2022 MMSF Operating Grant Recipients

Defining the role of the intestinal microbiome in the regulation of dietary fibre-associated inflammation in Inflammatory Bowel Disease patients

Dr. Heather Armstrong, MSc, PhD

Contributing partner: Children's Hospital Research Institute of Manitoba

Affiliations: University of Manitoba, Children's Hospital Research Institute of Manitoba

Humans do not digest dietary fibres – instead, they are broken down (fermented) by gut microbes (bacteria and yeast), typically promoting health. However, inflammatory bowel disease (IBD) patients can experience worsening symptoms after eating fibres for unknown reasons. Our previous work assessed several different fibres (e.g., β-fructans) and showed that whole, unfermented β-fructans can promote gut damage in specific IBD patients. This negative response was the result of a loss of patient gut microbe’s ability to break down β-fructan, more common in patients with active disease.

We believe that promoting growth of healthy gut microbes and their ability to ferment β-fructans will inhibit fibre-associated progression of IBD.

In this study we aim to:

(1) Identify how the human cells are involved in inflammation and cancer-promoting response to dietary β-fructans using cells in the lab and IBD patient biopsies cultured in the laboratory

(2) Uncover the precise role of the previously identified microbial factors in regulating host response to associated β-fructans by stimulating and/or inhibiting these predictive microbial factors and measuring outcomes

(3) Validate biomarkers or response to β-fructans in our readily available clinical biological specimens (stool, serum, biopsies).

Use of β-fructans is largely touted to provide benefits to healthy individuals and some persons with IBD in remission. However, our work is the first to demonstrate some patients experience negative effects of fibres. Understanding how this happens would allow us to develop more safe, readily available, and affordable dietary interventions and microbe-altering therapeutics to reduce disease burden in patients with dietary-fibre sensitivities.

The impact of inflammatory bowel disease

Inflammatory bowel disease consists of two diseases – Crohn's disease and ulcerative colitis. Symptoms include abdominal pain and cramping, diarrhea, bloody stool, rectal bleeding and nausea and vomiting.

Canada has among the highest incidence rates of Crohn's and colitis in the world – 300,000 people across the country, according to Crohn’s and Colitis Canada. The direct annual cost of caring for Canadians with IBD is estimated at $1.28 billion.

The prevalence of Crohn’s and colitis in Canadian children has risen more than 50 per cent in the last 10 years. Children with Crohn’s or colitis have different disease complications, respond differently to treatments, and are at a greater risk of side effects of medication as compared to adults.

Research shows that the probability of a person developing colorectal cancer after having Crohn’s or colitis for 10 years is two per cent. After that, risk continues to rise and is as high as 30 per cent after 30 years. In other words, as age increases, so does risk.

Of particular interest, dietary interventions, such as Exclusive Enteral Nutrition (EEN), have been successful as an initial therapeutic strategy specifically for the treatment of pediatric IBD; even more successful than steroid therapies. These data suggest that there is specifically strong clinical potential for more stringent dietary intervention and guidelines for children suffering from IBD.

Accelerated Remote Consultation Tele-POCUS in Cardiopulmonary Assessment (ARCTICA)

Dr. Tomislav Jelic, MD, FRCPC

Affiliation: University of Manitoba

Point-of-Care ultrasound (POCUS) is the use of ultrasound imaging devices at the bedside of patients. It provides a quick and accurate picture of the heart and lungs. Common clinical use includes the assessment of shortness of breath to determine whether the cause is heart- or lung-related.

While POCUS devices are now widely available, not all providers have the training and expertise to conduct POCUS. The Goal of ARCTICA is to create a Tele-POCUS training program and consultation service for providers who currently do not use POCUS in their practice.

The program will begin at St. Boniface and Health Sciences Centre, where physicians will be taught using a novel technologic platform incorporating augmented reality to learn new POCUS skills. To continue their Accelerated Remote Consultation Tele-POCUS in Cardiopulmonary Assessment (ARCTICA) Dr. Tomislav Jelic, MD, FRCPC learning and ensure they are making accurate diagnoses, experts in heart and lung ultrasound will give live video consultations to these physicians through a secure video call app. These video consultations will allow the heart and lung ultrasound experts to guide physicians as they diagnose patients directly at the bedside.

The exam image quality and the ultrasound skills of the physicians will be graded before and after expert advice is given. Once tele-POCUS workflow has been established, these sites will become expert “hub” sites for geographically remote or rural “spoke” sites in Manitoba. This has immense potential to improve more targeted and appropriate care if a diagnosis is made using POCUS under expert guidance.

Sibling Outcomes among probands with Autism Spectrum Disorder: A Population-wide Longitudinal Cohort Study

Dr. Cara Katz, MD, FRCPC

Affiliation: University of Manitoba

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder where people may have difficulty with social communication and interaction as well as restricted and repetitive patterns of behaviour, interests or activities.

On top of its effects on the patient, ASD comes with unique challenges for family members. Getting professional help for these neurodevelopmental disorders can be difficult and there are long wait times. Therefore, the ability to target interventions to whole families or other individuals within a family at risk of poor outcomes is important.

Previous literature has found increased mental disorders in siblings, but other areas of functioning, including physical health, injuries, medication use, and education remain unexplored. Using provincial health data, we will examine the impact over time of a sibling with ASD on the mental and physical health and education outcomes in other siblings. We will gain knowledge on which siblings are at greater risk and therefore identify potential targets for including family and sibling interventions within resource-strained neurodevelopmental programs.

With the onset of many mental disorders in youth, this is a critical time to be able to alter illness trajectories to help prevent onset of negative outcomes. This is the first study to examine the impact of an ASD individual on the educational outcomes of siblings, which can help identify important time points for intervention and an additional avenue for identifying sibling needs outside of the healthcare system.

One-year cognitive and mental health outcomes in hospitalized COVID-19 survivors

Dr. Maia Kredentser, C.Psych

Contributing partner: The Winnipeg Foundation

Affiliation: University of Manitoba

After being hospitalized with COVID-19, many people experience difficulties with their emotions – things like mood, worries/tension, difficulty sleeping. Many also have problems with how their brain works – things like thinking clearly, planning, and paying attention. Their family members may also feel very stressed and overwhelmed.

These difficulties can last many months and make it difficult to get back to normal life. This study will examine in detail these difficulties for patients and their family members one year after the patient was discharged from the hospital. Patients and family members will complete a psychological assessment that includes patients completing tasks that measure how they plan, think, pay attention and organize. Patients and their family members will also answer questions about their emotions and symptoms they may have.

We have information about these patients and family members from the time they were in the hospital one year ago until now, and we will therefore be able to examine how aspects of their illness, emotional and brain functioning are impacting their current symptoms.

Patients and their family members will also be asked about their experiences with COVID-19 illness, being in the hospital, how their recovery has been, and what they think would be helpful to support them in the recovery process. The findings from this study will help us understand what kinds of healthcare, information and support people need after they have been hospitalized with COVID-19. We will share these findings with other researchers and health care providers/organizations caring for people recovering from COVID-19.

Dial Don’t Drive – a Manitoba Acute Coronary Syndrome Network public awareness campaign to reduce patient delays in seeking medical attention for heart attacksand their caregivers

Dr. Shuangbo Liu, MD, FRCPC

Contributing partner: The Winnipeg Foundation

Affiliation: University of Manitoba

The goal of the Manitoba Acute Coronary Syndrome (ACS) Network’s “Dial Don’t Drive” project is to decrease delays for patients with chest pain and potential heart attack to receive medical care. The key message of “Dial Don’t Drive” emphasizes the importance of calling 911 instead of driving oneself to the doctor or the emergency department, and education about the typical and atypical symptoms of a heart attack. This includes not only chest pain, but shortness of breath, excessive sweating, nausea or heartburn.

The Dial Don’t Drive project will harness the power of social media for this mass media campaign through Facebook, Instagram and promotional material.

The elements of this multi-phased social media campaign include:

1. Team STEMI (showcasing health care professionals that a patient may meet when having a heart attack)
2. Patient Voices (describing patient journeys and experiences)
3. Education (focusing on patient education)
4. Ask Me Anything (interactive question and answer)
5. Seasonal (leveraging existing networks to celebrate key dates)

The DDD study objectives are to:

• decrease patient-related delays in seeking care for chest pain syndrome
• increase the proportion of patients calling 911 for chest pain syndromes instead of presenting to the emergency department
• improve clinical outcomes such as death, less heart damage and heart failure.

The effects of the DDD project will be immediate and impactful – leading to patient benefits as well as the improved efficiency and cost-savings for Manitoba’s healthcare system. Since heart attack patients will present sooner and receive appropriate treatment faster, they are less likely to have long-term complications or require complex cardiac care.

Determining the influence of sex and gender on the perception of dyspnoea

Dr. Yannick Molgat-Seon, PhD

Affiliation: University of Winnipeg

Shortness of breath (dyspnoea) is a common, debilitating symptom that affects patients with respiratory disease, but it also occurs in healthy adults during physical exertion. Females report greater levels of dyspnoea during exercise and activities of daily living than males, but it is unclear why. Most research has focused on how biological factors (such as lung size, airway size, and pulmonary function) influence the perception of dyspnoea in males and females; however, these biological factors fail to fully explain sex differences in dyspnoea. Gender, which encompasses several psychological, social and cultural factors, may better explain why females experience dyspnoea more than their male counterparts.

This study seeks to determine the impact of both sex and gender on the perception of dyspnoea in healthy males and females. To accomplish this goal, male and female participants will undergo detailed analysis of gender-related factors, pulmonary function testing, exercise testing, and a series of experimental trials designed to provoke sensations of dyspnoea. Throughout testing, the perception of dyspnoea will be evaluated using validated scales, while the ventilatory, cardiovascular and metabolic responses will be recorded using a cardiopulmonary testing system. We will determine, for the first time, how gender-related factors influence the perception of dyspnoea.

The results of this study will contribute to improving our understanding of causes of dyspnoea and how they may differ in men, women, boys, girls, and gender-diverse individuals. This work is important given that dyspnoea is an independent predictor of mortality, is remarkably common in older adults, and is difficult to treat effectively.

Evaluating the effectiveness of an electronic data collection platform to improve patient response rates in an orthopaedic surgery registry

Dr. Marc Morissette, MSc, PhD

Affiliations: University of Manitoba, Pan Am Clinic Foundation

Increasing patient involvement is becoming standard practice across healthcare in Canada, with the collection of patient-reported outcome measures (PROMs) serving as a common way to enhance patient-physician interactions and measure value of treatment from a patient-perspective.

Traditional PROMs collection involves the distribution of paper forms, resulting in low return rates, increased patient burden and missing data. This suggests that supplemental or alternative methods of PROMs collection are warranted. Interestingly, digital platforms allowing for the collection of electronic PROMs (ePROMs) have been shown to increase patient response rates in an orthopedic setting; however, findings are limited to patients receiving total joint replacements, they involve digital platforms not available in Canada, and they benefit greatly from additional staff (albeit at additional financial costs).

Our research proposal seeks to:

• compare response rates between paper-based PROMs and ePROMs for anterior cruciate ligament reconstruction (ACL-R), rotator cuff repair (RCR), and shoulder stabilization surgery pre-operatively and at three-weeks – with three- and six-month follow-up time points
• assess the impact of staff-facilitated ePROMs data collection.

The results from our study will inform various levels of healthcare, including at the patient/institutional, provincial, and national levels. Various divisions of healthcare are moving towards a patient-centric culture of care to ensure patients remain involved throughout treatment and rehabilitation. Given the lack of uniform PROMs collection prior to and following sports medicine orthopedic surgery, our study will provide novel evidence in support of ePROMs collection for ACL-R, RCR, and shoulder stabilization surgery that can be adopted across Manitoba and Canada.

The impact of attentional focus on postural stability in the aging brain

Dr. Natalie Richer, PhD

Affiliation: University of Winnipeg

Aging is an inevitable outcome of life that, eventually, is accompanied by declines in health and body functionality. One main result of these changes is a loss of balance that leads to an increased rate of falls. Many experiments have attempted to understand age-related changes in postural control. Recent advances in mobile brain imaging introduce a new possibility: to examine the neural control of balance and how it changes with age.

When we stand or walk, our minds usually aren’t idle. We focus our attention on a secondary task, such as a conversation, or we focus on various thoughts. My previous research suggests that what we place our focus on can influence our stability. I found that focusing attention away from the task of standing can improve stability in healthy young and older individuals.

My objective is to examine the effect that attentional focus has on postural control while examining brain activity to gain a better understanding of underlying processes and how they change with advancing age. I will use electroencephalography (EEG) to examine brain activity during quiet standing while changing the focus of attention in young and older adults.

This project will reveal new information about which brain structures contribute to reduced balance performance in older adults. The results will later be used to find ways to improve balance and reduce the risk of falls in this population.

Syndemics of Concern: Sex and Gender, Crystal Meth, HIV and STBBIs in Manitoba

Dr. Zulma Vanessa Rueda, MD, PhD, CRC

Affiliation: University of Manitoba

In Manitoba, injection drug use has been the most common mode of HIV transmission since 2018. Those who inject drugs are more likely to be infected with HIV, syphilis and Hepatitis C, often simultaneously. This is called a “syndemic” (many epidemics at the same time). In addition to HIV and syphilis, there are other 11 infections transmitted by sexual activity or blood products (called STBBIs).

In some people, a convergence of socio-economic factors, mental health concerns, violence and exploitation is driving a syndemic of new HIV and other STBBIs cases – with disproportionate representation of women who inject drugs. These determinants of health and disparities are exacerbated by public health measures. Methamphetamine use is growing in Manitoba and is known to affect access to care and treatment.

It is unknown how biological sex differences and gender intersect with living conditions, including experiences of violence and injection drug use. In this project, we will ask:

• How many people (by sex and gender) living with HIV have other STBBIs before and during COVID-19, and who is most at risk of acquiring other sexually transmitted and bloodborne infections, and why?
• How do sex and gender intersect with other factors to prevent this population from getting proper care and treatment that existed before and during COVID-19?

The explicit understanding of people living with HIV who use methamphetamine can identify unique gaps and resilience factors that can inform better, tailored testing and clinical and program responses.

Rural access and outcomes for Critical Care in Manitoba

Dr. Barret Rush, MD, MPH, FRCPC

Affiliation: University of Manitoba

The care of critically ill people in Intensive Care Units is a large and expensive part of health care. Each year, over two per cent of older Manitobans experience a critical illness.

Twenty per cent of Canadians live in rural areas. Compared to urban residents, they are thought to face additional barriers to obtaining health care and to have worse outcomes from illness. Such problems are likely even greater for those with critical illnesses. But little is actually known about rural versus urban disparities in care of critically ill people.

We will use data at the Manitoba Centre for Health Policy to study how living in rural Manitoba impacts access to care and clinical outcomes for patients with one of two important types of critical illness – COVID-19 pneumonia, and sepsis, which is organ failure due to infection (a common type of critical illness).

We hypothesize that rural residents will have higher rates of hospital admission, but lower rates of ICU admission due to lack of ICU care in rural areas. For patients who make it to the ICU, we anticipate that the rural residents will have higher mortality.

This work is important, because before those who make health care policy decisions can work to remove the disparities, they first need to understand them.

The Role of Adenosine Receptors in Fibrosis

Dr. Robin da Silva, BSc, PhD

Affiliation: University of Manitoba

Fibrosis arises when dying tissues are replaced by connective proteins during tissue repair. The immune system plays an important role in the removal of connective proteins during repair and maintenance of tissues in the body. Malfunction or death of immune cells can result in accumulation of connective proteins that leads to fibrosis. Many diseases, including cancers, diabetes and others involving tissue fibrosis are caused or made worse by either malfunction or death of immune cells. Unfortunately, there are currently no effective treatments for tissue fibrosis. The past few decades have brought great advances to our understanding of the immune system. However, despite these advances, much is still unknown about how immune cells communicate and perform their operations. The goal of this study is to further our understanding of how adenosine receptors are involved in immune cell communication in particular signals that result control the activation and death of immune cells. We will use molecular technique and bioinformatics to discover new pathways through which immune cells communicate and function. The findings from this study will provide new avenues that will allow us to manipulate immune cells to better manage and potentially cure tissue fibrosis.

Elucidating the role of oral microbes and their metabolites in peri-implant health

Dr. Chrysi Stavropoulou, DDS

Affiliation: University of Manitoba

Caused by mouth microbes, gum diseases are very common. They can present around teeth and dental implants, and they result in tooth/implant loss at the final stage.

So far, the cause of gum disease around implants is not fully understood. Also, little is known about the role of mouth bacteria and especially fungi around implants. The immune response could also play a role in the development of these diseases around implants.

Our goal is to identify mouth microbes (bacteria and fungi) that are important in gum heath. We also want to understand how bacteria and fungi talking to each other influence inflammation of the gums around implants. Saliva, dental plaque, and gum fluid will be collected once from people with healthy implants and people with diseased implants.

The plaque samples will be processed to isolate microbial DNA. The saliva samples will be analyzed for microbes’ by-products. Analysis of the gum fluid will show the role of immune response in gum disease around implants. Results from this study could assist in planning individual prevention or treatment options for gum disease around implants.

Autonomic cardiovascular, and respiratory regulation during postural transitions and acute and chronic exercise in females and males living with frailty

Dr. Rodrigo Villar, PhD

Affiliation: University of Manitoba

This research aims to:

1. determine how frailty and sex impact the brain, heart, vessels, and lungs regulation
2. determine how exercise can reverse frailty in older adults.

In study one, participants will perform three postural transitions:

1. sit-to-stand
2. lie-to-stand
3. lie-to-sit

Participants will also perform three identical constant workload walking tests.

The autonomic (brain, e.g., sympathetic and parasympathetic activity), cardiovascular (e.g., heart rate, blood pressure, cardiac output), and respiratory (e.g., oxygen consumption, carbon dioxide output, ventilation) functions will be assessed in females and males with different frailty statuses.

In study two, frail individuals will perform 15 weeks of progressive strength or aerobic training to determine how exercise can reverse frailty and improve autonomic, cardiovascular, and respiratory function.

Homeostatic dysregulation compromises rapid adjustments in the autonomic, cardiovascular, and respiratory regulatory mechanisms affecting maintenance of homeostasis, especially in vulnerable populations (e.g., older adults). The dysregulation exposes them to higher risks of frailty, chronic diseases, and falls.

Frailty is characterized by the degradation of biological and functional reserves to tolerate stressors, resulting in high vulnerability to adverse health outcomes. People living with frailty are under-recognized, under-served, under-appreciated, and poorly understood. This research proposal is critical because it will inform the future development of more robust early frailty risk detection assessments, frailty preventative, and rehabilitative treatment/intervention strategies considering sex differences. Advancements in the fundamental knowledge of the underlying mechanisms regulating autonomic, cardiovascular, and respiratory responses will inform how to promote health, well-being, and quality of life for females and males living with frailty.

Real-world Efficacy and Safety of Dual Antiplatelet Therapy with Ticagrelor as Compared to Clopidogrel

Dr. Evan Wiens, MD, BA, MSc, FRCPC

Affiliation: University of Manitoba

People that suffer a heart attack need emergency treatment to improve blood flow, treat complications and prevent future problems. To prevent future blood clots, patients are prescribed dual antiplatelet therapy. One of those medications is aspirin. The second type is a type of antiplatelet agent called P2Y12 inhibitors.

There are 3 P2Y12 inhibitors: clopidogrel, prasugrel and ticagrelor. Some studies have shown that ticagrelor is “stronger” than clopidogrel and a little better at decreasing complications of blood clots. However, ticagrelor can slightly increase bleeding. Our study aims to determine which type of P2Y12 inhibitors has the lowest risk of blot clots and death.

For our study, we will look at historical health records in Manitoba. We will look at every person who suffered a heart attack and who has been prescribed ticagrelor or clopidogrel and check whether they died or had to go to the hospital because of blood clots. From there, we will see if there are differences in those outcomes between the two types of medications. Patients are not identified to protect their privacy, but we can link records of prescriptions, hospital visits, and emergency department visits to a unique person.

We will share our findings with doctors and patients so we can help improve patient quality of life. Additionally, our findings have the potential to help the healthcare system be more efficient by lowering the number of times people need to go to the hospital or emergency room because of a blood clot event.

Maternal Milk is more than food: Milk contains bioactive components that shape offspring neurodevelopment

Dr. Sanoji Wijenayake, PhD

Affiliation: University of Winnipeg

Maternal obesity is a major public health problem. In the United States, more than 50 per cent of pregnant women are obese at the time of conception; the comparable percentage is 22-24 per cent for Canadian women. This means that a high percentage of infants born in North America are exposed to an overweight and/or obese gestational environment and to maternal over-nutrition during lactation.

Previous research established strong associations between maternal obesity and adverse metabolic conditions (e.g., type II diabetes), alternations in growth and development where obese parents tend to produce obese children, and variations in neurological development (autism spectrum disorders and

increased anxiety-like behaviors) in female and male offspring.

Breastfeeding is proposed as a solution to combat the risks of overweight/obesity in children. However, very little is known about the underlying biological mechanisms that confer this protective effect and how maternal obesity may affect the function of the bioactive compounds in breastmilk, especially the small, fat-coated vesicles known as milk exosomes that carry genetic information from mothers to their offspring.

My main objective is to characterize the role of milk exosomes as a functional regulator of early development and to characterize the cellular underpinnings of milk exosome transfer/localization. Mechanistic insights obtained from this research can be used to improve nutritional benefits of donor and formula feeding in neonates, where milk exosome-based signaling may be absent. Moreover, enrichment of formula with bioengineered milk exosomes could be used to treat a variety of metabolic syndromes and developmental complications that are associated with obesity.