Research Location: University of British Columbia

PRophylactic Indomethacin in MicropreemiEs (PRIME) – a retrospective cohort study

Infants born extremely prematurely, especially before 26 weeks’ gestational age (GA), are classified as micropreemies and are considered the most vulnerable population. These babies often face serious short and long-term health challenges. One common problem is intraventricular hemorrhage (IVH), a type of brain bleed that remains the leading cause of death in this vulnerable population. Severe IVH (sIVH) can lead to significant lasting effects such as cerebral palsy, reduced IQ, and overall neurodevelopmental disabilities. Clinical trials have shown that preventative indomethacin, a nonsteroidal anti-inflammatory drug, can prevent sIVH and death. In Canada, babies born before 26 weeks’ GA from 2018-2022 who received indomethacin had a 5% lower death rate and were 4% more likely to survive without sIVH in comparison to those who did not receive the drug. Although past studies have shown that prophylactic indomethacin can reduce both sIVH and death, its use in clinical practice remains inconsistent due to concerns about potential negative effects. The proposed study, PRophylactic Indomethacin in MicropreemiEs (PRIME), specifically examines the impact of prophylactic indomethacin on short- and long-term neurodevelopmental outcomes in the micropreemie cohort. The pan-Canadian retrospective observational study will link data from the Canadian Neonatal Network and Canadian Neonatal Follow Up Network to investigate the relationship between preventative indomethacin and death and disability in extremely premature infants. Additionally, neurodevelopmental outcomes will be explored at 18-24 months. Una Spasovski, a master’s student in the Women+ and Children’s Health program at the University of British Columbia, will lead this study in British Columbia. Under the supervision of Dr. Souvik Mitra, her research specifically focuses on improving outcomes for extremely premature infants at the BC Children’s Hospital Research Institute.

Nerve transfer surgery to restore upper-limb function after cervical spinal cord injury

One of the most devastating consequences of cervical spinal cord injury (cSCI) is the loss of hand movements, which severely impacts independence and quality of life. Nerve transfer surgery (NT) is emerging as a promising method to restore functions like hand opening and closing. While previous research shows NT is safe and potentially effective, robust scientific evidence of the effectiveness of NT is lacking. To address this gap, a national collaborative effort led by BC-based physiatrist and clinical assistant professor Dr. Michael Berger is conducting the first multi-centre prospective study on NT for individuals with cSCI (https://clinicaltrials.gov/study/NCT05638191). The primary aims of this study are to evaluate NT’s overall effectiveness in individuals with cSCI, identify patient subgroups most likely to benefit from NT based on factors like age and injury level, and explore patients’ lived experiences post-surgery. This study, supported by the CANTRAIN-CTTP & Michael Smith Health Research BC Post-Doctoral Fellowship 2024 Award Program, is being conducted across four Canadian interdisciplinary clinical programs (Vancouver, BC; Toronto, ON; Kingston, ON; Halifax, NS). Over four years, participants will undergo comprehensive assessments at baseline and regular intervals for 24 months post-surgery, enabling researchers to track changes in functional, motor, and patient-reported outcomes. By rigorously evaluating the efficacy, safety, and broader impacts of this innovative surgical technique, our team aims to provide individuals with cSCI the knowledge and confidence to make informed decisions about their treatment options. 

What is the baseline of Total Oxygenation Index (TOI) in transplanted tissue after Free Tissue Transfer (FTT) surgery

Head and neck cancer is the seventh most common cancer worldwide, with over 660,000 new cases and 325,000 deaths each year. After removing a tumor, a common reconstructive method called Free Tissue Transfer (FTT) is used. This involves transplanting skin, muscle, or bone, along with its blood supply, from one part of the body to the surgical site. 

A proper blood supply to the transplanted tissue is crucial. If blood flow is inadequate, complications or tissue death can occur, which may require further surgery or even lead to death. Early detection of changes in blood flow and oxygen levels is key to preventing these issues.

Currently, FTT monitoring relies on hourly visual checks by trained medical staff, which are subjective and not continuous. To address this, our team has developed an optical non-invasive sensor using near-infrared spectroscopy (NIRS). This technology uses light to measure blood flow and oxygen levels in the tissue. It provides a metric called Tissue Oxygenation Index (TOI), which reflects the health of the transplanted tissue. 

Initial testing on four patients showed the sensor could monitor tissue oxygenation continuously for 72 hours after surgery. Amir’s project aims to enhance this technology by creating a wireless, non-invasive sensor. It will transmit data to a monitor and remote systems, allowing doctors to track patient status and receive alerts if TOI changes. 

The next steps include clinical trials with 60 FTT patients to establish TOI baselines and improve the sensor’s hardware and software. The device recently received approval from Health Canada and Clinical Trial governments body. This innovation aims to reduce FTT failures, improve patient outcomes, and lower healthcare costs. 

Modulating Immune Cell Glycosylation as a Strategy to Improve the Anti-Tumor Response

Cancer cells develop ways of escaping and hiding from the immune system so that they are not recognized as unhealthy cells. If our immune cells could recognize the abnormal cancer cells growing in the body they would attack and kill the cancer cells. A big problem is that we don’t know enough about how different types of immune cells regulate their response to tumor cells; so we don’t how to manipulate the system to get the immune cells to engage and attack the tumor. One way that immune cells regulate their response to tumor cells is through the binding of sugars, called glycans. Glycans on immune cells and on tumor cells have been shown to be critical in the regulation of the anti-tumor immune response. Recently, we discovered unique glycan on immune cells in the breast tumor microenvironment. Patients whose tumors had high levels of this glycan on immune cells had worse survival outcomes. We think that this glycan controls the immune response and when expression levels are high, it prevents immune cell activation. To study how this glycan regulates the anti-tumor response, we propose to identify the immune cell subsets carrying this glycan and then study how this glycan effects their tumor killing functions. Our work will provide important details to help us understand how to trigger the anti-tumor immune response and may provide a new immune-checkpoint target for therapeutic development.

Regulating A Tumor-Specific Cell Surface Glycopeptide Epitope For Precision Immuno-Oncology

Unlike ‘liquid’ leukemias and lymphomas, most solid tumors are extremely difficult to target immunologically with antibody-based therapeutics. In an effort to overcome this limitation, we identified a novel peptidoglycan on the surface of aggressive solid tumor cells that are present in multiple cancer types. These include breast, ovarian, bladder, colorectal and oral squamous carcinomas as well as glioblastomas. Molecularly, this peptidoglycan is found on the extracellular domain of the cell surface mucin ‘podocalyxin’. Biologically, the emergence of the podocalyxin peptidoglycan is exquisitely tumor-specific and we have demonstrated that it can be successfully targeted immunologically in pre-clinical solid tumor assays in a manner that spares normal cells and tissues. This has been achieved using an antibody drug conjugate against the podocalyxin peptidoglycan that we have developed.

 

In this project, we will first use genome-wide editing screens to identify regulators of the tumor-specific podocalyxin peptidoglycan using CRISPR Cas9 technology. In preliminary proof-of-principle experiments we have identified twelve potential regulators from four different functionally-clustered intracellular signaling complexes. We will next manipulate such regulators, both genetically and pharmacologically with small molecule inhibitors, to precisely tailor the immuno-oncologic targeting of aggressive podocalyxin peptidoglycan-positive solid tumors. Finally, we will take a glyco-proteomic approach to identify additional tumor-specific peptidoglycans that can also be targeted immunologically. The overarching goal of this project is to develop a pipeline of novel antibody-based immuno-therapeutics that can be used to treat multiple aggressive solid cancers with precision and minimal side effects given that they will, by design, spare normal cells and tissues.

Identifying research priorities relating to stimulant use in the context of the unregulated drug poisoning emergency in British Columbia

Stimulants (i.e. cocaine and methamphetamine) are increasingly detected in drug toxicity (i.e. overdose) deaths in BC. Our recent analyses reveal high rates of chronic disease among people who have died of stimulant and;or opioid overdose in BC. For example, we identified high rates of heart disease and mental illness among people who experienced stimulant overdose. These analyses suggest possible opportunities for intervention across the health system in chronic disease care, to reduce overdose risk.

At the Provincial Health Services Authority, a new data platform holds health records for emergency department visits, hospitalizations, and primary care visits for all BC residents. In the context of rising stimulant use in BC, and this new data source, there is an opportunity to use these data to fill knowledge gaps on stimulant use and overdose risk in BC.

We aim to address this knowledge gap by bringing together a group of people with lived and living experience of stimulant use to form a Peer Advisory Group. The group will advise on how these data can be used to investigate the intersections of chronic health conditions and overdose risk, with attention to the specific risks faced by people who use stimulants.

Evaluating the impact of cannabis exposure and access on substance use trajectories among people who use unregulated drugs during the fentanyl era

The impact of cannabis access and use on the development of high-risk substance use behaviours remains controversial during the opioid overdose crisis. To address this knowledge gap, I plan to:

1. Identify how cannabis access and use impact early substance use careers, including the use of opioids, stimulants and injection drug use among at-risk youth;
2. Analyze how cannabis access and use impact overdose, as well as risk factors for overdose (e.g., binge opioid use) among high-risk subgroups of people who use drugs (e.g., people with chronic pain, HIV);
3. Characterize how cannabis use impacts engagement and effectiveness of addiction treatments. We will also investigate how cannabis use intentions (e.g., recreational vs. therapeutic use) shape addiction treatment outcomes.

This project will analyze data from three studies (N=3,375) of people who use drugs (PWUD). Established partnerships with the BC Ministry of Health and community groups of people with living experience of substance use will support the production of scientific evidence, policy briefings and community resources that will be important to inform clinical and public health practice, as well as policy responses to the overdose crisis during the fentanyl era.

Molecular mechanisms and genomic consequences of transposable element hijack strategies during embryogenesis

Transposable elements (TEs) are selfish genes that self-copy and move around the genome. Robust defense mechanisms silence TEs to prevent them from causing devastating mutations that break DNA and destroy genes. Failed TE suppression is associated with myriads of disease phenotypes including tumorigenesis and sterility. But the defense is not failsafe; TEs repeatedly acquire evasion tactics, enabling them to amplify at the expense of the genome. Using the powerful model organism, the Drosophila, this proposal aims to dissect hijack strategies TEs adopt during embryonic development. The first strategy is the timely activation of TEs before silencing is fully established. The second is for TEs to concentrate their activity near cells to increase the chance of passage to the next generation. To further reveal the full mutational impacts of TEs, we will artificially induce TE activity across multiple generations. Large numbers of new TE insertions will enable us to determine the deleterious impact on epigenetic state, gene regulation, and nuclear organization. Elucidating how TEs “cheat” and disrupt the genome will critically inform preventative and treatment plans for diseases caused by genome instability.

Effects of Cannabis on Stress Response: A Double-Blind Randomized Placebo-Controlled Crossover Trial (NCT05261321)

Approximately 50% of Canadians have used cannabis at least once in their lifetime. The vast majority of cannabis users report using cannabis to reduce stress. While there is some evidence to suggest that cannabis may impact the body’s stress regulation systems via the endocannabinoid system, there remains limited experimental evidence that cannabis does indeed reduce acute stress and the effects of cannabis on the brain during acute stress are not well understood. The current randomized control trial aims to examine the effects of oral cannabis (THC and THC+CBD vs placebo) on acute stress response in humans using a combination of functional Magnetic Resonance Imaging, psychoneuroimmunological assays, and subjective assessments. With stress dysregulation being a major risk factor for a range of physical and mental health disorders, and with stress reduction being a primary reason for cannabis use, the effects of cannabis on stress regulation may have significant public health implications.  

This study is occurring at the University of British Columbia. The study team includes Karina Thiessen (awardee), study qualified investigator Dr. Christian Schütz and co-investigators Dr. Alasdair Barr, Dr. Clare Beasley, and Reza Rafizadeh. Funding support includes research grant and student stipend funding from the Canadian Centre on Substance Use and Addiction, BC Mental Health and Substance Use Services, Brain Canada, and the Michael Smith Health Research BC-CIHR CANTRAIN Clinical Trials Training Platform Doctoral Studentship. 

End of Award Update – December 2024

 

Results

Once the study is complete, we hope that the results will provide important insights into how cannabis might be impacting people’s cognition and stress regulation system. By analyzing a combination of functional Magnetic Resonance Imaging (fMRI), saliva sample analysis, and participant reports, we will be able to assess how cannabis affects different brain regions, acute inflammatory responses, and people’s subjective experiences while experiencing an acute stressor under the influence of cannabis. Because so many people use cannabis, including for stress reduction, we are excited to look at the potential neuropharmacological effects of cannabis on stress in humans.  

 

Impact & Potential Influence

About half of Canadians over the age of 12 have tried cannabis. Many people report using cannabis to manage their mental health symptoms, including stress and anxiety. There is also interest in medical and research settings in the effects of cannabis on stress response, whether it be a positive or negative effect. However, there is not very much causal evidence of the effects of cannabis on stress in humans, and we hope that this study can contribute to the currently limited body of evidence on this topic to better inform people’s decision-making around cannabis use.  

 

Further, there have been substantial changes to cannabis research regulations in Canada in recent years. Our federal laws and policies have regulations around the study design, including eligibility criteria and cannabis products that can be used. This study is one of the first studies to be under the current regulatory system. By assessing the feasibility of the study, such as through our recruitment rates, and through study monitoring, we can pave the way for future experimental cannabis research under the relatively new regulatory system.  

 

Beyond the outcomes of this study, my experience in developing a clinical trial has led to some exciting opportunities that will have some broader impacts on health research. Last year, I had the opportunity to speak on cannabis research regulations on Clinical Trial BC’s AskUs webinar series with Dr. Jean Smart. I thoroughly enjoyed being a guest speaker and I hope that this helped any viewers that are involved in cannabis research to better navigate the regulatory space. Another result of my experience with cannabis research is my work with the UBC MATRIX-N (Multidisciplinary Alliance for Translational Research and Innovation in Neuropsychiatry) and the Canadian Academy of Addiction Psychiatry to enhance local and national capacity for clinical trials and translational research for psychiatric disorders.

 

Next Steps

Once data collection and analysis are complete, our knowledge mobilization activities will take a multi-pronged approach to target a range of knowledge users, including other researchers, clinical professionals, government, and public audiences. As is standard for clinical trials, we will submit a final report to Health Canada and plan to continue to attend Health Canada’s consultation meetings on cannabis research policies. Academic and clinical knowledge translation activities include presentations, workshops, and publication in a peer-reviewed scientific journal. We also plan to use findings from this study to inform the design and direction of future cannabis research. 

 

Useful Links

To learn about projects happening in the B.R.A.I.N. Lab, including this study, visit https://brainlab.med.ubc.ca/.  

Canadian Primary Care Research Network – Phase 2

Health Research BC is providing match funds for the BC Primary Health Care Research Network (BC-PHCRN) Phase 2, the BC node of the Canadian Primary Care Research Network (CPCRN), which is funded by the Canadian Institutes of Health Research’s (CIHR) Strategy for Patient-Oriented Research (SPOR) Primary Care Network. 

 

The goal of the BC-PHCRN is to encourage, facilitate, and support collaborations between government, health authorities, health professionals, patients and researchers. The CPCRN and BC-PHCRN objectives include:

  • Expand PBRLNs by recruiting new primary care practices and providers  to include more electronic medical record data for research purposes,
  • Participate in CPCRN research and quality improvement projects and other projects as well,
  • Support development of a pan-Canadian primary health care information system that integrates electronic medical records with Patient Reported Experience Measures (PREMs) and Patient Reported Outcome Measures (PROMs),
  • build a network of primary care researchers, patient partners, clinicians, decision-makers and trainees to facilitate communications and knowledge mobilization, and
  • build capacity in patient-oriented primary care research in BC and beyond.

In British Columbia, the network is participating in both funded and non-funded research projects. Funded projects include:

  • OECD PaRIS to measure the outcomes and experiences of health care that matter most to people,
  • SPIDER to deprescribe potentially inappropriate prescriptions among elderly living with chronic conditions, and
  • Choosing Wisely antibiotic prescribing to provide CPCSSN providers with portrait detailing their antibiotic prescribing for respiratory tract infections.

Non-funded projects include:

  • Evaluation of ICD-11 and ICPC-3 codes to build evidence for updating Canada’s Disease Classification Systems in primary care, and
  • Team-based care to understand functioning of teams in primary care.

The Nominated Principal Investigator of BC-PHCRN is Dr. Rubee Dev. Dr. Dev is an Assistant Professor in the UBC School of Nursing & Associate Faculty in the Centre for Health Services and Policy Research, University of British Columbia, with research foci in global health and primary health care nursing. Dr. Dev leads the BC PHCRN along with Dr. Nathaniel Hawkins who is also Director of Research and Associate Professor at the UBC Division of Cardiology.