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Monocular Vision Development Research Q&A

Authors:
Richelle Baddeliyanage
Coordinator, Retinoblastoma Champion Program
Retinoblastoma Survivor

Dr. Ben Thompson
Professor and Associate Director for Research, University of Waterloo
Adjunct Professor, McGill University
Professor, University of Auckland

Dr. Ari Chakraborty
Brain Canada Fellow, University of British Columbia
Adjunct Assistant Professor, University of Waterloo

Introduction:
Richelle interviews Ben and Ari to learn more about their monocular (one eyed) vision development research.

Research Overiew:
The goal of our retinoblastoma-related research is to understand how the removal of one eye in childhood effects subsequent development of the visual system. During the early years of life, the brain learns how to interpret information from the eyes and modifies its structure and function to optimize vision. Eye conditions in childhood that impair the ability of the two eyes to work together (binocular vision) such as the misalignment of one eye (strabismus) or unequal focusing power between the two eyes (anisometropia) can disrupt this developmental process and cause vision impairment later in life. The loss of one eye in childhood may have similar effects. Alternatively, the brain may learn to use the remaining eye normally because there are no conflicting signals from the other eye. To investigate this question we used a multimodal approach, comprising behavioral and neuroimaging experiments, to compare the visual system in children with one eye with an age-matched control group. A particular focus of our research was motion perception because previous research from York University, led by Dr. Jennifer Steeves had reported motion perception deficits in adults with a history of monocular enucleation. We investigated whether motion perception was affected earlier in development by inviting school-aged children with one eye to participate in our study. We found that all of our participants had normal clinical measures of vision (visual acuity, contrast sensitivity etc.), however our participants with one eye had a different pattern of results on our motion perception measure. Motion perception was normal when images moved from the temple towards the nose, but worse than normal when motion was from the nose towards the temple. Our neuroimaging data suggest that this difference in the development of motion perception involves a region the cerebral cortex called the middle temporal area. Our results have improved our understanding of vision in people who experience monocular enucleation in childhood. The results also help us to understand the role of binocular vision in normal visual development and provide a neural signature that may be useful to detect binocular vision problems in children with two eyes.

Question & Answer:

Richelle: Can you speak to the importance of your research and how it affects retinoblastoma patients.

Ben & Ari: Unilateral enucleation for retinoblastoma typically takes place in early childhood when visual brain areas are rapidly developing. The human brain has evolved to process information from two eyes. Therefore, unilateral enucleation has the potential to considerably alter visual system development. Our research aims to map the effect of unilateral enucleation on visual development. In particular, our studies are designed to identify whether unilateral enucleation effects vision in healthy eye of children with a history of retinoblastoma. Any effects that are detected could potentially be addressed using rehabilitation techniques such as visual perceptual learning – targeted training of specific visual functions.

Richelle: You mention that a study led by Dr. Jennifer Steeves found “motion perception deficits in adults with a history of monocular enucleation”. Did the adults also have normal motion perception when images moved from the temple towards the nose, but worse than normal motion perception when images were moved from the nose towards the temple? Did these adults have an enucleation in childhood?

Ben & Ari: The 2002 study by Dr Steeves reported a similar bias in motion perception towards nasalward motion, whereby the motion perception was better when moving dots moved towards the nose than when those dots moved towards the temple. All but one of the participants in the study had an enucleation in childhood.  Our theory is that the motion perception asymmetry occurs because of altered visual input to the brain when it is still undergoing rapid development in childhood. We predict that unilateral enucleation in adulthood would not have the same effect because the development of visual brain areas is complete.

Richelle: Your research results indicate that motion perception is challenged in children who have lost one eye early in life. Would you expect similar results in patients that didn’t have an enucleation but had very poor vision in one eye (e.g., only light perception)? Has research examined if other senses such as hearing compensate for the loss of vision?

Ben & Ari: This is a very interesting question and one that we are actively pursuing. There are a number of conditions that can cause a difference in vision between the two eyes in childhood. These include an eye turn (strabismus), a blurred image in one eye due to refractive error and childhood cataract affecting one eye. A difference in the images seen by each eye in childhood can alter the development of visual brain areas resulting in abnormal processing of information from the affected eye within the brain, a condition known as amblyopia. A number of studies have identified motion perception deficits in individuals with amblyopia, however motion asymmetry has not yet been studied. We currently have three active projects investigating this question. These projects currently focus on participants with a history of childhood cataract in one eye.

Richelle: In children who have had monocular enucleation, are there any aspects of visual function that are enhanced during development?

Ben & Ari: Although we did not observe any enhancement of vision in our study of children, previous studies have reported better visual acuities in adults with a history of childhood monocular enucleation in comparison to a control group who completed testing wearing an eye patch.

Richelle: Are there any exercises/activities that can help mitigate the effects of monocular vision? Alternately, do you imagine any advancements in the future that would mitigate motion perception deficits in monocular enucleation?

Ben & Ari: It is certainly possible that training on vision tasks using a technique called perceptual learning could improve motion perception in children with a history of monocular enucleation. The next step for us it to understand the origin of the motion perception asymmetry within the brain. We have been pursuing this question using a brain imagining technique called Magnetoencephalography (MEG). Once we understand the origin of the asymmetry, we may be able to design techniques to treat it.

Richelle: What information is useful for parents trying to understand challenges resulting from their monocular vision? As you know, the Canadian Retinoblastoma Research Advisory Board is committed to patient engagement in research including the translation of research findings. How can we make sure retinoblastoma patients are aware these challenges?

Ben & Ari: This is an excellent question. Through forums such as this blog, we hope to make our research accessible to parents. We are also always open to new ideas on how best to communicate our research to parents.

Richelle: What are your recommendations for further studies that focus on the removal of one eye in childhood?

Ben & Ari: A key issue that we face as researchers is being able to enroll enough participants in our studies to reach scientifically valid conclusions. Future research should endeavour to include more participants. In addition, the rapid development of advanced neuroimaging techniques provides us with an excellent opportunity to understand the effects of childhood unilateral enucleation on the structure and function of the brain. This information could then be used to guide the development of treatments for any vision problems that are detected in the healthy eye of children with a history of unilateral enucleation.

To learn about opportunities at the Human Visual Neuroscience Laboratory at the University of Waterloo, email hvnl@uwaterloo.ca.

The Helen Keller Prize for Vision Research

On May 1, 2018, Dr. Brenda Gallie was honoured as 1 of 4 Scientists to receive the Helen Keller Prize for Vision Research.

The other 2018 Helen Keller Laureates are:

• Webster Cavenee, PhD, Ludwig Institute for Cancer Research, University of California, San Diego
• Thaddeus Dryja, MD, Harvard Medical School and Massachusetts Eye and Ear Infirmary
• A. Linn Murphree, MD, Keck School of Medicine, University of Southern California

This award honours scientific excellence in vision research, and is presented by BrightFocus Foundation.

As published on the BrightFocus Website:
“Helen Keller remains a timeless, iconic name in the battle against blindness. The Helen Keller Prize for Vision Research therefore bestows a unique, peerless honor on the outstanding vision researchers who receive it,” said Robert Morris, MD, President of the Helen Keller Foundation for Research and Education.

“This year’s prize recognizes how collaboration across scientific disciplines can to lead game-changing breakthroughs. The 2018 Laureates are exemplary researchers who are driving the ability of science to save sight,” said Stacy Pagos Haller, BrightFocus Foundation President and CEO.

Child Life Blog: Using Social Narrative Stories for Preparation…

Author:Morgan Livingstone MA CCLS CIIT

The hospital experience can include many disruptions and can be difficult for even the happiest child. For children and families facing a retinoblastoma diagnosis and the treatments that follow, there can be a feeling of sensory overload with so many smells, sounds, textures and bright lights. The unpredictable nature of wait times can be frustrating and stressful, with very little time to transition from one appointment to another, or from one assessment to another test. So many specialists, doctors, nurses and medical team members mean many new people to meet. Changes from the familiar routine, and changes in familiar foods, and even fasting before procedures and surgeries can all add to the difficulties children and families face in clinics, hospitals and healthcare settings.

But what if there was something you could do to improve this experience? Even just a little bit?

With a little preparation for upcoming procedures, check-ups and tests, children of all ages can cope better.

Why is preparation helpful to a child?

Decreases fear and anxiety.
Promotes long-term coping to medical challenges and experiences.
Increases cooperation with medical team.
Clarifies misconceptions and misinformation.
Some simple ways that parents and caregivers can prepare children for upcoming appointments can start with using familiar wording and strategies to keep things consistent. Focus on the sensory experience and gently offer positive touch in areas child(ren) may be touched often like their faces, near and around their eyes. Take turns with this gentle play and let your child practice these gentle touches and strokes on your face as well. Parents and caregivers are being watched by children at all times, so you can also model appropriate behavior and use stress management techniques to improve you own coping. Offer children coping strategies – this can include something as simple as a hug, or pacifier, or deep breathing activities like blowing bubbles or a pinwheel toy. Naturally parents can offer positive reinforcement and verbal praise as children learn to navigate their medical experience, learning what they need to do to be and feel successful.

Teaching steps and skills using stories:

Children learn a great deal about social norms through stories. Whether you tell stories verbally, read books together, listen to audiobooks, or even sing songs that tell stories, these are wonderful ways to communicate and explore what happens in different situations and what to do or how to do something when facing a challenge. It can be fun to create your own family songs for different routines like bath time and mealtimes using a familiar melody from children’s songs and nursery rhymes. Songs can also be created to help prepare and explore the steps a child goes though during medical experiences.

Here is an example of a creative song about an Eye Ultrasound, sung to the tune of Jingle Bells:

Slip and slide
Slip and slide
On the special jelly
Cold and wet is how it feels to help you see inside!

Written by Daisy Lloyd and Morgan Livingstone

There are many helpful published books that explore hospitalization and medical experiences for children of all ages. Many can be found at mainstream bookstores, while more specific RB focused books can be found though charities like CHECT here:

https://chect.org.uk/about-retinoblastoma-2/childrens-area/rb-and-me-1-6/

Social Narrative Stories:

Social stories were developed by Carol Gray in the 1990’s as a way to explain social interactions and situations for young children. Though the extension of these social stories, child life specialists and parents can create customized narrative stories for children with RB to help familiarize and prepare them for routine procedures and any other aspect of care that they will experience over the course of their treatment.

There are some simple components to consider when creating your own social narrative story:

• Predictability
• Sensory Components
• Appropriate Behavior
• Short/Concrete language
• Key Details

A team of child life specialists and psychologists at Boston Children’s Hospital have created many FREE preparation stories for difference medical experiences and appointments that you can download here:

http://www.childrenshospital.org/patient-resources/family-resources/child-life-specialists/preparing-your-child-and-family-for-a-visit/my-hospital-story

Big thanks to child life specialists Kristin Dietzel and Andrea Lerude, and psychologist Dr. Carrie Mauras.

Here is a narrative social storyto help prepare a child with RB (and their family) for a routine Examination Under Anesthesia.

Preparing for an EUA book

Environment and preparation:

Despite all the knowledge we have about the benefits of a child friendly environment on a child’s medical experience, not all clinics are child friendly. Parents can improve this routine experience by planning ahead and bringing familiar items with them that will help make this space more comfortable for their child. Bring your own favorite story books, a blanket, pillow or special stuffed toy that helps as a comfort item for your child and even consider “creating” a safe space for your child within their stroller.

When appropriate, always bring favorite snacks and a few quiet activities that will help your child engage in play, express themselves and offer normalization.

When creating social narrative stories, you can take actual photos of the hospital or clinic environment with you and your child in the photos. This can help with familiarization and preparation for each step of your visit, assessments and procedures. However, as children get older they can be encouraged to help with the creation of these stories and assist by writing the narrative, drawing the pictures and adding the details they feel are important to them…..especially whether they think pizza or ice cream is needed at the end of the story.

Teaching children coping skills can become a creative opportunity to use imagination to relax your body. Here is an example of a simple coping skills story using mindfulness meditation created by a child and a child life specialist:

• 

• 

• 

• 

WE all want the best for children:

Best possible outcomes mean’s working together to prepare and communicate the medical experience clearly so that children know what to expect and can practice these steps, which promotes mastery. Creating social narrative stories can be a fun part of everyday life, like mealtimes and toileting, or it can have an important purpose in preparing them for upcoming procedures, appointments and examinations.

Work with your medical team to ensure you know what to expect, talk to other families about their experiences, and seek out help from Child Life so that you can better prepare yourself and your child for appointments. This can reduce stress and relieve undue worry that many children and families face when they don’t know what will happen, and imaginations can run wild. Instead try using imagination to create stories, songs and narratives you will all enjoy together!

About the Author:

Morgan Livingstone is a Certified Child Life Specialist and Certified Infant Massage Instructor/Trainer that is passionate about improved child life and psychosocial supports for children and families affected by retinoblastoma. Working as the Child Life Officer of World Eye Cancer Hope, Morgan contributes to the website Child Life Sections, and speaks globally about child life supports for children with RB. Most recently, Morgan has been providing enriched multi-day child life programming for children of all ages at both the 1 RB World meeting in Washington, D.C in October 2017 as well as the Canadian Retinoblastoma Research Advisory Board meeting in December 2017.

In addition to her work with RB, Morgan writes and creates resources for children and adults, participates in child life research studies, and was the winner of the inaugural Innovation Grant at Operation Smile for developing an APP that uses Virtual Reality to prepare children receiving cleft lip and palate surgery for their operation.

Morgan’s helpful parent manual for supporting children’s worries using Worry Eaters

http://www.haywiregroup.com/files/8014/6601/9104/Worry_Eaters_Parents_Guide_pdf.pdf

The Canadian retinoblastoma clinical practice guidelines are being updated

Author: Fiona Hendry

What are the clinical practice guidelines?

Clinical practice guidelines are recommendations based on the best available evidence about a particular therapeutic area. They are intended to enhance patient care.

Clinical practice guidelines for retinoblastoma

Published in 2009, the Canadian National Retinoblastoma Strategy was the first ever set of retinoblastoma clinical practice guidelines. These guidelines were adapted for the Kenyan National Retinoblastoma Strategy, published in 2014.

Thanks to ongoing research, there have been great strides in improving the outcomes of children with retinoblastoma. That’s why a newer, updated set of clinical practice guidelines are being produced.

This project co-chaired by Dr. Katherine Paton and Dr. Brenda Gallie. Dr. Paton is an Ocular Oncologist at BC Children’s Hospital and Head of the Division of Ocular Oncology and Clinical Professor in the Department of Ophthalmology and Visual Sciences at the University of British Columbia. Dr. Gallie is Head of Retinoblastoma Programs at The Hospital for Sick Children and Alberta Children’s Hospital and Professor in the Departments of Ophthalmology and Vision Science, Medical Biophysics and Molecular Genetics at the University of Toronto.

Retinoblastoma clinical practice guidelines sections

There are 10 guidelines sections, as follows:

1. Screening
2. Features and Classification of Retinoblastoma Treatment Centres
3. Referral and Diagnosis
4. Genetic Analysis
5. Pathology
6. Imaging
7. Treatment
8. Follow-up
9. Psychosocial Care and Access to Services
10. Public Awareness and Education

How are the Canadian retinoblastoma clinical practice guidelines being developed?

The retinoblastoma clinical practice guidelines will be developed following a rigorous process, including a structured review of the quality of every relevant research study and how it might apply in clinical practice. Like the original clinical practice guidelines, the process will also include a review by additional experts, including retinoblastoma survivors and family members, and international experts.

Retinoblastoma experts (generally from Canada) were selected to lead the aforementioned sections. Section leads started meeting remotely in late 2017 with an in person meeting June 1, 2018.

Stay tuned for more information about the clinical practice guidelines, including opportunities for retinoblastoma survivors and families to participate!

The updated Canadian retinoblastoma clinical practice guidelines were discussed by a group of retinoblastoma experts during the annual Canadian Ophthalmological Society meeting June 1, 2018. Top Row (left to right): Dr. Lisa Lagrou, Dr. Katie Clapson, Dr. Kelsey Roelofs, Dr. Stephanie Kletke, Dr. Andrew Budning, Dr. Carlos Solarte, Dr. Patrick Hamel, Dr. Ian Clark, Dr. Louis-Etienne Marcoux , Dr. Jane Gardiner, Dr. Annick Fournier, Dr. Rob Downie. Bottom Row: Ms. Beverley Griffiths, Dr. Katherine Paton, Dr. Brenda Gallie, Ms. Kaitlyn Hougham, Dr. Hilary Racher, Dr. Junyang Zhao

Retinoblastoma Treatment: Past, Present and Future

Author: Dr. Ella Bowles

As a 35-year-old patient who was treated for retinoblastoma that many years ago, I am curious how retinoblastoma treatment has changed over the years? I had bilateral retinoblastoma, and one of my eyes was removed; in the other, I had xenon arc (an older type of laser) therapy and cryotherapy. At that time, external beam radiation and radioactive patches were also common retinoblastoma treatments. I know that these therapies have been fine-tuned since then, but I don’t know much more than that. To answer my questions, I sat down with Dr. Brenda Gallie to talk about how care has changed over the years, and what future directions may look like.

Me: How has the field of retinoblastoma changed over the last 30 or so years?

Dr. Gallie: The field of retinoblastoma has changed a lot. Now it is totally feasible for all 8000 children who have retinoblastoma in the world to live, and DePICT is one of the tools at the center of this possibility. Retinoblastoma could be a zero-death cancer in the next ten years. DePICT is a digital tool where all patient information, including all treatments, can be archived, and patients have the ability to access it. DePICT also provides tremendous opportunity for research, as it will preserve a lot of information that is lost in the current patient record system.

Major developments in retinoblastoma treatment include intra-arterial chemotherapy (chemotherapy delivered to the eye via ophthalmic artery) and intra-vitreal chemotherapy (injection of chemotherapy into the eye) in 2010 and 2011, as well as removal of the tumor and vitreous from inside the eye (2017). These new therapies are changing how eyes are treated, and the DePICT^RB  database will allow clinicians and researchers to assess if the treatments are better or worse, how they are better, and for which patients they are appropriate.

In addition, a new staging system for retinoblastoma (TNMH stage vs the Murphree A-E classification) was developed from outcome data on 1,728 eyes in 13 countries, to help all doctors ‘speak the same language’ about retinoblastoma and compare patients across centres.

A child now diagnosed with:

1. T3 eye: eye must come out

2. T1a eye: treat with laser, cryotherapy

3. T1b eye: treat with chemotherapy then laser, cryotherapy

4. T2a eye (retinal detachment with no seeding): treat with chemotherapy then laser, cryotherapy

5. T2b eye (any subretinal or vitreous seeding): treat first with chemotherapy, then injection of chemotherapy directly into the vitreous, and the new idea to surgically remove the tumor in some eyes when other treatments fail. We think that vitreous seeds may be easier to treat than subretinal seeds, and we will know once we have complete data in the DePICT^RB

Intra-arterial chemotherapy in particular has swept the world without evidence of outcomes. It definitely has an important role, and we look forward to full data on the outcomes of all children who receive intra-arterial chemotherapy, so we can know which children it serves well and which children do better with systemic chemotherapy.

Me: How much involvement do patients usually have in treatment decisions for their kids?

Dr. Gallie: Each treatment is a discussion, and every treatment is agreed to by the parents of patients. What clinicians need to do better is showing the parents the outcomes of each choice, for example how far to go to save a blind and dangerous eye.

Me: Where is the best place for patients and families to go to get information about treatment?

Dr. Gallie: World Eye Cancer Hope, which can be found here: https://wechope.org.

As a patient, I feel invested in the implementation of DePICT, Dr. Gallie’s passion project, perhaps for the same reasons as she is. I was treated 35 years ago, and since then I have moved many times, with my family, to go away to school, and now for work. Over all those moves, so much information about my treatment has been lost – well, it could be found, but it is locked in clinic basements in files, and nobody wants to go look for it. All I have is a series of letters. DePICT will allow for continuity of care, and for data about treatment and follow up to be retained so easily. As a patient, I also value the possibility that it will allow easy discussion among physicians about treatment in cases where collaboration on care would be beneficial. And lastly, as a patient, I think it would be beneficial for researchers to have comprehensive data for retrospective studies. For example, Dr. Gallie spoke of how intra-arterial chemotherapy has swept the world as a treatment without evidence that it is better. DePICT can provide the data to test that. Other examples of retrospective studies are: a lot is not yet understood about why second cancers arise, whether there may be particular RB1 mutations that predispose to second cancers, or what types of consequences arise from specific treatments. DePICT holds promise to facilitate all of this.

Save The Date: 3rd Annual Canadian Retinoblastoma Research Advisory…

The third annual Canadian Retinoblastoma Research Advisory Board meeting will be held in Toronto January 26 & 27, 2019.

The purpose of this free meeting is to bring together people affected by retinoblastoma (i.e., patients and families), health professionals, researchers and policy makers to discuss retinoblastoma research.

More information about the meeting will be made available later 2018.

Opinion Piece: Knowledge, Experiences and Attitudes Concerning Genetics Among…

Authors:

Richelle Baddeliyanage, Student, and retinoblastoma survivor

Lynn Nahachewsky, Social worker and retinoblastoma survivor

Sepideh Selfi, Patient & customer engagement administrator

Helen Dimaras, Scientist

Introduction:

In trying to understand the complexities behind retinoblastoma as a rare genetic disease, there are many misunderstandings and gaps in knowledge among the patient community. In the study, “Knowledge, Experiences and Attitudes concerning Genetics among Retinoblastoma Survivors and Parents”, participants expressed a need for accessible and adequate information and support. Click below to watch a video summary of the paper. We offer our opinions on the paper, representing both the patient and healthcare community perspective.

Lynn: I really enjoyed how the paper was able to discuss each of the possible misunderstandings or misconceptions of the study group. I enjoyed that patients were quoted verbatim, even if there was slang used, as this accurately depicts how real people talk about and understand their cancer. Retinoblasotma is such a complex subject with so many variables and the interviews and research for this paper were very rich in all areas.

Richelle: As a survivor of bilateral retinoblastoma, my own patient experience aligns with most of the issues expressed in the article. While I had a basic understanding of retinoblastoma, I lacked access to new information and research on the long-term medical consequences of the disease. Important concepts are often miscommunicated and misconstrued, and there are several challenges involved in accessing the appropriate materials on retinoblastoma genetics. In addition, participants of the study found that there was a lack of psychosocial support. I also feel that there is a great need for retinoblastoma patients and family members to belong to a community of shared experiences that promotes open discussion and collective support.

Helen: I think for me the issue I took away is the inconsistencies in how people understood the basic biology and inheritance patterns of retinoblastoma. Some had excellent understanding, while many others remained confused, despite having received genetic counseling. One of the most common misconceptions was that unilateral retinoblastoma is not associated with a heritable RB1 mutation – and therefore allegedly does not confer risk of future cancer or future affected pregnancies. This is not true; about 15% of patients with unilateral retinoblastoma have a predisposing error in the RB1 gene, and are therefore at risk of second cancers and passing on the mutation to children (click here for more information on the genetics of retinoblastoma). There was confusion also between the words ‘inherited’ and ‘heritable’ – they are not the same thing, yet were often considered as such. It is important for people to understand that just because the error in the gene may not have been inherited from a parent, it does not necessarily mean that the error that developed in the child isn’t heritable by the next generation.

Sepideh: What I took away from the research is our need in the system for continuous patient support for patients. Specifically, if patients are walking away with questions and concerns after genetic counselling, how can similar service be implemented as a psychosocial/genetic information program through different channels? A problem has been unsurfaced through this research, requiring us to come up with new ways of meeting patient needs.

A way forward:

There is an opportunity to address these gaps in the system, through the Canadian Retinoblastoma Research Advisory Board and the Registry. Through these forums we can work with the patient community to co-create materials to support patient understanding of the complex genetic concepts in retinoblastoma. We will work together to produce tangible resources in various forms from informative pamphlets, books and posters, to workshops and videos and focus groups. Patient-oriented approaches to understanding retinoblastoma genetics will undoubtedly improve communication, and understanding of information and new research.  Patient engagement will also foster a network of peers that have shared interests and goals and can simultaneously act as an informal support network for the retinoblastoma community. It is our hope that patient engagement in retinoblastoma research will fill the gaps currently present in the healthcare system and ultimately improve health outcomes for future patients.

Job Opportunity for Individuals with Lived Experience of Retinoblastoma

Researchers at The Hospital for Sick Children will soon be recruiting an individual with lived  experience of retinoblastoma (e.g., survivor, parent etc.) to help lead a research project. More information about this paid researcher position will be distributed on social media. If interested, email retinoblastoma.research@sickkids.ca.

The Retinoblastoma Research Priority Setting Workshop Was A Success!

From October to December 2017, we conducted a project to identify the top 10 retinoblastoma research priorities.

Thank you to everyone who participated! Results will be made available spring/ summer 2018.

Save the Date: Retinoblastoma Research Symposium

December 9 & 10, 2017
Toronto, Ontario
Click here to learn more.