A spinal cord injury diagnosis is life-changing for patients and their families. In acute care, beyond surgery and cardiovascular support, clinicians have limited tools to improve outcomes. Current guidelines recommend increasing blood pressure during the first three to seven days post-injury to enhance spinal cord blood flow. However, it remains unclear whether this approach improves oxygen delivery to the injured spinal cord or risks further damage at the injury site. To address this, we have developed a near-infrared spectroscopy (NIRS) sensor to measure oxygenation and blood flow to the injured spinal cord in real time. Implanted during spinal surgery, the sensor emits near-infrared light into the spinal cord, assessing oxygen delivery based on light absorption. This BC-based study, conducted at Vancouver General Hospital under the leadership of principal investigator Dr. Brian Kwon, aims to recruit six patients with acute spinal cord injuries undergoing surgical repair. The sensor will be implanted during surgery, remain in place for up to seven days post-injury, and then be removed. Our primary objectives are to evaluate the safety, feasibility, and effectiveness of this novel monitoring approach in a clinical setting. Ultimately, our goal is to provide clinicians with real-time information about spinal cord oxygenation and blood flow, enabling personalized care to improve patient outcomes.
Research Location: Univerity of British Columbia
Developing a multiplex serology assay for the detection of highly pathogenic influenza
Since 2021, North America has experienced devastating outbreaks of Highly Pathogenic Avian Influenza virus (HPAIV) driven by HPAIV H5N1 clade 2.3.4.4b. Recently, it has spilled over into dairy cattle in the USA, raising concerns about its adaptation to mammals and potential human spread. Wild birds are the natural carriers of avian influenza viruses (AIV), but H5N1 can also infect wild mammals. Current HPAIV surveillance programs sample dead wildlife and use molecular methods that only detect active infection, underestimating the true number and distribution of infected animals. Serological tools measure antibodies from previous exposure and not active infection. However, current serology assays are not specific for HPAIV H5N1, can only be used in a limited number of species, and/or are too complex for large-scale implementation. To address this challenge, the BC based leadership team (Dr. Agatha Jassem at UBC/BC Centre for Disease Control and Dr. Chelsea Himsworth at BC Ministry of Agriculture) will design a new assay to detect antibodies specific for AIV. The test will detect multiple subtypes in one sample and can be used on different animal species with confirmatory testing done at the Canadian Food Inspection Agency (Dr. Yohannes Berhane) and cross-validation at Public Health Ontario (Drs. Maan Hasso and Vanessa Tran). This research will generate a standardized test crucial for nationwide comparative analyses. Its species independent nature allows for easy use in domestic animals and humans as needed, providing crucial insights into antibody reactivity, cross-reactivity, and infection reservoirs.
Harmonized biomarkers to measure response to ustekinumab in type 1 diabetes
In type 1 diabetes (T1D), immune cells called T cells destroy insulin-producing beta cells, causing lifelong insulin dependence. Blood glucose control remains imperfect despite insulin injections, leading to an increased risk of complications from chronic hyperglycemia and a shortened lifespan. An antibody known as ustekinumab has been found to inhibit inflammation and can be safely administered to young adults with recent-onset T1D.
Our clinical trial, UST1D2, aims to test ustekinumab’s ability to halt progression of recent-onset T1D in young adults using patient samples collected from the BC Diabetes Clinic and the Mount Sinai Hospital in Toronto. This drug was previously demonstrated to decrease inflammatory proteins thought to damage beta cells, IFN-γ and IL- 17. Changes in inflammatory proteins and in the balance of immunoregulatory versus inflammatory cells may elucidate ustekinumab’s mechanism of action and biomarkers of response to therapy. The mechanistic studies will be conducted in Dr. Megan Levings’s lab at BC Children’s Hospital Research Institute, with Dana Lao, a Master of Science student at the University of British Columbia, acting as the lead trainee for the project.
To comprehensively evaluate mechanism and response biomarkers, the mechanistic studies carried out are harmonized between UST1D2 and another study called USTEKID that tests ustekinumab in children. This increases sample size, allowing for faster determination of treatment effectiveness. Our project contributes toward evaluating ustekinumab as a treatment for T1D patients and represents a new collaborative model to evaluate outcomes from international, multi-centre clinical trials.
This project is supported by the CANTRAIN-CTTP & Michael Smith Health Research BC 2024 Masters’ Studentship co-funded by the Canadian Consortium of Clinical Trial Training Platform (CANTRAIN) and Michael Smith Health Research BC.
The effects of diesel exhaust air pollution exposure on inhaled corticosteroid treatment in late-onset asthmatic patients
With the advancement of global urbanization, the prevalence of air pollution continues to become of increasing concern for individuals worldwide. Asthma is a respiratory disease characterized by narrowing of the airways, leading to difficulty breathing. To manage symptoms, inhaled corticosteroids (ICS) are prescribed to reduce symptoms. However, studies have shown that exposure to air pollution, particularly in the form of diesel exhaust (DE), reduces the effectiveness of ICS, resulting in overprescription of the drug that can cause side-effects. To understand how DE exposure confers with ICS efficacy, I, Michael Yoon, alongside members of the Air Pollution Exposure Lab (APEL; https://www.pollutionlab.com/) will be conducting a controlled human exposure study where asthmatic participants will be exposed to regulated levels of DE. Through this study, we will be able to understand the biological changes associated with reduced ICS effectiveness for improved treatment.
This BC-based project has been funded by the Canadian Consortium of Clinical Trial Training Platform-Clinical Trials Training Program (CANTRAIN-CTTP) & Michael Smith Health Research BC Doctoral Studentship 2024 Award Program as well as the Canadian Institutes of Health Research (CIHR) organization. The primary goal of the proposed project is to determine how DE interferes with ICS treatment, where our aim is to translate our findings to improve current health policies regarding ICS administration, resulting in safer usage.
Targeting Lipid Nanoparticles (LNPs) to Antigen-Presenting Cells Through Siglecs to Improve Vaccine Response and Durability
Vaccines can provide both short-term and long-term protection from deadly pathogens. This was demonstrated during the COVID19 pandemic, which saw the rapid production of lipid nanoparticle (LNP) mRNA vaccines. LNP-based mRNA vaccines are easy to produce in large quantities with a great degree of quality control on a relatively short time scale. These vaccines generally rely on passive uptake by antigen-presenting cells (APCs) to initiate priming of B and T cells, which are both required for a robust humoral (antibody) response. While LNP-based mRNA vaccines induce robust antibody responses, there are still questions about the durability of the immunological memory induced by these vaccines. Such a factor is a critical feature of a vaccine that keeps people protected over the course of years to decades. In contrast, many pathogens and viruses are actively taken up by glycan-binding proteins expressed on our immune cells that recognize host-derived glycans. Therefore, passive uptake of LNP-based mRNA vaccines misses out on this natural route of uptake. We hypothesize that targeting LNPs to immune cells, particularly APCs, may help improve the efficacy of vaccines. To do so, we will target sialic acid binding immunoglobulin-type lectins (Siglecs) that are carbohydrate-binding cell surface receptors found on immune cells. Siglecs are an ideal target for delivery because of their endocytic properties, their selective expression on immune cell subsets, and the availability of high affinity and selective glycan ligands for targeting. Here, we propose three aims to test this main hypothesis. In Aim 1, we will synthesize next-generation carbohydrate-based Siglec ligands for improved targeting. In Aim 2, we will formulate LNPs with ligands targeting Siglec-1, Siglec-3 (CD33), or Siglec-7/E to direct LNPs to macrophages, monocytes, and dendritic cells, respectively. Successful targeting will result in enhanced uptake of LNPs and increased expression of encapsulated mRNA in the cell type of interest. In Aim 3, we will examine the ability of Siglec-targeted LNPs to induce robust primary antibody responses directed at the spike protein of SARS-CoV-2, as well as memory responses following a boost. In summary, this project will develop Siglec-targeted LNPs to enhance immune responses as an improved vaccination approach.
GlycoCaged N-heterocycles for improved treatment of inflammatory bowel diseases
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is increasing in Canada and world-wide. IBD is painful and debilitating. In addition to significantly impacting quality-of-life, IBD is a major economic burden on the Canadian health care system. Current IBD treatment uses anti-inflammatory drugs, which can cause harmful off-target side effects. Therefore, the holy grail is to precisely target IBD drugs to sites of inflammation to improve patient outcomes.
Our team has developed a new strategy to release drugs specifically in the lower gastrointestinal tract, which we call GlycoCage Technology. This approach combines the power of synthetic carbohydrate chemistry with the unique ability of the human gut microbiota to break-down the complex carbohydrates in dietary fiber. GlycoCaged drugs are taken orally and are protected from absorption in the stomach; they are released at the location of disease by specific enzymes made by our gut bacteria.
Previous funding enabled us to do key experiments demonstrating the effectiveness of our GlycoCage technology using a powerful corticosteroid, dexamethasone. We found that we could use lower doses of drugs and eliminate side effects through this approach. In our current project, we will investigate the benefits of GlycoCaging important drug classes that are being used to treat IBD. In the long-run, we aim to establish GlycoCage Technology as a new treatment option to improve current therapies for people with IBD.
Human neuraminidase enzymes as therapeutic targets in skin inflammation
Chronic skin inflammation (CSI) includes two major groups of conditions: psoriasis, and atopic dermatitis (eczema) that, together, affect up to 6% of the population worldwide. Both diseases are characterized by a chronic and non-curable symptom. White blood cells in both diseases produce signalling molecules that trigger local inflammation. Using mouse models, we found that a human enzyme, neuraminidase 1 (NEU1), may play an essential role in inflammation of the skin.
In this project we will investigate the role of enzyme, NEU1, in chronic inflammatory diseases of the skin. We will investigate the mechanism of inflammation in skin diseases like psoriasis and the role of NEU1 using genetic knock-outs. Using previously developed inhibitors of NEU1, we will test if pharmacological strategies could be used as therapeutics. To learn more about the mechanism of skin inflammation in humans, we will use an in vitro model of human skin to examine the role of the NEU1 enzyme in inflammation. These studies will expand our understanding of the role of glycosylation in mechanisms relevant for in psoriasis and atopic dermatitis and could lead to new clinical strategies for these diseases.
Impact of social determinants of mental health on child and parent risk, resilience and support access in the COVID-19 era: A nested mixed-methods study of short and long-term outcomes
This award is co-funded by Health Research BC, through CIHR’s Operating Grant: Understanding and mitigating the impacts of the COVID-19 pandemic on children, youth and families in Canada.
Project co-leads include Evelyn Stewart MD and Hasina Samji PhD, who brought together their extensive collaborative networks. Dr. Stewart is a UBC professor, child and adolescent psychiatrist and Director of Research for Child and Adolescent Psychiatry, BCCH. Dr. Samji is an epidemiologist, SFU assistant professor and senior scientist at BCCDC.
Between November 2020 and July 2021, the group collected baseline data for the Personal Impacts of COVID-19 Survey (PICS), a Canadian study identifying vulnerability factors to poor mental health related to preexisting medical and living conditions, sex/gender minorities and poverty. Based on our PICS baseline findings, which includes 3,351 Canadians, rates of several COVID-era mental illnesses were several-fold higher than expected; and one quarter of parents reported needing but not receiving mental health support.
Our mixed-methods study will build upon PICS findings by re-contacting participants to better understand their pandemic-era mental health service access, future preferences and the role of social risk and resilience factors. It will also identify those with persisting, resolving and newly emerging mental illness during the COVID-19 recovery phase. In this way, our study will provide a current, comprehensive perspective on families’ experience of the COVID-19 pandemic and how services providers, community organizations and policymakers can best serve child and parent populations at highest risk for ongoing mental health impacts.
End of Award Update – July 2024
Results
Only 35% of participants reported accessing mental health supports for their youth throughout the pandemic. 20% reported needing but not receiving support. Most participants attributed their mental health needs to pandemic-related reasons. Those with unmet needs reported mostly needing a publicly funded psychiatrist/psychologist, or a private counsellor/psychologist. Participants also reported needing more mental health support from schools and community mental health teams. For many youths, informal coping strategies were very important, such as relying on friends for emotional support or engaging in hobbies and extracurriculars. These coping strategies were the most impacted by the pandemic and left many youths without both formal supports and informal coping strategies. Overall, these results highlight the amount of Canadian youths who needed but did not receive mental health services.
Impact
Participants will hopefully receive indirect benefits from this project in the form of improved provincial support services and policies regarding youth mental health and well-being during the COVID-19 pandemic recovery. Results from this project have informed the creation of a provincial report that is aimed at providing recommendations and action items for provincial service providers and policymakers who are in positions to make informed decisions and act on the outcomes reported in this project.
Additionally, we have been able to provide families and youths an opportunity to share their experiences and feel heard during a time that was very challenging and isolating. Several of our participants expressed positive therapeutic effects of participating in qualitative research and feeling connected and able to contribute to better outcomes in the future.
Potential Influence
The results and recommendations from this study have been shared widely with provincial healthcare providers, health institutions, patients, provincial decision-makers, and community organizations through posters, presentations, social media, infographics, and a provincial report. We hope that through wide dissemination to these different groups, the results of this project can contribute to the greater discussions on how to support BC resident’s mental health during the pandemic recovery phase. Our recommendations have already been incorporated into the ‘Improving Youth Mental Health and Well-Being During the COVID-19 Recovery Phase in BC Report’ that was organized and compiled through the combined efforts of the BC Children’s Hospital, The University of British Columbia, and Simon Fraser University. The purpose of this report was to identify strategies to support youth mental health and well-being during the pandemic recovery period. Findings from this project were presented at deliberative dialogue events to attendees that included partners from the education, health, community, and nonprofit sectors, alongside youth and families. These findings contributed to the report’s objective by examining the mental health impacts of the COVID-19 pandemic on youth, identifying which groups of youth have been disproportionately impacted, and what modifiable factors and coping strategies have helped to buffer the effects of the pandemic. This report presented recommendations and key action steps to hopefully guide youth mental health partners in the province to focus on recovering from the societal and mental health impacts of the pandemic.
Next Steps
We currently have two manuscripts in submission that we will continue to pursue for publication. This project has already provided opportunities for research trainees and will continue to provide opportunities for future trainees to conduct projects, particularly those examining how best to mitigate risk factors and support vulnerable identities that were most impacted during the pandemic.
Notably, we continue to collect longitudinal data through periodic survey follow-ups, which allows us to continue to track the long-term outcomes of COVID-19 on Canadian wellbeing and mental health and will support future analyses and manuscripts.
Open MRI for assessing joint biomechanics – applications for osteoarthritis
Hip osteoarthritis is prevalent, disabling and costly to individuals and the healthcare system. Symptomatic hip osteoarthritis affects 4.2 percent of people over 50, and radiographic degenerative changes are seen in almost 20 percent of the same population. In many patients, total hip arthroplasty is used to relieve pain and improve function. Though effective in improving a patient’s quality of life, joint replacements will eventually fail and require revision surgeries that have a higher complication rate and less predictable results. Better strategies to delay or stop the progression of osteoarthritis are needed, which can only be created with a clearer understanding of the disease’s etiology.
While there is strong evidence that structural changes around the hip are major etiological factors in the development of osteoarthritis, it is not clear how to protect hips from the disease. Anatomical abnormalities such as cam-type femoroacetabular impingement (a deformity of the hip bones) may account for 90 percent of hip osteoarthritis cases. However, it is not clear why only some people with these deformities get hip osteoarthritis. It is widely assumed that the relationships between activity and deformity size and their effect on joint mechanics are critical. Investigating these relationships has not been possible to date because there have been few well-validated methods for assessing impingement directly in vivo. This project will answer two research questions:
- Which activities lead to direct cam impingement at the hip in patients with FAI deformities?
- How is this impingement influenced by deformity size?
To answer these questions, we will use gait analysis to measure hip movements and mechanics in symptomatic and healthy subjects for a range of activities associated with hip pain. These measurements will be used to develop subject-specific numerical models predicting direct impingement for each participant. Model predictions of direct impingement will be validated by scanning participants using an established protocol in UBC’s upright open MRI scanner.
We have developed a knowledge translation strategy for this project with the Arthritis Patient Advisory Board; they will post the project summary on their website as well as profile the research findings on social media. Results will be published in both clinically- and research-oriented journals and at conferences for both clinicians and scientists.