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A new study from Lawson Health Research Institute and the Institute for Clinical Evaluative Sciences (ICES) has cast doubt on the clinical significance of brain deposits of gadolinium (a chemical contrast agent commonly used to enhance MRI imaging).

In 2015, the US Food and Drug Administration raised safety concerns over reports of retained gadolinium in the brain for patients undergoing four or more gadolinium-enhanced MRIs. The FDA launched an inquiry at the time, stating that “it is unknown whether these gadolinium deposits are harmful.” Pending further investigation, the FDA suggested limiting the use of gadolinium-based contrast agents (GBCAs) to circumstances where contrast information is clinically necessary, and to evaluate the need for repetitive GBCA MRIs based on treatment protocols.

Studies since that time have shown deposits of gadolinium may be found long after they are administered. They tend to concentrate in the globus pallidi, a region of the brain that can cause parkinsonian symptoms if it is damaged. Parkinson’s disease is an example of a specific brain disorder that is commonly associated with parkinsonian symptoms.

“Given the concern around possible neurotoxicity of gadolinium, and because these deposits were found in the globus pallidi region of the brain, we wanted to see if people exposed to gadolinium MRIs have higher rates of subsequent parkinsonism,” says Dr. Blayne Welk, the lead author of the study who is an adjunct scientist with ICES Western and Lawson.

To test a possible link between GBCAs and parkinsonism, Welk and his team examined anonymized health care records for 246,557 patients in Ontario over the age of 66 who underwent an initial MRI in a 10-year period between 2003 and 2013. They excluded patients whose initial MRI was of the brain or spinal cord and those with prior parkinsonism or neurosurgery. Comparing patients who were exposed to gadolinium-enhanced MRIs with patients whose MRIs did not include gadolinium enhancement, they looked for differences in rates of future parkinsonism symptoms or treatment.

They found that the rates of parkinsonism for exposed vs non-exposed patients were virtually identical, at 1.2 per cent. These findings indicate that there is no increased risk for parkinsonism associated with the use of gadolinium in MRIs.

However, the researchers caution that this study does not clear up all the worries about gadolinium, since they investigated only its connection to parkinsonism.

“While these findings should be reassuring for patients and their care providers that gadolinium exposure does not appear to be associated with higher risk of developing parkinsonism symptoms, there have been other reports of nonspecific neurologic symptoms including pain and cognitive changes associated with prior gadolinium exposure which do require further study,” comments Dr. Welk.

The researchers also note that gadolinium may have different effects in younger patients (who were not included in this study), or in those with neurologic diseases (who may have been excluded based on the types of MRIs included in this study).

“Association between Gadolinium contrast exposure and the risk of parkinsonism” was published on July 5, 2016 in the journal JAMA.

Author block: Blayne Welk, Eric McArthur, Sarah A. Morrow, Penny MacDonald, Jade Hayward, Andrew Leung, Andrea Lum.

Prostate cancer can be elusive.

Wayne Smith’s journey with prostate cancer began 16 years ago when his family physician noticed increasing levels of prostate specific antigen (PSA) in his blood. PSA is a protein expressed by the prostate. A blood test is used to monitor levels of the protein as a screening tool for prostate cancer.

“My doctor referred me to Dr. Stephen Pautler, Urologist at St. Joseph’s Health Care London. Although we did a number of tests, we weren’t able to locate any spots of cancer,” says Wayne, a 71-year-old man from Ingersoll, Ontario. “We were able to manage my PSA levels for a number of years until they jumped up too high.”

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Above: Wayne Smith

In 2012, Wayne was sent for a CT scan. This test finally revealed spots of cancer at the back of the prostate. “Dr. Pautler discussed my treatment options with me and I chose to have surgery to remove my prostate,” explains Wayne. “The team did a great job but we eventually realized some cancer remained. I asked about a PET scan to locate it but the technology was not available at that time.”

After consulting with Dr. Pautler and Dr. Glenn Bauman, Radiation Oncologist at London Health Sciences Centre, Wayne chose to postpone further treatment and monitor the cancer over time. It was undetectable for five years before his PSA levels started rising again. Earlier this year, the levels doubled. 

“I was told a PET scan was available through research and that it could help locate the disease,” says Wayne. He went for the scan earlier this year at St. Joseph’s Hospital, part of St. Joseph’s Health Care London. “Nothing showed up on the scan, but that was good news; it meant the cancer was microscopically small.”

The PET scan helped Wayne and his care team in making decisions about his treatment. They decided on hormone therapy and radiation therapy to hopefully eradicate any cancerous cells. He was treated at London Health Sciences Centre’s (LHSC) London Regional Cancer Program.

“Early evidence suggests that a clear PET scan despite rising PSA levels is likely associated with persistent cancer at the original site,” explains Dr. Glenn Bauman, Lawson Scientist and Radiation Oncologist at LHSC. “Based on the scan, Wayne was able to do a much shorter round of hormone therapy – six months rather than being on hormone therapy indefinitely.” 

“After the first hormone treatment, my PSA levels dropped significantly. With the added radiation, we’re confident this will be the end of my battle with prostate cancer,” says Wayne, who is currently enjoying retired life by spending time with his wife, two children and five grandkids. “Despite my diagnosis and treatments, I carried on with my life. I did what I had to do but still went places on weekends, did chores around the house and went golfing.”

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Above: Dr. Glenn Bauman (left) and Wayne Smith (right)

Wayne is one of 1,500 Ontario men who will participate in the PSMA-PET Registry Trial. Led by researchers at Lawson Health Research Institute, the multi-centre registry trial is testing the use of a new imaging tracer, called a PSMA tracer, for early detection of recurrent prostate cancer. The registry gives patients access to a new type of imaging and will assess the impact on patient care.

PSMA tracers are used in positron emission tomography (PET) scans to target a protein found in prostate cancer cells called prostate specific membrane antigen (PSMA). Supported by Cancer Care Ontario and McMaster University’s Centre for Probe Development and Commercialization (CPDC), the goal of the registry trial is to capture detailed PET images to guide treatment decisions made by patients and their care teams.

Eligible participants are those with suspected prostate cancer that cannot be detected in conventional bone and CT scans. Participants have a PET scan using a specific PSMA tracer called 18F-DCFPyL. The tracer is injected and spreads out in the body to find spots of cancer which are then visible on the scan.

“With this trial, men in Ontario can access a promising test that could impact their treatment outcomes,” says Dr. Bauman. “The PSMA tracer may be able to locate prostate cancer that was once undiscoverable.”

Led by Dr. Bauman along with Drs. Ur Metser and Tony Finelli at University Health Network (UHN), the trial is currently available across multiple sites in Ontario: London Health Sciences Centre; St. Joseph’s Health Care London; St. Joseph’s Health Care Hamilton; Sunnybrook Health Sciences Centre; Princess Margaret Cancer Centre (UHN); and Thunder Bay Regional Health Sciences Centre. The trial is also expected to open at The Ottawa Hospital this year. 

The PSMA tracer is considered an investigational agent in Canada and is currently only available through clinical trials. After studying the accuracy of the tracer in detecting early cancer recurrence, the research team hopes to have enough data to recommend when it could be used in the clinic. 

Patients from London, Ontario and region who are enrolled in the PSMA-PET Registry Trial have their scans performed at St. Joseph's Hospital. In 2016, Lawson researchers were the first in Canada to use the 18F-DCFPyL PSMA tracer to capture PET images with a patient at St. Joseph’s Hospital. The tracer is provided by CanProbe, a joint venture between CPDC and UHN located in Toronto, and was set up with funding from the Movember Foundation.

“We conducted an initial trial that included 20 men with prostate cancer who were having their prostate removed. The goal was to determine how effective the PSMA probe was in detecting disease at the time of initial treatment,” explains Dr. Bauman. “We found the PET scan was able to detect spots of cancer in almost all participants, which corresponded to spots of cancer identified in the prostate after it was removed and examined under the microscope.”

The initial trial was made possible with donor funding through London Health Sciences Foundation, which provided initial funding to hire Research Associate, Catherine Hildebrand, who set up citywide cancer imaging workshops and helped the team prepare successful grant applications to secure key funding from CIHR and OICR.

Dr. Bauman notes that conventional imaging tests like bone scans and computed tomography (CT) are not always effective for detecting prostate cancer. While other PET probes can be used to detect a number of different cancer types, they are unable to identify prostate cancer. The PSMA probe opens new avenues for prostate cancer diagnosis, prognosis and treatment guidance. 

For patients like Wayne Smith, access to this advanced imaging is critically important.

“It’s fantastic we have access to this PET scan. It certainly gave me relief knowing nothing showed up on the scan and that, even if something did, it would light up to show us where to treat,” says Wayne. “I know PET scans are used for other cancers too and I think they’re imperative. They give you more of a chance through knowledge of where the disease is located.”

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Researchers at Lawson Health Research Institute and Western University have launched a new study to help us better understand how the body’s immune system responds to COVID-19.

Any time there is a threat to the body, the immune system is activated. Some early reports from scientists and physicians working with COVID-19 patients indicate that this virus may cause a cytokine storm, or a heightened immune response, in some patients. 

A cytokine storm, or a heightened immune response results when excessive levels of cytokines, the activating compounds of immune cells, are released into the bloodstream to attack the virus. This can lead to lung inflammation and respiratory distress. The leading cause of death for patients with COVID-19 is respiratory failure with or without multiorgan dysfunction. 

“Some researchers are suggesting that mortality could be improved with immunosuppressive therapies, however, evidence to support this is severely lacking at this time,” explains Dr. Douglas Fraser, lead researcher and Paediatric Critical Care Physician at London Health Sciences Centre (LHSC).

Daily blood samples are being taken from patients at LHSC who are presumed to have COVID-19. The samples are tested for inflammatory biomarkers and this information is recorded to track the changing immune response over time. The immune response in COVID-19 positive patients will also be compared to the immune response in patients with other infections, as well as in healthy controls. Clinical data of enrolled patients is also being recorded, and can be used in future studies. 

Dr. Fraser, also a Lawson Scientist and Professor at Western’s Schulich School of Medicine & Dentistry, explains, “if a hyperinflammatory response is found to contribute to greater adverse outcomes from COVID-19, there are current therapies available to help these cases. This study could also inform why some people become critically ill and others do not, and help determine who will respond to certain therapies.”

This research will help provide an overall understanding of how the immune system reacts to COVID-19. With this understanding, targeted therapies can be developed to improve patient outcome and reduce Intensive Care Unit (ICU) demand. As a hospital-based research institute, laboratories at Lawson are uniquely positioned to handle these types of studies, as close proximity to patients and sample collection is essential.

COVID-19, also referred to as the 2019 Novel Coronavirus, is a new respiratory virus first identified in Wuhan, China. On March 12, 2020, the World Health Organization declared COVID-19 a global pandemic. As of March 26, 2020, there are over 510,000 confirmed cases and over 22,000 recorded deaths world-wide. 

A new population-based retrospective validation study, using ICES data collected between 2007 and 2014 in Ontario, has found that health records can be used to track service use as well as the needs of individuals experiencing homelessness. Researchers found that the algorithms tested were able to accurately identify up to 35 per cent of individuals who experience homelessness in a given year.

The best performing algorithm estimated a large increase in homelessness prevalence between 2007 and 2016, with approximately one in 200 adults in Ontario experiencing homelessness in 2016.

“We do not know how many people experience homelessness yearly in Ontario, or in the country as a whole. Current methods rely on shelter data, or large point-in-time counts that require large investments, and are only done in specific communities,” explains Lucie Richard, Lawson researcher and lead author of the study. “Also, not all people who are homeless use shelters. This approach gives us an alternative that can include a wide range of communities and different types of homelessness over time.”

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While numerous computer algorithms are already used to analyze administrative databases and identify disease populations to measure the burden of chronic diseases in Canada, this study, conducted by researchers at Lawson Health Research Institute and Western University, is one of the first to validate and track a social determinant of health with good accuracy.

People who experience homelessness often face mental and physical health challenges, have an increased risk of illness and death, and are among the highest users of emergency and other health care services. Homelessness is an important health issue for Canadians.

This ability to track individuals experiencing homelessness over time using administrative databases provides inexpensive, long-term monitoring, which will inform efforts to improve housing and health status in the community and across the country. Researchers and health care providers can now track health status and health care usage of individuals experiencing homelessness. 

Understanding how many people experience homelessness and what demographics correlate with homelessness will allow for better service planning, and providers will have the information needed to more appropriately meet the needs of this vulnerable population.

The study, “Validation study of health administrative data algorithms to identify individuals experiencing homelessness and estimate population prevalence of homelessness in Ontario, Canada” is published in BMJ Open. 

James Armstrong, an MD/PhD student at Western University’s Schulich School of Medicine & Dentistry conducting research at Lawson Health Research Institute, is creating a 3D bio-artificial tissue model to study wound healing following glaucoma surgery.

There are currently no curative treatments for glaucoma, the leading cause of irreversible blindness world-wide. The only therapy that can delay the progression of the disease is the reduction of intra-ocular pressure, which can be accomplished by taking drugs or undergoing surgery. Surgery is usually a last resort if pharmacological treatment is unsuccessful as many of these surgeries fail due to excessive healing of the surgical wound. A dense, scar-like tissue can develop at the surgical site, which blocks the pressure-lowering effect and leads to surgical failure, revision and even blindness.

Armstrong will identify risk factors for fibrotic glaucoma surgery failure through reviews of electronic patient records and literature. Using the constructed model of the ocular tissue involved in glaucoma surgery, he will simulate the surgical wound to study the physiology of how the tissue heals and test potential drugs designed to modulate the wound healing process.

The project has been awarded a Lawson Internal Research Fund (IRF) Studentship, and is supervised by Lawson scientist and St. Joseph’s Health Care London physician Dr. Cindy Hutnik.

“Right now there is a shift happening towards earlier surgical interventions for glaucoma so an understanding of the wound healing response is critical to ensure safe and successful outcomes for patients,” Armstrong says. “Future work in this area could include developing a diagnostic test to inform physicians of a patients’ likelihood of excessive healing before the patient even sets foot in the operating room. This will allow surgeons to ‘customize’ how they pre-treat each individual patient with wound healing modulating drugs.”

Although this study is focused on wound healing within the eye, the same processes are at work in many other diseases. Understanding and having the ability to manipulate wound healing mechanisms could have widespread applicability, not only for glaucoma, but also for other diseases such as atherosclerosis, interstitial pulmonary fibrosis, hepatic fibrosis, systemic sclerosis or muscular dystrophy, as well as heart, kidney or liver failure.

“The IRF has given me the opportunity to pursue research in an area where any progress could impact a significant portion of the population,” Armstrong says. “It’s a great way for researchers who are early in their career to get a foot in the door. It allows them to collect the amount of data necessary to receive funding from larger granting agencies.”

The IRF is designed to provide Lawson scientists and students the opportunity to obtain start-up funds for new projects with the potential to obtain larger funding, be published in a high-impact journal, or provide a clinical benefit to patients. Funding is provided by the clinical departments of London Health Sciences Centre and St. Joseph’s Health Care London, as well as the hospital foundations (London Health Sciences Foundation and St. Joseph's Health Care Foundation).

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Hospital-based research is uniquely positioned to tackle the unprecedented COVID-19 challenge and quickly translate results into illness prevention and care for patients. Lawson Health Research Institute, the research institute of London Health Sciences Centre (LHSC) and St. Joseph’s Health Care London, has awarded more than $202,000 to its research teams to support critical discoveries during the pandemic. 

Over 14 projects ranging from improved diagnostics to understanding the impact of the COVID-19 pandemic on frontline health-care workers have been funded through Lawson’s Internal Research Fund (IRF) COVID-19 Pandemic Response Competition. 

“Lawson researchers are an intrinsic part of health care in London. Our research community has mobilized quickly to the COVID-19 pandemic and has come forth with innovative ideas to prevent infections, aid recovery and reduce the likelihood of mortality in those most seriously affected,” says Dr. David Hill, Scientific Director for Lawson. “Lawson has reallocated internal granting resources to enable some of the most exciting and credible ideas to be explored.”

Launched in March, this rapid response competition was focused on funding projects, such as two described below, that could impact the management of the pandemic and enhance our understanding of the novel coronavirus. 

Using genetic therapy to block entry of the virus 

Progression of COVID-19 depends on human proteins that the virus uses to escort itself into lung cells to cause disease. “There are three such ‘virus entry’ proteins that are particularly important for infection. We see them as potential targets for drugs to prevent and treat COVID-19,” explains Dr. James Koropatnick, Lawson Scientist and Principal Investigator for one of the funded studies. 

There could be dangers in targeting these proteins, particularly for patients taking certain blood pressure-reducing drugs. The team is studying the safe use of a new type of drug – powerful “antisense” agents that block messenger RNAs which are the biological “blueprints” for the target virus entry proteins – to stop the virus from using those proteins to infect lung cells. They are testing two types of antisense molecules that reduce the amount of the virus entry proteins. “With our existing knowledge and infrastructure in place, this testing could rapidly lead to new, non-vaccine agents to prevent and treat COVID-19, as well as future coronaviruses with pandemic potential,” adds Dr. Koropatnick.  

The impact of the pandemic response for those with disabilities 

The COVID-19 pandemic has disrupted the daily lives of Canadians, with worsening mental health as people adapt to different stressors. “While many are struggling with this new normal, the degree of disruption resulting from the pandemic presents unique challenges for those with spinal cord injury and brain injury,” says Dr. Eldon Loh, Lawson Associate Scientist also leading one of the funded studies.  
 
Relatively simple tasks such as frequent hand washing can be challenging for those with disability, and they may be more vulnerable to poor outcomes because of the decreased respiratory function many already face. The research team will document and evaluate the effect of the pandemic on the physical and mental health of those with spinal cord and brain injuries. “We plan to use our findings to provide guidance to those living with spinal cord and brain injury, and improve their quality of life during this challenging time. We expect that this study will not only help those with spinal cord and brain injuries, but also people living with other disabilities as well,” notes Dr. Loh. He is also a Physical Medicine and Rehabilitation Specialist at St. Joseph’s.  

The IRF competition is supported with funding from clinical departments at LHSC and St. Joseph’s, and from London Health Sciences Foundation and St. Joseph’s Health Care Foundation.

Congratulations to all of the researchers and their teams who have been awarded funding: 

• Dr. Ian Ball - Predictors of clinical deterioration in hospitalized patients with COVID-19: The CORAL study
• Dr. Doug Fraser - Translational Research Centre: Repository of biological specimens from patients
• Dr. Sean Gill - Rapid identification of therapeutic targets mediating pulmonary microvascular endothelial cell dysfunction in COVID-19 patients
• Dr. Marnin Heisel - Testing Online Meaning-Centered Men’s Groups to Promote Psychological Well-Being and Reduce Despair in the Face of the COVID-19 Pandemic
• Dr. Kimia Honarmand - The impact of the COVID-19 pandemic on frontline healthcare workers: A Southwest Ontario survey
• Dr. Michael Knauer - Improving diagnostic and epidemiologic detection of SARS-CoV-2
• Dr. Jim Koropatnick - Targeting the SARS-CoV-2 receptor with candidate antisense drugs to prevent infection and disease progression
• Dr. Eldon Loh - COVID-19 and Disability: The Impact of a Societal Lockdown on those with Spinal Cord and Brain Injuries
• Dr. Len Luyt - Stapled Peptides as SARS-CoV-2 Fusion Inhibitors
• Dr. Claudio Martin - COVIDOPATHY – An observational study of coagulation abnormalities in patients with COVID-19
• Dr. Tianqing Peng - Developing new ssDNA aptamers targeting S protein receptor binding domain of SARS-CoV-2 to disrupt virus infection cycle as a potential therapy
• Dr. Eva Turley - Hyaluronan signaling through the inflammasome is a target for blunting acute respiratory distress syndrome (ARDS) in COVID-19 patients
• Dr. Ruud Veldhuizen - Next generation exogenous surfactants for COVID-19 and future respiratory pandemics
• Dr. Blayne Welk - Characterizing the burden of surgical care in COVID-19 positive patients

Human lungs are coated with a substance called surfactant which allows us to breathe easily. When lung surfactant is missing or depleted, which can happen with premature birth or lung injury, breathing becomes difficult. In a collaborative study between Lawson Health Research Institute and Stanford University, scientists have developed and tested a new synthetic surfactant that could lead to improved treatments for lung disease and injury.

Lung surfactant is made up of lipids and proteins which help lower tension on the lung’s surface, reducing the amount of effort needed to take a breath. The proteins, called surfactant-associated proteins, are very difficult to create in a laboratory and so the surfactant most commonly used in medicine is obtained from animal lungs.

London, Ontario has a rich legacy in surfactant research and innovation. Dr. Fred Possmayer, a scientist at Lawson and Western University, pioneered the technique used to purify and sterilize lung surfactant extracted from cows. Called bovine lipid extract surfactant (BLES), the therapeutic is made in London, Ontario and used by nearly all neonatal intensive care units in Canada to treat premature babies with respiratory distress.

“When we look at treating adults, surfactant therapy is more difficult. For example, their lungs are 20 times bigger than those of babies and so we need much higher doses of surfactant,” explains Dr. Ruud Veldhuizen, a scientist at Lawson and an associate professor at Western University’s Schulich School of Medicine & Dentistry. “We therefore need to find novel approaches to surfactant therapy for adult patients.”

In this collaborative study, the research team took a new approach to creating synthetic surfactant. Rather than trying to recreate surfactant-associated proteins in the lab, scientists at Stanford created protein mimics. Pioneered by Dr. Annelise Barron, associate professor at Stanford, these protein mimics look like surfactant-associated proteins and have similar properties but are easier to create and more stable. As a result, the team was able to create a new synthetic surfactant.

Collaborating with the Stanford team, Dr. Veldhuizen evaluated the synthetic surfactant in animal models in his research lab at St. Joseph’s Health Care London. The study showed that, unlike other synthetic surfactants currently on the market, the new surfactant equaled or outperformed the animal-derived surfactant in every outcome. This included outperforming animal-derived surfactant in oxygenating blood, which is the lungs’ main purpose.

“The unique ability of the Veldhuizen lab to perform these rigorous and sophisticated studies was a critical aspect of the success of this project,” says Dr. Barron.

“These are very promising results,” says Dr. Veldhuizen. “For the first time, a synthetic surfactant has been developed which appears to be just as effective, if not more so, as that taken from the lungs of animals.”

The team estimates that the synthetic surfactant could be produced at as low as one quarter of the cost of the animal-derived surfactant. With a lower cost the synthetic surfactant could be tested with more lung diseases and injuries in adults and made available in more developing countries.

The team hopes to continue their research with further testing of the synthetic surfactant, including its long term effects. The team also hopes to test its ability to be customized for specific diseases. “Since it is made in the lab, we could combine the surfactant with other drugs like antibacterial agents and deliver it to specific areas of the lung, such as those where an infection is located,” explains Dr. Veldhuizen.

One disease the scientists would like to further study is acute respiratory distress syndrome (ARDS). ARDS is characterized by a low amount of oxygen in the blood due to difficulty breathing. While current surfactants have been tested with ARDS patients, they have not been effective. Dr. Veldhuizen wants to combine this new synthetic surfactant with anti-inflammatory agents and antibacterial agents to test whether patient outcomes are improved.

The study, “Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins,” is published in Scientific Reports.