary care access while she finishes her PhD and cares for her patients.

“I find myself more alert to what my patients are experiencing that could be answered through policy solutions and through research. These areas fuel each other,” she says. “My clinical care fuels my curiosity, and my interest in research leads me to do these projects that then may have an impact on my patients.”

“Historically this population has been underfunded, so it’s really important that PSI has funded dysvascular amputee research. We were happy to get this PSI grant, and it really built the confidence of the researchers in Ontario so that now we can work together and do bigger things.” – Dr. Amanda Mayo, Sunnybrook Health Sciences Centre

“We’re very grateful to PSI for funding this work because it really lit a spark and galvanized our research community, and it will ultimately improve the quality of life for the limb loss community.” – Dr. Sander Hitzig, Sunnybrook Health Sciences Centre

A PSI Foundation–funded grant to examine the health and quality of life of people with dysvascular limb loss has not only provided important insights into this understudied population but has also helped to develop the limb loss research field in Canada.

“Our overarching goal of is to develop collaborative research so that our patients do better, but to do this, we need to know how they’re doing and the resources they lack,” says Dr. Amanda Mayo, a physiatrist at St. John’s Rehab at Sunnybrook Health Sciences Centre who specializes in amputee rehabilitation. “This funding has allowed us to build a more cohesive and collaborative research program, but also work toward the greater aim of improving clinical outcomes for this patient population.”

Each year, approximately 1,500 people in Ontario have a major lower limb amputation due to dysvascular causes such as peripheral vascular disease or diabetes, making it the most common cause of lower limb loss in Canada. And the problem is expected to grow as the incidence of diabetes increases.

While any type of amputation can be traumatic, people with dysvascular limb loss face different challenges than those who lose limbs due to other causes, such as accidents.

“They’re a very vulnerable and frail population. They are usually older and tend to have a high number of comorbidities leading up to their amputation, in particular heart disease, arthritis and neuropathy,” says Dr. Amanda Mayo. “After the amputation, they’re at greater risk of complications, falls, depression and not being able to get back to community living.”

In 2018, Dr. Mayo and her co-principal investigator, Dr. Sander Hitzig, a scientist focused on aging and disability also based at St. John’s Rehab, received a PSI Foundation Clinical Research Grant to examine the health and quality of life outcomes of people with dysvascular limb loss – the largest study of its kind in Canada.

Study finds that physical and mental health decline post-amputation

In the study, the research team interviewed more than 230 people with limb loss about their physical and mental health, mobility, social connections and quality of life after amputation. They also interviewed 35 people from this group in more depth about their experiences of living in the community after amputation.

The study results showed some troubling trends. The people they interviewed experienced poor physical health, with an average of five comorbidities, most commonly diabetes, pain and high blood pressure. After amputation, mental health also tended to decline, and many people became more isolated; about one-third of interviewees expressed that they were lonely.

But the study also identified factors that could help people to cope better after limb loss; less impactful morbidities, a higher sense of self-confidence, and strong levels of social support were associated with better physical or mental health.

The interviews were done before the COVID-19 pandemic, but anecdotally it is likely that the pandemic has hit this population particularly hard.

“I think the pandemic has magnified how significant being socially isolated can be for anyone, and this was an isolated population before the pandemic,” says Dr. Hitzig. “We don’t have data about this yet, but they may have become more isolated and disconnected due to many of them being immunocompromised, and their physical health may have declined because of clinics being closed, not being able to get to the hospital, or surgeries being delayed.”

Results will help inform supports for vulnerable group

In addition to the interviews, Dr. Mayo and Dr. Hitzig analyzed data from a large cohort of Ontarians with lower limb amputations to understand their health care usage and the economic cost of dysvascular amputation. While this part of the project is not yet complete, early results suggest that people with limb loss are very high users of the health care system, visiting family physicians, specialists and emergency departments multiple times in the year following their amputation.

In fact, approximately 30% of people with dysvascular limb loss are admitted to long-term care and 30% die within two years of their amputation.

“These people are having significant health issues. We try to help them recover as best as possible through rehab, but many continue to decline,” says Dr. Hitzig. “There is a negative impact on the person and their family members, but there is also a health care system cost that we’re now hopefully starting to better understand.”

With a better understanding of the quality of life for people with dysvascular lower limb loss and the related social and economic costs, Dr. Mayo and Dr. Hitzig hope that the results from this project and their larger research program can be used to screen people who may be at greater risk of social isolation, as well as develop or connect people with programs to support their physical and mental health after an amputation.

“Predicting which patients are most at risk of isolation or not successfully integrating into the community would allow us to do more targeted rehab or pre-operative care,” says Dr. Mayo. “Looking at the data from this project, we see many opportunities for future collaborative research and ways to use the results to improve quality of life.”