Coxsackie virus B (CVB) is the number one cause of viral heart inflammation leading to heart failure and sudden death in ~20 percent of infected children and young adults. In most people, CVB infection causes mild symptoms. However, individuals with underdeveloped and/or compromised immune systems are at increased risk of severe disease. Normally, our healthy immune system acts as a first line of defense against viruses, but excessive and sustained activation of our immune system can be harmful, leading to chronic inflammation and injuries to the heart. The objective of my project is to study how CVB hijacks a novel immune pathway called cGAS-STING, to trigger harmful inflammation in the heart. Our knowledge gap is that we do not completely understand how CVB hijacks the cGAS-STING immune pathway and whether blocking this pathway with drugs can protect the heart. To accomplish this goal, we will precisely identify which cells and immune pathways are responsible for harmful inflammation of the heart. Findings from this study have the potential to open new therapeutic avenues to combat existing and emerging viral threats.
Award Partner: St. Paul's Foundation
Evaluating the use of prescription psychostimulants for the treatment of methamphetamine use disorder
Crystal meth is a powerful stimulant that is increasingly implicated in the ongoing overdose crisis in BC. Despite steadily increasing rates of crystal meth detection in overdose deaths, little is understood about the specific role that it may be playing in the overdose crisis, and treatment options for those suffering from crystal meth use disorder (MUD) are limited.
One class of medications that has previously shown some promise in the treatment of MUD are prescription stimulants such as those used to treat ADHD. While research in this area remains inconclusive, there is some suggestion that these medications may play a helpful role in the treatment of MUD, especially among patients with an overlapping diagnosis of opioid use disorder.
This proposal will employ a variety of research methodologies to explore two related questions: (1) Can we identify patients who use crystal meth and opioids that are at particularly high risk of overdose, and (2) Are prescription stimulants a helpful tool in the treatment of MUD in a population of patients who use opioids? These results will have significant implications for both healthcare providers and those suffering from MUD, at a time where new tools are sorely needed.
Understanding the link between lung genomics, transcriptomics, and sex differences in COPD
Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease that causes respiratory symptoms such as shortness of breath and is the fourth leading cause of death worldwide. While COPD affects both males and females, females, in general, have worse symptoms and more COPD complications compared to males. We still do not have a good understanding as to why COPD behaves differently in females versus males. COPD was thought to mainly affect elderly males who were cigarette smokers; thus, most of the research have focused on males rather than females. To shrink this gap in knowledge, it is necessary to include females in biomedical and clinical studies and investigate the biological reasons behind why sex might affect how COPD develops. We hypothesise that some of the genes associated with COPD have different effects on males and females. In this project we will use a patient’s genetic code and how their genes behave to determine sex-specific signatures in their lungs and airways, and then measure how these signatures can predict the development of future COPD. This project can potentially contribute to the improvement of COPD treatment (particularly in females) and to identify new therapeutic targets for COPD.
Ventilation heterogeneity in asthma, COPD and asthma-COPD overlap: oscillometry and pulmonary MRI
Airways disease is a hallmark finding in both asthma and chronic obstructive pulmonary disease (COPD). Although tobacco cigarette smoking is the largest known cause of COPD, recent studies have revealed that 10% of patients with life-long asthma may develop COPD later in life without ever smoking. The mechanisms underlying asthma transition to COPD are unknown. To better understand this transition, this proposal will use 129Xe magnetic resonance imaging (MRI), computed tomography (CT) imaging and oscillometry to measure airway abnormalities in patients with asthma, COPD, and asthma-COPD overlap. These measurements will provide a better understanding of airway abnormalities that contribute to development of COPD in these patients with asthma. COPD is the most common cause of hospital admission in Canada and treatment costs in BC alone are estimated to be over $600M/year. The results generated from this proposal may identify new ways to treat COPD or halt its development in patient with asthma, contributing to reduced hospital admissions and costs related to COPD.
End of Award Update – March 2024
Results
With the emergence of long COVID, we pivoted our novel lung imaging methods to investigate the lungs of people who experienced COVID-19 infection with persisting, long term symptoms over 1-year after infection. In collaboration with colleagues at the University of Kansas Medical Center and Duke University, we created a multi-centre dataset of patients with long COVID to better understand how long COVID may differ across different patients. We used xenon gas magnetic resonance imaging (MRI) to measure how effectively the lungs of patients with long COVID were performing gas exchange (the main function of the lungs). Our results showed that there are 4 different sub-types of long COVID that have different lung abnormalities. We anticipate that the xenon MRI results can be used to help determine appropriate treatment for patients experiencing long COVID.
Impact
In our centre, the xenon MRI results have been used to help determine appropriate for different patients with long COVID. Our results uncover the lung-specific abnormalities that are related to long COVID.
Potential Influence
We anticipate these results will help to better understand and classify patients with long COVID, towards appropriate treatment and alleviating patient symptoms.
Next Steps
We are using similar xenon MRI methods to investigate other forms of lung exposures including cigarette smoking, cannabis smoking, and vaping.
Useful Links
https://erj.ersjournals.com/content/early/2024/02/02/13993003.02301-2023
Connecting clinical research and economic evaluation by mapping lung function to EQ-5D-5L in patients with interstitial lung disease
Interstitial lung disease (ILD) is a group of diseases that cause inflammation and scarring of the lungs. It is important to identify ways to improve quality of life (QoL) for patients living with this chronic condition. This research will explore how QoL changes over time in ILD and identify factors that can potentially be modified to improve QoL.
Mycophenolate mofetil (MMF) and azathioprine (AZA) are two common medications used to treat certain ILDs and improve QoL. Despite MMF being better tolerated, only AZA is initially covered by PharmaCare in BC. This research will determine whether MMF is more cost-effective than AZA and could inform drug reimbursement policies.
Economic evaluations are used by funding agencies in Canada to determine whether a drug should be funded or not. However, economic evaluations for ILD drugs are limited because clinical trials do not provide the required information. This research will create an algorithm that allows economic evaluations to be completed even when these required data are not available. These economic evaluations can then be used to guide decisions on funding effective treatments in ILD.
Investigating women’s socio-structural risk environment of overdose
British Columbia, Canada, continues to grapple with an overdose epidemic. Substantial gaps remain in the implementation and scale up of overdose prevention strategies, including attention to gender equity. Little has been said regarding how marginalized women (trans inclusive) are impacted by the crisis, or how they might be differently navigating overdose risk environments or access to life-saving health services.
The ultimate goal is to generate new evidence to reduce overdose-related harms among women who use drugs and increase the responsiveness of existing and emerging overdose interventions to gender inequities. The objectives of this research program are to:
- Identify how women’s overdose risk is shaped by evolving individual, social, structural, and environmental factors;
- Investigate factors that create barriers to (or that facilitate) women’s engagement with existing, novel and emerging overdose prevention interventions; and
- Document perspectives, experiences, and impact of women who use drugs working in overdose-related interventions to inform how best to optimize their engagement in ongoing and future initiatives.
The effects of 60% oxygen during exercise training in patients with fibrotic interstitial lung disease
Breathing discomfort is common in patients with interstitial lung disease (ILD) and often results in an inability to perform physical activity, leading to a poor quality of life. Exercise training can reduce breathing discomfort and enable ILD patients to perform physical activity. However, severe breathing discomfort makes it challenging for these patients to withstand the amount of training they need to get the most benefit. A recent study showed that ILD patients breathing supplemental oxygen had less breathing discomfort and were able to exercise for longer compared to breathing room air. Another study showed that breathing supplemental oxygen was safe for patients with ILD for a single exercise session. However, we still do not know if these findings can be applied to a long-term exercise program.
Therefore, the purpose of this study is to determine if using a higher amount of oxygen during a rehabilitation program is a safe intervention that translates to greater benefits from training compared to the same regimen without the additional oxygen. We are also interested in examining if higher intensity training sessions with added oxygen affects every day physical activity levels.
Structural valve degeneration in bioprosthetic heart valves
Bioprosthetic heart valves (BPHVs), valves made of biologic tissues rather than synthetic materials, have revolutionized the treatment of heart valve disease, which constitutes a significant health and economic burden in BC, Canada and around the world. BPHVs serve as an alternative to mechanical valves, which require lifelong treatment to prevent clotting and therefore lead to an increased risk of bleeding.
With the development of new transcatheter methods for delivery of BPHVs, they now represent the overwhelming majority of valves. Despite these successes, the long-term durability of BPHVs is not well established and remains a concerning potential limitation.
Dr. Sellers’ research will look to determine how BPHVs degenerate and potential strategies to assess this in patients. This will include using a combination of analysis of dysfunctional valves and novel imaging approaches using computed tomography (CT) imaging.
The results of this research will help determine the long-term durability of BPHVs and improve decision-making for patients with heart valve disease.
Optimizing care for opioid use disorder in British Columbia
British Columbia is facing an unprecedented and escalating opioid crisis, underscoring the urgent need for innovative science-driven solutions. There is critical implementation gap of evidence-based care for opioid use disorder (OUD), this research will seek to narrow this gap.
First, Dr. Socias will seek to advance the implementation of evidence-base treatments for OUD, by leading a series of ongoing and planned clinical trials evaluating innovative and promising models of care (e.g. take-home strategies) and alternate treatment options (e.g. slow-release oral morphine).
Second, leveraging vast data from two long-standing cohort studies of over 3,000 people who use drugs, she will apply innovative quality metrics (i.e., cascade of care framework) to evaluate the impacts of addiction health system implementation efforts in BC over time. Identifying individual-, social- and structural-level facilitators and barriers to uptake and effectiveness of novel interventions, as well as to how these new addiction programs may impact health care access and outcomes of OUD care and related comorbidities (e.g. HIV, hepatitis C) will be key to informing efforts to improve the delivery of addiction care in BC.
End of Award Update – April 2024
Results
Findings from the OPTIMA trial showed that more flexible approaches to opioid use disorder care are similarly effective than more traditional approaches requiring people to go to the pharmacy every day. This has important clinical and policy implications as there is substantial evidence, including from my own research, that rigid models of care are one of the main barriers to retention in treatment, and that discontinuation from treatment increase the risk of overdose and death. We are now evaluating the effectiveness of novel pharmacotherapies in real-world settings.
Impact
Findings from my research have informed clinical guidelines, and policy decisions (re-introduction of methadone formulation in the OAT program in BC).
Potential Influence
I expect that findings from my research evaluating slow-release morphine will have implications to better understand its benefits and risks in the continuum of care of opioid use disorder.
Next Steps
I will continue with research to close the implementation gap in substance use care, including opioid use disorder, but also using some of the learnings to address alcohol use, which has a substantial burden of disease.
Opioid addiction research program to improve prescribing practices and reduce overdose
Canada is amid an opioid crisis, with six or seven deaths a day due to opioid overdose. Prescription opioid misuse can also transition to illicit opiate and intravenous drug use, substantially increasing the risk for overdose and blood-borne infections. Rates of overdose death due to counterfeit fentanyl have also risen and represent a growing crisis in most regions in Canada, with British Columbia (BC) being particularly hard hit. Half of the 800 anticipated overdose deaths for 2016 in BC are expected to involve fentanyl.
Dr. Fairbairn’s research will:
- Address the effectiveness of a randomized controlled trial to evaluate a designated opioid prescriber intervention using BC’s centralized prescription network to reduce inappropriate opioid dispensation and overdose risk.
- Inform overdose prevention strategies by characterizing the inter-relationships between medication prescribing patterns and patterns of illicit drug use.
- Evaluate the longitudinal impacts of new overdose prevention initiatives and addiction treatment guidelines on overdose outcomes.
This research directly responds to BC’s recent declaration of a public health emergency, Health Canada’s urgent call to develop strategies to tackle the overdose epidemic, and the global challenge of prescription opioid abuse by generating evidence for safer prescribing practices and informing and broadening the evidence base for the treatment of opioid addiction.