IMS MAGAZINE THINK. LEARN. DISCOVER.
Maternal & Child Health TREATING DEPRESSION IN WOMEN DURING PREGNANCY Interview with Dr. Sophie Grigoriadis
CHALLENGES OF RESEARCH IN CHILDREN Applying Adult Data to Paediatric Populations
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IN THIS ISSUE Letter from the Editors............................... 4 Director’s Message.................................... 5 Commentary............................................... 6 Twitter Feature........................................... 7 Feature: Maternal and Child Health.......... 8 Special BMC Feature............................... 22 Viewpoint................................................. 24 Faculty Spotlight...................................... 30 Student Spotlight..................................... 32 Future Directions...................................... 34 Past Events............................................... 36 Sketch Your Science................................ 38 Editors’ Pick.............................................. 39
MAGAZINE STAFF EDITORS-IN-CHIEF
Kasey Hemington Rebecca Ruddy
Anna Badner Ekaterina An Meital Yerushalmi Petri Takkala Sarah Peters
JOURNALISTS & EDITORS
Aadil Ali Aaron Wong Adam Betel Alexandra Mogadam Aravin Sukumar Archita Srinath Arman Hassanpour Arpita Parmar Arunima Kapoor Benjamin Markowitz Cricia Rinchon Fadl Nabbouh Felicity Backhouse Gaayathiri Jegatheeswaran Hira Raheel Jessie Lim Joshua Rapps Jonathon Chio Jung (Lily) Ye Lindsay Caldarone Lisa Qiu Melissa Galati Muhtashim Mian Nancy Ji Natalie Osborne Pontius Tang Pratiek Matkar Rachel Dragas Samia Tasmim Sarasa Tohyama Shokoufeh Yaseri Usman Saeed Yekta Dowlati Yena Lee
38 SKETCH YOUR SCIENCE IMS students express their research visually
Cover Art By Midori Nediger
8 FEATURE INFOGRAPHIC By Lauren Huff
Copyright © 2017 by Institute of Medical Science, University of Toronto. All rights reserved. Reproduction without permission is prohibited.
SOCIAL MEDIA & WEB EXECUTIVES
Beatrice Ballarin Tahani Baakdhah Valera Castanov
Christine P’ng Judy Rubin Lauren Huff Midori Nediger Ursula Florjanczyk
Antigona Ulndreaj Carina Freitas
Grace Jacobs Mikaeel Valli
The IMS Magazine is a student-run initiative. Any opinions expressed by the author(s) are in no way affiliated with the Institute of Medical Science or the University of Toronto.
IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH | 3
LETTER FROM THE EDITORS
LETTER from the
Photo credit Meital Yerushalmi
REBECCA RUDDY (left) KASEY HEMINGTON (right) Editors-in-Chief, IMS Magazine
nother new year means another exciting winter issue of the IMS Magazine! Last year, topics in maternal and child health frequently appeared in the news, particularly with the spread of the Zika virus and the reemergence of childhood diseases like measles. Research into these global issues is critical: investigating aspects of maternal and child health can improve our understanding of certain diseases, and will ultimately lead to better and more comprehensive treatments. For this issue of the IMS Magazine, we focused on the phenomenal research related to maternal and child health that is ongoing at the Institute of Medical Science. Our journalists sat down with experts in this field including Dr. Patrick McNamara, who discusses the importance of continued research in neonatal cardiology; Dr. Sophie Grigoriadis, who highlights antenatal depression and its effects on the mother and child; and Dr. Emily Tam, who features her journey to and life as a neonatal neurologist. In addition, we have highlighted the work of Dr. Svetlana Popova, who studies Fetal Alcohol Spectrum Disorders; and Dr. Daphne Korczak, who gives insight into the Childrenâ€™s Integrated Mood and Body program at SickKids. The winter issue also features an interesting article detailing the annual Ori Rotstein Lecture in Translational Research. This yearâ€™s keynote speaker was Dr. Peter Liu, who gave a fascinating talk about discovering biomarkers for heart failure. In addition to highlighting research and events within the Institute of Medical Science, this issue includes insights from our own journalists on the placebo effect and on the ever-evolving peer review process. This winter issue marks our last with the IMS Magazine as co-Editors-in-Chief. Although our term has been short, we have greatly appreciated the opportunity to work with an amazing team of journalists, photographers, artists, and designers. We would like to thank Dr. Mingyao Liu and everyone at the Institute of Medical Science for their continued support of the IMS Magazine. We hope you enjoy the winter issue. Happy reading!
Kasey Hemington & Rebecca Ruddy Editors-in-Chief, IMS Magazine 4 | IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH
Photo credit Tahani Baakdhahv
am excited to welcome readers to another issue of the IMS Magazine and to another year with the IMS. This winter, the IMS Magazine is featuring maternal and child health, drawing on the expertise of IMS faculty members Dr. Daphne Korczak, Dr. Svetlana Popova, and Dr. Patrick McNamara, as well as U of T’s Dr. Emily Tam. The issue highlights the IMS’s outstanding work in areas such as Fetal Alcohol Spectrum Disorders, the intersection between child and mental health, and neonatal cardiovascular health, to name a few. During this past fall of 2016, the IMS hosted another successful Ori Rotstein Lecture in Translational Research. The lecture was given by Dr. Peter Liu, who is a Professor of Medicine at both the University of Ottawa and the University of Toronto. IMS students and faculty alike were captivated as Dr. Liu discussed his work developing tissue-specific protein biomarkers for heart failure. Following the lecture, we were fortunate to have Dr. Rotstein moderate an insightful panel discussion on the challenges and rewards of partnering with the private sector to develop one’s ideas. I would like to extend my congratulations to the IMS Magazine’s co-Editors- in-Chief, Kasey Hemington and Rebecca Ruddy, as well as the executive editors, on the production of this quarter’s thought-provoking issue. I would also like to thank the entire team at the IMS Magazine for all of their dedication and hard work. The IMS Magazine has been a tremendous success and is just one of the many wonderful, student-led initiatives that make the IMS a very special institute. I look forward to sharing this Winter 2017 issue with friends and colleagues.
Mingyao Liu, MD, MSc
Director, Institute of Medical Science Professor, Department of Surgery, and Physiology, Faculty of Medicine, University of Toronto Senior Scientist, Toronto General Research Institute, University Health Network
On behalf of everyone at the IMS, I would like to wish everyone a happy and successful new year.
Sincerely, Mingyao Liu, MD, MSc
Director, Institute of Medical Science
IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH | 5
ARTIFICIAL INTELLIGENCE in
Translational Research By Meital Yerushalmi, Cricia Rinchon, and Hira Raheel
recent graduate course I took at the University of Toronto was concluded with the suggestion that in the “-omics” era, patient history and physical examination may be on their way out owing to advances in clinical technologies. While futuristic assertions of this type may seem fitting in a course dedicated to the application of advanced technologies in research and medical care, entertaining the idea of a time where technology could almost entirely eliminate the need for human interaction left me perplexed. The “-omics” era may hold true beyond the advances in the “-omics” of biomedical science, and we may see developments in engineering and computer science in medicine through the inclusion of artificial intelligence (AI) systems into the healthcare setting. But can AI replace the very human qualities of compassion, empathy, and creative thinking that remain difficult for a computer to emulate? AI often evokes thoughts of humanoid robots that imitate human consciousness, much like Ava from Ex Machina (2015) or Sonny from I, Robot (2004). Contrary to such common imageries from popular Hollywood films, AI does not necessarily strive to imitate human empathy, but rather in a more realistic setting, it uses algorithms, memory, and information about past, present, and future conditions to make rational decisions. Big data and
machine learning allow AI systems to learn through iteration, integrate new data, and adapt their algorithms based on previous experiences. From marketing to medical research and health care, AI systems are revolutionizing nearly every field imaginable. AI systems are already available to the public in various forms, such as Apple’s Siri and Microsoft’s Cortana, and have been adopted by large medical clinics to help physicians make decisions on treatments. Watson, a system developed by IBM, was unveiled to the public in 2011 on Jeopardy! as a question-answering AI system that uses machine learning and massive resources of information to answer trivia questions. Watson has since been in use at the Memorial Sloan-Kettering Cancer Center in New York to help diagnose and suggest evidence-based treatment options for lung cancer patients,1 thereby showcasing the implementation of AI in a real-world setting. IBM envisions “a new partnership between humanity and technology,” and Watson is only getting more accurate and confident in recommending treatment options. To many of us, a consideration of the importance of AI in translational research may be of interest. Translational research aims to implement findings from laboratory experiments into medical practice to improve treatment efficacy.
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This process typically involves a stepwise progression from basic science to clinical use, which may take up to 17 years before public health care benefits are seen from basic research findings.2 AI has the potential to considerably reduce this time lag and bring clinicians and researchers closer than ever before. The ability of AI systems to integrate information, automate large-scale quantitative analysis, and perform rational decision making enables biomedical researchers and clinicians to bring their research results to practical use in medicine. As IBM envisions, AI systems can work alongside physicians and researchers to serve as a valuable tool for providing the best treatment option. Students should be encouraged to embrace the integration of AI in research and clinical settings, and be able to benefit from it. Learning about how these systems work, as well as their limitations, would help students get ahead of curve. After all, with a system that potentially “has all the answers”, it is important that researchers know which questions to ask.
References 1. “Memorial Sloan Kettering Trains IBM Watson To Help Doctors Make Better Cancer Treatment Choices | Memorial Sloan Kettering Cancer Center”. Mskcc.org. N.p., 2016. Web. 12 Dec. 2016. 2. Morris ZS, Wooding S, Grant J. The answer is 17 years, what is the question: understanding time lags in translational research. Journal of the Royal Society of Medicine. 2011 Dec 1;104(12):510-20.
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IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH | 9
STANDARDIZED CARE or
PATIENT WELFARE? Novel Approaches to Clinical Training and Individualizing Treatment in Neonatal Health: An Interview with Dr. Patrick McNamara By Felicity Backhouse
r. Patrick McNamara has been a staff neonatologist at the Hospital for Sick Children since 2003. To address gaps in our current understanding of neonatal health, he headed a collaborative development of a training program for incoming neonatologists to increase the efficacy of diagnosis and treatment of neonatal hemodynamic disease. This program trains two neonatologists a year, and optimizes patient care by providing access to specialists with better insight into the health of a newborn’s heart. The program provides standardization of treatment with novel imaging techniques that are used for individualized treatment. Neonatology has expanded as a specialty over the past 30 to 40 years, and Dr. McNamara reflected on the progression in his field. “There has been a focus on neonatal lung disease, finding better ways to provide nutrition to babies, and in the last five to ten years, protecting babies’ brains from injury.” Despite recognizing the importance of addressing these issues, Dr. McNamara has noted many gaps in the field’s clinical focus, particularly the paucity of research trying to understand the neonatal heart. Dr. McNamara explained: “[Doctors] were making decisions about [neonatal] cardiovascular health based on very limited information… based on physiological and pathological guesses as opposed to managing actual physiology. A lot of our therapies from neonatology
have been translated down from adult medicine, and a lot of our therapies and approaches to care, when it comes to newborn hemodynamics, are based on blood pressure, not on physiology. So, babies would be managed in a very regimental way without actually thinking, ‘Is that therapy relevant to the physiology?’, and in some situations, the therapies that they may have been using were incorrect. In others, they may have been harmful.” According to Dr. McNamara, the presumed “gold standard” methods used to treat infants lacked solid evidence, including scientific or clinical validity. An example of such a treatment was the surgical ligation of vessels in premature infants to treat patent ductus arteriosus (PDA). Infants with PDA are born with blood vessels that have not closed, resulting in recirculation of oxygenated blood from the aorta to the pulmonary artery, at the expense of systemic circulation. In the mid-2000s, up to 80-90 babies per year underwent surgical ligation at the Hospital for Sick Children when medicinal therapies did not help close the ductus. Dr. McNamara revealed the problems with this treatment method in certain premature infants. “What was happening to these babies was they would come for surgery, they would look very good for the first 6 hours, and then in the middle of the night, the baby would start to become sick, develop very low blood pressure, and the clinical response [was] to give
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[vasoconstricting] drugs to increase blood pressure. The babies would continue to get sick and some even died. What had never been done was an actual physiological examination of what was actually going on with the babies.” Thus, a lack of specialized treatment was fatally affecting many premature babies. This limited understanding of infant mortality after surgical ligation encouraged Dr. McNamara to follow up with further research. “From a physiologic perspective, ligation of the ductus really means you are eliminating the low resistance pulmonary vascular bed from the systemic circulation. Before surgery, the left ventricle is pumping blood out of the aorta, most of which goes to the body, but some [which goes] back into the lungs leading to mixed resistance. Once you ligate the ductus, your peripheral vascular resistance, or the afterload to which the left ventricle is pumping, will rise, which increases the work of an immature left ventricle. Without this information, clinicians were only intervening when the blood pressure fell many hours after the initial change in physiology, and the use of vasoconstricting drugs to increase blood pressure was physiologically counterintuitive, and in some cases harmful.” A solution to this problem has been to better understand individual differences in response to treatment. Now, Dr. McNamara and his team perform echocardiograms on all patients after receiving a surgical ligation, which helps
Patrick McNamara PhD, MB, BCh, BAO, MSc, MRCP, MRCPCH
the team answer questions including, “Is the heart contracting well?”, “Are there transitional shunts?”, “What is the pressure in the lung?”, and “What is the pressure in the body?”. He described the novel diagnostic approach as a method of managing individual physiology, as opposed to previous treatment methods that provided little insight into the actual biological problem. For many new neonatology trainees, Dr. McNamara’s discoveries have provided practical applications for problem solving. “Now, if there are concerns with a patient’s heart, trainees will perform an echocardiogram and assess the patient clinically, and then the clinical team will have a discussion around the clinical results of the assessments.” For Dr. McNamara, “The impact of that has been
threefold: first, enhanced care for patients; second, provision of a higher and more thoughtful level of education for trainees; and finally and perhaps most importantly, identifying knowledge gaps which will lead to scientific discovery and novel approaches to intervention based on actual physiology and disease mechanisms.” Dr. McNamara explained that the program has been a catalyst for understanding issues with PDA surgical ligation and predicting which babies are likely to suffer from complications. Additionally, the program enhances the practice of managing pulmonary hypertension in preterm babies. In a short period of time, Dr. McNamara and his colleagues have helped establish similar training programs all across Canada, and are now working towards creating similar programs in the
United States. “This is now a clinical standard of care and it’s becoming an academic enterprise. Because we train people in a very standardized manner, we can now do multi-centre, collaborative, physiologybased studies across all Canadian sites because people are measuring the same thing in the same way, so it’s standardized. It is perfect in terms of doing collaborative research, team grants, et cetera.” Dr. McNamara has revolutionized the way we think about treating patients on an individual basis and has made great leaps in training the next generation of neonatologists. He has set the groundwork for further developments in neonatology which will surely lead to many improvements individualizing patient care.
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Photo credit Grace Jacobs
Clinician Investigator and Staff Neonatologist, The Hospital for Sick Children Associate Professor, Department of Paediatrics, and Physiology, Faculty of Medicine, University of Toronto Associate Scientist, Physiology & Experimental Medicine, Sick Kids Research Institute, The Hospital for Sick Children Associate Member, Institute of Medical Science
WHY SHOULD WE RESEARCH
Fetal Alcohol Spectrum Disorders
By Dr. Svetlana Popova
lcohol causes harm to more people than just the drinkers. Fetal Alcohol Spectrum Disorder (FASD) is one of the most dramatic examples of such harm. FASD is still an under-researched area, and I feel lucky to be working as an epidemiologist in this field. Fetal Alcohol Syndrome (FAS), the most severe form of FASD, was only officially recognized about 40 years ago when the first child diagnosed with the syndrome was described in the medical literature. Therefore, biomedicine, genetics, epidemiology, and other related fields of research are still in their infancy when it comes to FASD; we, the researchers, have a lot of things to discover. FASD is an “invisible” disability, which makes people with FASD invisible to society—rejected and forgotten. Although it is almost impossible to physically detect FASD, people with these neurological injuries due to prenatal alcohol exposure are unable to meet societal expectations. Indeed, FASD is a seriously debilitating condition as prenatal alcohol exposure affects not only the central nervous system, but also many other organs and systems of the body. In fact, over 400 co-morbid conditions that co-occur in individuals with FASD, spanning across 18 of 22 chapters of the International Statistical Classification of Diseases, were recently identified by our team at the Institute for Mental Health Policy Research, Centre for Addiction and Mental Health, and our findings were published in the Lancet earlier this year.1 Based on such a wide range of impairments, it is not
surprising that this population faces numerous challenges in all aspects of life. Almost all people with FASD have mental health problems, and a vast majority has a disrupted school experience. Many also have problems with addiction and exhibit inappropriate sexual behavior (i.e., assault, indecent acts). Moreover, a lot of these people cannot work and live independently, are homeless, and experience trouble with the law: our team recently demonstrated that FASD is a huge risk factor for incarceration. We estimated that in a given year, youths with FASD are 19 times more likely to be incarcerated than youths without FASD.2 Why do individuals with FASD experience more trouble with the law than the general population? People with FASD may have learning difficulties, exhibit impulsive behaviours, and generally have a poor understanding of societal norms and expectations. At the same time, they frequently aim to please others. These characteristics can make FASD-affected individuals vulnerable to manipulation by others and to involvement in crime. In addition to their intellectual impairment, about 80 percent of people with FASD face language difficulties, a huge barrier when communicating and defending themselves in legal proceedings. Other symptoms include poor memory and difficulty in learning from past experiences, which in turn may result in higher-than-average rates of recidivism—a vicious circle. Further, FASD is an intergenerational issue. Since intergenerational alcohol use problems are common, it is likely that parents of children living with FASD are
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themselves affected by FASD. There is also a heightened risk of FASD among younger siblings of affected elder siblings. Taken together, this suggests that FASD diagnosis is an important risk marker, not just for individuals with FASD, but also for their families.
Currently, the prevalence of FASD is unknown for most countries including Canada. According to a very conservative and rough estimate, approximately 1% of Canadians—about 355,000 people—may have FASD. Although it is not a very large population, the economic cost associated with their numerous problems is huge. Our team recently estimated that the annual cost associated with FASD in terms of health care, special education, social services, children in care, law enforcement, productivity losses due to morbidity, premature mortality, and other issues is about $1.8 billion in Canada.3 As the first step towards understanding the severity and impact of FASD in different parts of the world for the planning of adequate policy and program responses, the World Health Organization (WHO), with support of the National Institute on Alcohol Abuse and Alcoholism, initiated an International Collaborative Research Project on Global Prevalence of FASD. Our team at CAMH is in charge of this project. Currently, seven low- and middle-income countries from Central Europe, Eastern Europe, and Africa, as well as Canada, are involved in this project. The prevalence of FASD will be estimated by screening elementary school children (7-9 years of age) from different populations. Our team (the WHO Collaborating Centre)
Svetlana Popova, MD, PhD, MPH
Photo credit Dr. Svetlana Popova
Senior Scientist, Institute for Mental Health Policy Research, Centre for Addiction and Mental Health Associate Professor, Epidemiology Division, Dalla Lana School of Public Health, University of Toronto Associate Professor, Factor-Inwentash Faculty of Social Work, University of Toronto Graduate Faculty Associate Member, Institute of Medical Science, University of Toronto
at CAMH are providing coordination and technical support for project implementation.
other professionals. All of these initiatives have the potential to improve the diagnosis and monitoring of FASD.
In addition to active case-ascertainment studies, our team also recently provided global, regional, and country-specific estimates on the prevalence of FAS and prenatal alcohol consumption, using existing data from available published studies, and making predictions for countries with no data.4
Despite public health efforts, approximately one in every ten women in Canada consumes alcohol while pregnant,5 and one out of every 67 of these women will deliver a child with FAS. This translates to 119,000 children born with FAS in the world every year (estimated by our team).4 Therefore, further prevention efforts targeting prenatal alcohol consumption are needed.
Unfortunately, FASD is not wellrecognized by health professionals, so prevention, treatment, and care interventions are not being implemented or addressed at the policy and program levels. One of the main reasons for this is that FASD was not officially recognized as a medical diagnosis, and consequently, it was not included in either the Diagnostic and Statistical Manual of Mental Disorders (DSM), or the International Classification of Diseases (ICD; with the exception of Fetal Alcohol Syndrome). Only in mid-2013 was “Neurodevelopmental Disorder associated with Prenatal Alcohol Exposure (ND-PAE)” included in the appendix of the fifth edition of the DSM as a condition warranting future research. Another problem is that medical schools do not teach FASD diagnostic or screening procedures; very few medical doctors, usually only those specializing in the addiction field, receive training to diagnose FASD. It is crucial to include FASD in medical school curricula and implement mandatory training of healthcare providers, psychiatrists, psychologists, social workers, individuals working within the justice system, and
Lastly, there is an urgent need to establish an FASD surveillance system in order to monitor the incidence and prevalence of FASD throughout the world. Measuring the prevalence of FASD and monitoring its rates and trends over time in the general population, as well as in population subgroups, is necessary to understand and identify vulnerable populations, develop prevention and treatment resources, and establish benchmarks to evaluate the effectiveness of prevention and treatment strategies. Our team recently received funding from the Public Health Agency of Canada to develop a multi-source surveillance system on FASD and prenatal alcohol exposure in Canada, with the work set to begin in early 2017. Such departmental research milestones would be impossible to accomplish without the help of students, including students from the Institute of Medical Science (IMS): Shannon Lange (current PhD student), Kevin Shield (former PhD student), and Sameer Imtiaz (current PhD student). The longest
relationship I have had is with Shannon Lange, who started working with me in the field of FASD about six years ago as a volunteer, then as a research assistant, Master’s student, and currently, as an IMS PhD student. Her PhD research aims to develop a distinct neurodevelopmental profile of children with FASD, which will aid in its accurate diagnosis and help differentiate it from other idiopathic neurodevelopmental disorders (such as Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder, etc.). It will also improve targeted interventions and enhance clinical services to this population. In conclusion, I want to emphasize that FASD is preventable! However, there is no safe amount or type of alcoholic beverage, nor is there any safe time to drink alcohol during pregnancy. Make a safe choice for your child—do not drink any alcohol during pregnancy or when you are trying to get pregnant.
References 1. Popova S, Lange S, Shield K, et al. Comorbidity of fetal alcohol spectrum disorder: a systematic review and meta-analysis. Lancet. 2016;387(10022):978-87. 2. Popova S, Lange S, Bekmuradov D, et al. Fetal alcohol spe5ctrum disorder prevalence estimates in correctional systems: a systematic literature review. Can J Public Health. 2011;102(5):336-40. 3. Popova S, Lange S, Burd L, et al. The Economic Burden of Fetal Alcohol Spectrum Disorder in Canada in 2013. Alcohol Alcohol. 2016;51(3):367-75. 4. Popova S, Lange S, Probst C, Gmel G, Rehm J. (2017). Estimation of national, regional and global prevalence of alcohol use during pregnancy and fetal alcohol syndrome: a systematic review and meta-analysis. Lancet Global Health. doi: http://dx.doi.org/10.1016/ S2214-109X(17)30021-9. 5. Lange S, Quere M, Shield K, et al. Alcohol use and self-perceived mental health status among pregnant and breastfeeding women in Canada: a secondary data analysis. BJOG. 2016;123(6):900-9.
IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH | 13
Treating Depression in Women During By Yena Lee
n striving to implement her team’s research findings into clinical practice, Dr. Sophie Grigoriadis is at the forefront of clinical research. Her numerous clinical and academic affiliations put her at an optimal position for devising clinical tools for mental health practitioners. She is the Head of the Women’s Mood and Anxiety Clinic: Reproductive Transitions at the Sunnybrook Health Sciences Centre and is a scientist at the Sunnybrook Research Institute; an associate professor at the Institute of Medical Science, Department of Psychiatry, University of Toronto, and staff psychiatrist at University Health Network. Dr. Grigoriadis’s research interests focus on the treatment of mood disorders in women across the lifespan; of particular interest to Dr. Grigoriadis is antenatal depression (depression during pregnancy) and its short- and long-term health consequences on maternal and fetal health.
treatments can improve outcomes in antenatal depression.
Depression is a prevalent and pervasive mental illness that affects women differently across their lifespan, particularly during and after pregnancy. Approximately 10% of pregnancies worldwide are afflicted by antenatal depression, otherwise known as prenatal depression, which carries risks for both the mother and child. Mothers suffering from depression during their pregnancy carry a significant risk for post-partum depression, while their child may suffer poor short- and long-term health and developmental outcomes (e.g. preterm birth, lower breastfeeding rates, among others).1 Despite the significant consequences of depression on maternal and fetal health, up to 80% of women suffering from antenatal depression are not treated adequately.2 As part of this feature article, I met with Dr. Grigoriadis to discuss how depression affects maternal and fetal health and how existing
The diagnosis of depression in pregnant mothers is often missed because, in general, pregnant mothers often complain of depressive-like symptoms including fatigue, sleepiness, and poor attention and concentration, especially during the first trimester. What delineates pregnant mothers with depression from pregnant mothers without depression, however, is the presence of symptoms indicative of psychopathology, such as depressed mood, anhedonia [reduced or lack of ability to feel pleasure], decreased self-esteem, anxiety, rumination, hopelessness, and suicidality.
At what stage during a woman’s life is she most vulnerable to depression? Pregnancy and postpartum are peak periods. Whether it is more common for women to get depressed during pregnancy or in the postpartum period is still, to some extent, controversial. Some studies suggest that the prevalence of depression is highest in the second trimester of pregnancy, but the evidence is not consistent. Overall, it looks like women are at greatest risk for depression after giving birth. It’s important to note, however, that it’s not equally a high-risk period for all women in general; women with a history of anxiety and/or mood disturbances are at significantly greater risk. How is depression diagnosed during pregnancy?
What are the neurobiological correlates of increased vulnerability during the postpartum period? Taking a biopsychosocial approach, the postpartum period is a prime example of when an individual experiences
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significant biological, psychological, and social changes. For example, the significant endocrinological changes during pregnancy and around childbirth may explain some of the elevation in risk for depression. This change obviously doesn’t hold for all women so it’s just a part of the picture. Psychosocially, the postpartum period is a significant transition time—the mother needs to adjust to the new baby; if she was in a traditional relationship, her relationship with her husband changes as they both adjust to the baby individually and as a couple. Caring for a baby is very demanding and, of course, there’s sleep deprivation. The pathoetiology of depression during the postpartum period is an excellent example for how the biopsychosocial model can help us understand why women may be most vulnerable to depression during this period. How does antenatal depression affect the baby? We led a large systematic review and meta-analysis to examine the effects of antenatal depression on mothers and babies. We identified a number of factors that are potentially associated with depression during pregnancy, such as preterm birth; lower birth weight babies; and less breastfeeding initiation.1 A number of additional factors weren’t consistently significant including increased NICU admission, lower birthweight, and increased preeclampsia. Nevertheless, what’s important in a systematic review and meta-analysis is the data that goes into it. We had observational data, which isn’t as robust as data from randomized clinical trials, and I think with time and more data, the results may change. What we weren’t able to look at were the
Photo credit Mikaeel Valli
Sophie Grigoriadis PhD, MD,
FRCPC Head, Women’s Mood and Anxiety Clinic: Reproductive Transitions, Sunnybrook Health Sciences Centre Scientist, Sunnybrook Research Institute Associate Professor, Department of Psychiatry, Faculty of Medicine, University of Toronto Associate Member, Institute of Medical Science
long-term effects of exposure to depression in utero because we didn’t have the data to do that. Is depression associated with long-term effects in the child, like cognitive development and autism? That’s the area we know the least about because there isn’t enough data, but we do know that depression in the mother has been associated with depression in the child, even in teenagers. What are the current recommendations for treating depression during pregnancy? Generally, psychotherapy (e.g., cognitive behavioural therapy (CBT) and interpersonal psychotherapy (IPT)) is recommended for milder episodes, while medications are recommended as a first-line treatment for more severe episodes. When a patient is severely depressed, they may not have the cognitive ability to engage effectively in psychotherapy (although some evidence suggests that CBT may also be effective in treating more severe depression). Other therapies are being investigated, but there’s not yet sufficient evidence to make recommendations as first- or second-line treatment. It’s also important to discuss lifestyle changes like exercise, sleep normalization, and nutrition.
How effective are treatments for depression during pregnancy? The literature supports the efficacy of antidepressant therapy in the general population, but few studies assessed their efficacy specifically in pregnant women. One important consideration when treating pregnant women is the potential for adverse effects with pharmacotherapy. The meta-analytic work I previously mentioned also investigated the potential side effects of antidepressants, comparing unmedicated and medicated mothers with depression. As was observed among pregnant mothers with depression when compared to pregnant mothers without depression, antidepressants were associated with greater risk of preterm birth, lower APGAR scores, and poor neonatal adaptation syndrome, among others.3,4 Yet, it’s important to recognize that the effects that have been observed so far have very small odds ratios. One limitation of studying depression during pregnancy is the fact that you can’t randomize the women to treatment and no treatment groups and measure the differences in outcomes. I understand you’re developing a patient decision aid tool to educate women
with depression during pregnancy about available treatments. Could you tell me more about this tool? The patient decision aid tool came out of the meta-analysis we had discussed before, where we were looking at the effects of depression and antidepressants during pregnancy. We wanted to develop a “reference guide” to help clinicians facilitate treatment selection. We also wanted to look at the patient’s side to help with decisional conflict in treatment selection. Evidence suggests that pregnant women are hesitant to use medications, fearing their effects on the fetus, so the decision aid tool we’re working on looks at information we can give to patients to help her make a more informed decision. References 1. Grigoriadis S, VonderPorten EH, Mamisashvili L, Tomlinson G, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A, Radford K, Martinovic J, Ross LE. The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis. J Clin Psychiatry. 2013 Apr;74(4):e321-41. doi: 10.4088/ JCP.12r07968. 2. Stewart DE. Clinical practice. Depression during pregnancy. N Engl J Med 2011; 365:1605.1. 3. Grigoriadis S, VonderPorten EH, Mamisashvili L, et al. The impact of maternal depression during pregnancy on perinatal outcomes: a systematic review and meta-analysis. J Clin Psychiatry 2013; 74:e321. 4. Ross LE, Grigoriadis S, Mamisashvili L, Vonderporten EH, Roerecke M, Rehm J, Dennis CL, Koren G, Steiner M, Mousmanis P, Cheung A. Selected pregnancy and delivery outcomes after exposure to antidepressant medication: a systematic review and meta-analysis. JAMA Psychiatry. 2013 Apr;70(4):436-43. doi: 10.1001/jamapsychiatry.2013.684. Review.
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Dr. Emily Tam NEONATAL NEUROLOGIST, CLINICIAN-INVESTIGATOR, & MOTHER Emily Tam, MDCM, FRCPC, MAS Clinician Investigator and Staff Neurologist, The Hospital for Sick Children
Photo credit Sick Kids Photographer
Associate Scientist, Sick Kids Research Institute Assistant Professor, Department of Paediatrics, Faculty of Medicine, University of Toronto Associate Member, Institute of Medical Science
By Cricia Rinchon
r. Emily Tam completed medical training at McGill University (2003) and residency in Paediatric Neurology at The Hospital for Sick Children (SickKids) in 2008. She concurrently completed a fellowship in neonatal neurology and a Master’s in Clinical Research at the University of California San Francisco (2010). In 2012, she joined the Division of Neurology at SickKids as a Clinician Investigator with an expertise in neonatal neurology. Presently, she is investigating nutritional and metabolic risk factors for brain injury and adverse long-term outcomes in preterm and term newborns. What inspired you to pursue a career in neonatal neurology?
Throughout my early years, I was lucky enough to have inspiring role models and mentors who propelled me into this career path. When I think about the “beginning” of my journey, what comes to mind is being inspired by my own paediatrician. She had a strong character, with the ability to be productive as both a doctor and a mother. Later, during my undergraduate training at McGill University, I developed an interest in neurology and research. When combined with my early interest in paediatrics, paediatric neurology seemed like an appropriate career. Neonatal neurology was attractive to me—I was amazed by how new it was as a field and how much there is still left to learn. Even the founding fathers of neonatal neurology are still actively working.
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What inspired you to begin conducting research in addition to practicing as a physician? I started in the basic sciences, completing my undergraduate degree in biochemistry. Simultaneously, I developed an interest in becoming a clinician and a researcher. A defining experience was concurrently pursuing my neonatal neurology fellowship and Master’s in Clinical Research at the University of California San Francisco (UCSF). I had the wonderful opportunity to train with Dr. Donna M. Ferriero (MD, MS), the Chair of Paediatrics and Head of UCSF’s Children’s Hospital. She continues to be a great mentor who not only taught me clinical and research skills, but also showed me
how to balance the multiple aspects of my career and personal life. Fast-forward to the present day: there are many benefits to being able to wear both my clinician and researcher “hats.” While serving as a clinician, I can see patients and witness the results of my work in real time. On the other hand, the timeline of research is much longer, often spanning decades. The results may thus have a much broader and longer-lasting impact. The opportunity to do both—see patients and use these encounters to help formulate research questions—is an inspiring part of my job. What led to the hypothesis of your CIHR-funded study on neonatal hypoglycaemia entitled, “Neurological Outcome of Hypoglycemia in Neonatal Encephalopathy”? During my residency at SickKids, I conducted research on how hypoglycemia is associated with increased risk for brain injury and adverse visual outcomes. This is where my interest in how blood sugar levels affect development in babies began. It is surprising that something as simple and fundamental as blood sugar levels is still so poorly understood. Currently, intermittent blood tests are used to monitor blood sugar levels. However, now we can apply technology from the diabetes world, continuous glucose monitoring, to determine the duration and severity of low blood sugar that contribute to brain injury and adverse long-term neurodevelopmental outcomes in newborns. The aim is to develop evidencebased monitoring and intervention
strategies for blood sugar levels.
What would you consider the most rewarding part of your job?
What does a typical day for you look like? One of the greatest perks of my job is that I don’t really have a “typical” day. It does help to have some routine. Tuesday and Thursday afternoons I’m usually in the clinic, Mondays and Fridays are reserved mostly for research, and Wednesdays are full of meetings. Generally, I spend about half of my time dedicated to the clinic and the other half to research. Between both, I do a lot of teaching. SickKids is a teaching hospital where we train students, residents, and fellows. I also lead the Neonatal Neurology Fellowship Program. With all of these different “hats” that I’m wearing, there isn’t a standard day and it is all quite dynamic. What are some challenges to your line of work? Challenges, that really are advantages, are the many unknowns in the field of neonatal neurology. As I mentioned earlier, it is a relatively new specialty and there is a rapid rate of progression in research and technology resulting in tangible improvements for patients. For example, therapeutic hypothermia, which involves the deliberate reduction of core body temperature, has only recently been demonstrated to reduce morbidity and mortality after hypoxic-ischemic encephalopathy. In the last number of years, it has become standard-of-care throughout the world. It’s an exciting time to be studying brain injury in newborns, as there is still much for us to figure out.
You look at people with successful careers and personal lives, and you doubt your own ability to do the same.”
Each aspect of my job is rewarding in its own way. More specifically, I enjoy making the full circle of observing a question in clinic, conducting research to contribute to the bank of knowledge, and then working to implement these findings in the clinic. For example, we discovered that docosahexaenoic acid (DHA) is important in preterm brain development. Now, how can we change these levels? We also learned that steroids are bad—how do we minimize the negative effects safely? How do we apply the knowledge we acquire to improve the outcomes in newborns? Also, as head of the Neonatal Neurology Fellowship Program at SickKids, we train fellows from all over the world, including Asia, Europe, Australia, and North America. One of our recent graduates, Dr. Sangita Terumalay, has gone back to Malaysia and is the first neonatal neurologist in Southeast Asia. Knowing that I play a role in spreading our knowledge and skills world-wide is extremely rewarding. Thank you for agreeing to do this feature with us while you were on maternity leave. Do you have any advice for young researchers who hope to juggle as many “hats” as you? I want to encourage women to not feel like they need to choose between research and having children. Especially in Canada, academic institutions have made great strides in appreciating the benefits of supporting women on faculty, and encouraging their promotion. Everyone has been very supportive of my maternity leave time, and this has been a very positive experience for me. Having a child has definitely given me better perspective on my clinical work and research—this experience makes me a better paediatrician. I know it’s daunting to think about growing a family and growing a clinical and research career at the same time. You look at people with successful careers and personal lives, and you doubt your own ability to do the same. A good piece of advice from my mentor, Donna, which has stuck with me: “I didn’t do it all at the same time.”
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PAEDIATRIC MENTAL HEALTH
Photo credit Mikaeel Valli
An Interview with Dr. Daphne Korczak
Daphne Korczak, MD, MSc, FRCPC Director, Childrenâ€™s Integrated Mood and Body (CLIMB) Program, The Hospital for Sick Children Staff Psychiatrist, The Hospital for Sick Children, Assistant Professor, Department of Paediatrics, Faculty of Medicine, University of Toronto Associate Member, Institute of Medical Science
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By Arpita Parmar
r. Daphne Korczak is a Child and Adolescent Psychiatrist at the Hospital for Sick Children and an Assistant Professor at the Department of Psychiatry at the University of Toronto (U of T). She is also an associate graduate faculty member at the Institute of Medical Science. Dr. Korczak is the Director of the Children’s Integrated Mood and Body (CLIMB) Program, a unique clinical research initiative integrating physical and mental health. I had the opportunity to sit down with Dr. Korczak, who shared her passion of being a clinician-investigator dedicated to improving mental health outcomes in the paediatric population. Can you tell us about your Education background and training? I obtained my Bachelor of Science in Biological Sciences at the University of Guelph and also spent a year in England finishing my degree. I completed my medical training at Queen’s University and came to the University of Toronto for post-graduate training. I did my residency in paediatrics here at SickKids, and during that time I discovered how much I liked child psychiatry. I decided to do a second residency in psychiatry, and worked as a paediatrician during off-hours through the residency program. Afterwards, I completed my Masters of Science while on staff at SickKids.
adolescents and the relationship with future cardiovascular disease risk factors, such as obesity. Cardiovascular disease is known to be a leading cause of death in individuals with depression, and research has shown that teens with depression are at higher risk of developing atherosclerosis earlier, and dying prematurely from cardiovascular causes compared to their non-depressed peers. We are interested in understanding how and when this association occurs, so that we can improve the health outcomes of depressed children. As a result, we formed the Children’s Integrated Mood and Body (CLIMB) program, which was designed to integrate physical and mental health care using an interdisciplinary team, including experts in psychiatry, cardiology, endocrinology, and general paediatrics. Patients are referred to this program based on depressive symptoms, but cardiovascular factors are also assessed, and integrated recommendations are made. Our research projects are embedded within this program. What are the main impacts of your research?
What is the main focus of your research, and how is it interdisciplinary?
Our main impact (so far) has been in raising mental health awareness, particularly that children and adolescents can and do experience depression, and that effective treatments exist. Being at SickKids and having multiple areas of expertise under the same roof, allows us to ask the kind of impactful interdisciplinary research questions that we need to have answered. For example, through the CLIMB program we are able to increase awareness about the relationship of depression in childhood and adolescents and the risk of future obesity and cardiovascular disease. [For example], that physical and mental illnesses are commonly co-morbid and cluster together. In addition, as a result of the new knowledge and insights that we gain, we will be able to incorporate new suggestions for clinical care and provide our patients with more up to date and evidence-based information.
Over the last few years, I have been focusing on depression in children and
What are the main barriers to mental health care in the paediatric population?
Why did you decide to incorporate research into your career as a physician? I first became interested in research during my undergraduate degree, especially in England where there is a strong focus on reading current research and independent study. I was exposed to research again during my clinical training, and remembered the thrill of discovering, learning new things, and asking interesting questions. Being a clinician-investigator is having the best of both worlds: the clinical work informs the research, and the research enhances the clinical care.
The stigma surrounding mental illness remains the number one barrier. There are still a lot of children and families that are frightened about the prospect of having a mental illness; there are still a lot of myths and misperceptions about what that means. Because of stigma, patients may fail to recognize how treatable their condition may be, and may not seek help. This is very challenging for mental health care professionals, because if we can’t detect the problem, we can’t address it. What are some controversies in the field of mental health right now? Overall, there has been increased interest and excitement in understanding mental health problems and treatments, resulting in more potential treatments, or potential ways of managing mental health problems that are increasingly being suggested. The challenge is that there are many more suggested management strategies than there are data evaluating their evidence for efficacy, leaving patients and families asking about treatments that haven’t been evaluated yet. This can frustrate everyone—patients, families, and clinicians. What is the most rewarding part of your job? I have the best job! I get to work with an incredible team and international experts in the field. I also get to work in a teaching environment and see students grow, develop, and move on in their own careers. On top of that, I get to help children, and see patients improve and become healthy. What is your best advice for graduate students? Find good mentorship. I have had tremendous mentors and they have been key to my growth and development. Graduate students need to make sure they find a mentor that they trust and enjoy working with. Research is full of excitement, but also disappointments, so having a mentor that can support you and help guide you along the road is very important.
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The Lifelong Consequences of
Adverse Childhood Experiences By Yena Lee
hildhood abuse and neglect are prevalent and have enduring consequences on the overall health and development of affected children. Abuse and neglect may also impair children’s future economic and social mobility. The economic burden of childhood abuse and neglect in the United States is estimated to be approximately $124 billion, largely attributable to increased health care expenditure and debased human capital.1 These economic costs are to be considered alongside the tremendous human costs of adverse childhood experiences (ACEs). Decades of observational research indicate that ACEs are associated with lower levels of educational attainment and higher risk for mental and physical health conditions, teen pregnancy, juvenile delinquency, and adult criminality.2 The term ‘ACE’ was characterized by Kaiser Permanente and the Centre for Disease Control and Prevention (CDC) in the eponymous Adverse Childhood Experiences Study, published in 1998.3 Broadly, ACEs are defined as childhood exposure to abuse (e.g., emotional, physical, or sexual), neglect (e.g., physical, emotional), and/or
household dysfunction.3 Examples of household dysfunction include mental illness, domestic abuse, incarceration, and substance abuse among household members. The ACE study is, to date, one of the largest investigations of the longterm, cumulative effects of various forms of early childhood adversity on long-term health outcomes. The original ACE study surveyed more than 17,000 individuals and the CDC continues to periodically survey the prevalence and impact of ACEs in the United States. Childhood maltreatment and household dysfunction are more common than one might expect. Of those who participated in the original ACE study, more than half (52.1%) of respondents reported that they had experienced at least one form of ACE, while 6.2% reported exposure to at least four types of ACEs.3 In a 2016 update by the CDC, almost two-thirds (63.9%) of respondents reported exposure to at least one ACE and 12.5% of respondents reported exposure to at least four types of ACEs.4 Substance abuse in the household was most commonly reported, with over a quarter of respondents having lived with someone with alcoholism and/or illicit drug use. Of those reporting exposure to
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substance abuse in the household, 69% of respondents also reported additional forms of childhood abuse or household dysfunction. Sexual abuse in childhood was the second most commonly reported type of ACE (22.0%).3 More alarming than the prevalence of ACEs, however, may be the multiple linear, dose-dependent correlations between exposure to childhood adversities and various risk factors for mental and medical illnesses. Experiencing at least one category of ACE increased the odds of smoking, substance abuse, high-risk behaviour (e.g., sexual promiscuity), depressed mood, and history of suicide attempts. For example, individuals with one category of ACE were 1.5 times more likely than those without ACEs to have been depressed in the past year; this elevated likelihood increased to 4.6 times for individuals with four or more types of ACEs. Suicide attempts were 12.2 times more likely among those with at least four categories of ACEs when compared to those without ACEs. Cardiovascular and other seemingly unrelated medical conditions were also more common among those with ACEs, particularly among those with multiple categories of
ACEs. For example, individuals with at least four categories of ACEs were 2.2 times more likely than those without ACEs to have ischemic heart disease, 1.9 times more likely to have cancer, 2.4 times more likely to have a history of stroke, and 1.6 times more likely to have severe obesity.3 The short- and long-term social and health consequences of ACEs are hypothesized to be mediated, in part, by the neurobiological and anatomical changes that occur with exposure to psychological and/or physical stressors.5,6 Early childhood, especially before the age of five, is considered a window of opportunity for brain development because the brain is most vulnerable to changes in the external environment. Adverse childhood experiences can have detrimental effects on the brain and alter brain regions responsible for cognitive functions, such as fear- and anxiety-related behaviours (e.g., amygdala), decision-making (e.g., prefrontal cortex), and learning and memory (e.g., hippocampus).6 In addition to neurobiological and neuroanatomical sequelae, malnutrition, family violence, and other forms of ACEs can disrupt the normal development of other maturing organs. For example,
exposure to ACEs can lower the threshold for sympathetic activation, which may further heighten the risk for chronic disease. Excessive stress activation, via overstimulation of the hypothalamicpituitary-adrenal axis and autonomic, metabolic, and inflammatory systems, can shift the body’s resources to benefit immediate survival at the cost of longterm development.7,8 Taken together, ACEs can result in physiological disturbances and patterns of adaptation that undermine the affected child’s overall health and life prospects. There is a compelling need for effective interventions to promote health and prevent disease in young children and families experiencing significant adversity. For example, mentorship and coaching programs targeting caregivers raising children in less fortunate circumstances provide the tools for developing stable and supportive relationships with their children.9 These programs have been demonstrated to provide caregivers with transferable skills, which also improve their employability and likelihood of greater financial stability. While innovative strategies for reducing poverty, community violence, and other threats to a child’s well-being will reduce the likelihood
of exposure to ACEs, caregivers have a critical role in protecting young children, and interventional programs for reducing ACEs should provide support for caregivers to transform their own lives.
References 1. Fang X, Brown DS, Florence CS, et al. The economic burden of child maltreatment in the United States and implications for prevention. Child Abuse Negl 2012; 36: 156–165. 2. Lansford JE, Miller-Johnson S, Berlin LJ, et al. Early physical abuse and later violent delinquency: a prospective longitudinal study. Child Maltreat 2007; 12: 233–245. 3. Felitti VJ, Anda RF, Nordenberg D, et al. Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med 1998; 14: 245–258. 4. The ACE Study Survey Data. U.S. Department of Health and Human Services, Centers for Disease Control and Preventionhttps:// www.cdc.gov/violenceprevention/acestudy/about.html (2016, accessed 5 December 2016). 5. National Scientific Council on the Developing Child. From Best Practices to Breakthrough Impacts: A Science-Based Approach to Building a More Promising Future for Young Children and Families. Center on the Developing Child, Harvard Universityhttp://46y5eh11fhgw3ve3ytpwxt9r.wpengine.netdna-cdn.com/ wp-content/uploads/2016/05/From_Best_Practices_to_Breakthrough_Impacts-3.pdf (2016). 6. Shonkoff JP, Garner AS, Committee on Psychosocial Aspects of Child and Family Health, et al. The lifelong effects of early childhood adversity and toxic stress. Paediatrics 2012; 129: e232–46. 7. McEwen BS. In pursuit of resilience: stress, epigenetics, and brain plasticity. Ann N Y Acad Sci 2016; 1373: 56–64. 8. Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiol Behav 2012; 106: 29–39. 9. Shonkoff JP, Fisher PA. Rethinking evidence-based practice and two-generation programs to create the future of early childhood policy. Dev Psychopathol 2013; 25: 1635–1653
https://www.cdc.gov/violenceprevention/acestudy/ace_graphics.html IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH | 21
BIOMEDICAL COMMUNICATIONS MASTER OF SCIENCE IN
As a student in the Biomedical Communications Masters program, Savanna said that her goal in creating the piece is to capture atherosclerosis on both the cellular and gross anatomical level. She wanted to demonstrate the highly complex cellular composition of an atherosclerotic plaque while also clearly exhibiting how the slow buildup of local cellular changes within a vessel can have large-scale effects on cardiovascular health. Currently, Savanna is creating a 2D animation to explain her Masterâ€™s Research Project CANVIS: Citation, Annotation & Visualization Integration System, a web application that will allow medical illustrators to embed citation information directly into their visual media.
Savanna Jackson, IT7 22 | IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH
As a student in the Biomedical Communications Master’s Program, Mark is interested in merging illustrations with didactic and educational materials. He is currently working with a team of nephrologists and transplant specialists at St. Joseph’s Healthcare Renal Transplant Program (Hamilton) to develop a 2D animation reinforcing the importance of post-transplant medication adherence. Over the summer, Mark had the opportunity to create medical illustrations for McMaster University’s Education Program of Anatomy. Mark also enjoys flexing his creative and artistic skills in commercial projects outside of medical illustration. More of Mark’s work can be found at www.markbelan.com.
Mark Belan, IT7 IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH | 23
Real Relief Artwork by Nancy Ji Chu
By Sarasa Tohyama
uring World War II, wounded American soldiers were treated with morphine, a drug used to relieve pain. When morphine ran out, then medic Henry Beecher decided to replace it with saline solution but continued telling the soldiers that they were receiving morphine. Astoundingly, almost half of the soldiers reported pain relief from the saline treatment. Today, we understand the saline solution to be a placebo. In general, a placebo constitutes a substance, measure, or procedure that offers no intended therapeutic value to the patient. The resulting symptom improvement from a placebo is known as the placebo effect— precisely the phenomenon that Beecher discovered. But how real is the placebo effect? Is it just an illusion, or is it a tangible psychological response? Is there a biological explanation to prove it? Scientists have begun to uncover the mystery behind our brain’s natural ability to self-medicate.
through a number of psychological factors, including verbal suggestion, conditioning, observational learning, interpersonal interactions, and psychological disposition. These factors generate expectations that elicit the placebo effect. The phenomenon is well documented, particularly for conditions that rely on subjective symptoms, such as pain and depression. For example, Kam-Hansen and colleagues1 found that patients with migraine headaches who took a placebo labeled as “ritzatriptan”—a treatment
The placebo effect is thought to occur 24 | IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH
for migraines—experienced the same magnitude of pain relief compared to patients who took ritzatriptan labeled as “placebo.” However, when ritzatriptan was correctly labeled, its therapeutic effect increased by 50%. This study not only demonstrates the placebo effect in chronic pain patients, but also reveals the powerful influence that expectations have on placebo response. Psychological factors that mediate the placebo effect are associated with certain
The placebo effect is an enigma that scientists and clinicians have puzzled over for decades.”
neurobiological mechanisms in the brain. When wounded American soldiers were given morphine, the drug acted directly on the brain’s opioid system, which reduced their pain. Levine, Gordon, and Fields2 were the first researchers to demonstrate that the same opioid system generates the placebo effect in pain. Following Levine and colleagues’2 innovative work, subsequent brain-imaging studies have confirmed the involvement of the opioid system in placebo analgesia (i.e., the placebo effect in pain). 3-10 Neurobiological evidence suggests that patients are not pretending to experience relief, nor are they imagining it. In fact, when given a placebo, their brain mimics the effects of the real treatment. Time and time again, researchers have found that placebo treatments produce real biological responses and patients report genuine symptom relief. The idea of using sugar pills to treat patients sounds absurd, but given the real effects that placebos have, could we actually incorporate placebos in medical care? Until recently, the use of placebos in clinical practice was controversial because of the assumption that deception is required for placebos to work (i.e., doctors lie to patients, who must falsely believe that they are taking a real drug to experience any benefit). Deception violates the code of conduct that forms the foundation for the doctor—patient relationship—it is ethically unacceptable. Consequently, placebo treatments have historically been greatly criticized. However, Ted Kaptchuk, director of the Program in Placebo Studies and the Therapeutic Encounter (PiPS) at Beth Israel Deaconess Medical Center and Harvard Medical School, and his colleagues found that patients with migraines, 1 irritable bowel syndrome,11 depression,12 and more recently chronic low back pain,13 who are administered “open-label” or “honest” placebos (i.e., patients are honestly told that they will be receiving a placebo), experience significant symptom improvements. This new line of evidence challenges the belief that deception is necessary to produce placebo
effects. More importantly, it demonstrates the overwhelming influence psychological factors have on treatment response— simply engaging in the medical routine (i.e., visiting the hospital, being cared for by a healthcare practitioner, swallowing a pill, etc.) alters brain chemistry to heal symptoms. Open-label placebos are revolutionary and provide new opportunities to design personalized treatment regimens. For example, Carvalho and colleagues’13 study of chronic low back pain patients showed that compared to patients who remained on their usual medication, patients who knowingly took two placebo pills on top of their treatment regimen experienced significant pain reduction. Adding sugar pills to a patient’s existing treatment plan may be beneficial, especially if patients are resistant to treatment. However, instead of adding open-label placebos, a potential avenue of treatment could be to intersperse placebos with real drugs, thus controlling for the side effects and toxicity of a drug. For instance, if a patient were prescribed morphine once a day, everyday, and experiences nausea and constipation, one could replace morphine with placebo twice a week, to reduce the side effects while maintaining the drug response. This approach could also prevent harmful reactions such as drug abuse, addiction, tolerance, and even reduce costs. Open-label placebos may also determine how well patients respond to real drugs even before they begin a treatment plan. Peciña and colleagues14 found that depressed patients who respond more strongly to placebo treatment (shown by subjective report of relief and engagement of emotion-related brain areas) experience greater benefit when subsequently given a real antidepressant medication. Although Peciña and colleagues’14 study did not use open-label placebos—patients were told they were receiving a new drug for depression before receiving existing antidepressants—researchers may have seen very similar results if openlabel placebos were used. Therefore, for conditions that are known to have large placebo effects, such as pain and depression, one strategy to predict whether
a real drug would be effective is to use open-label placebos as a first line of treatment. The placebo effect is an enigma that scientists and clinicians have puzzled over for decades. We are now beginning to understand the biopsychosocial factors that influence the placebo effect, and the tremendous impact a person’s psychology has on treatment response. While the concept of open-label placebos is in its infancy, attitudes about placebos are changing, and so have strategies to develop a more personalized medical approach. For certain conditions, placebos have the potential to become a legitimate component of a patient’s treatment plan. Placebos cannot shrink tumours, cure cancer, or repair broken bones, but their effect on disorders like pain, depression, or anxiety could be remarkable. References 1. Kam-Hansen S, Jakubowski M, Kelley JM, Kirsch I, Hoaglin DC, Kaptchuk TJ, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Science Translational Medicine. 2014;6(218):218ra5-ra5. 2. Levine J, Gordon N, Fields H. The mechanism of placebo analgesia. The Lancet. 1978;312(8091):654-7. 3. Eippert F, Bingel U, Schoell ED, Yacubian J, Klinger R, Lorenz J, et al. Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron. 2009;63(4):533-43. 4. Petrovic P, Kalso E, Petersson KM, Ingvar M. Placebo and opioid analgesia--imaging a shared neuronal network. Science. 2002;295(5560):1737-40. 5. Scott DJ, Stohler CS, Egnatuk CM, Wang H, Koeppe RA, Zubieta JK. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Archives of General Psychiatry. 2008;65(2):220-31. 6. Wager TD, Scott DJ, Zubieta JK. Placebo effects on human μ-opioid activity during pain. Proceedings of the National Academy of Sciences. 2007;104(26):11056-61. 7. Zubieta JK, Bueller JA, Jackson LR, Scott DJ, Xu Y, Koeppe RA, et al. Placebo effects mediated by endogenous opioid activity on μ-opioid receptors. The Journal of Neuroscience. 2005;25(34):7754-62. 8. Bingel U, Lorenz J, Schoell E, Weiller C, Büchel C. Mechanisms of placebo analgesia: rACC recruitment of a subcortical antinociceptive network. Pain. 2006;120(1):8-15. 9. Lui F, Colloca L, Duzzi D, Anchisi D, Benedetti F, Porro CA. Neural bases of conditioned placebo analgesia. Pain. 2010;151(3):81624. 10. Wager TD, Rilling JK, Smith EE, Sokolik A, Casey KL, Davidson RJ, et al. Placebo-induced changes in FMRI in the anticipation and experience of pain. Science. 2004;303(5661):1162-7. 11. Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP, et al. Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PloS One. 2010;5(12):e15591. 12. Kelley JM, Kaptchuk TJ, Cusin C, Lipkin S, Fava M. Open-label placebo for major depressive disorder: a pilot randomized controlled trial. Psychotherapy and Psychosomatics. 2012;81(5):3124. 13. Carvalho C, Caetano JM, Cunha L, Rebouta P, Kaptchuk TJ, Kirsch I. Open-label placebo treatment in chronic low back pain: a randomized controlled trial. Pain. 2016;157(12):2766. 14. Peciña M, Bohnert AS, Sikora M, Avery ET, Langenecker SA, Mickey BJ, et al. Association between placebo-activated neural systems and antidepressant responses: neurochemistry of placebo effects in major depression. JAMA Psychiatry. 2015;72(11):108794.
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Challenges of Research
in Children: Applying Adult Data to Paediatric Populations By Arman Hassanpour
t may come as no surprise to our readers that it is challenging not only to conduct a well-designed research trial, but also to decide who will benefit from its findings. In the field of translational medicine, paediatric research is especially difficult. Projects involving paediatric subjects often require closer attention to risk avoidance, making it easier for researchers to only use adult subjects. Thus, health research is generally done on adults and later extrapolated to children.
Paediatrician Harry Shirkey coined the term â€˜therapeutic orphansâ€™ about 60 years ago to explain the lack of and insuffiencies in paediatric research at the time.1 Since then, efforts have been made to include more children in clinical research. Specifically, the passage of the Best Pharmaceuticals for Children Act in 2002 and the Paediatric Research Equity Act in 2003 by the Food and Drug Association (FDA) triggered a rapid emergence of paediatric studies.2 However, there remain
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a number of challenges to overcome before establishing clinical paediatric research as standard practice. With rapid advancements in health care and the increasing importance of translational research, more efforts should be undertaken to fill the gap between adult and paediatric research. This article aims to illuminate some unique challenges involved in the field of translational paediatric research and cast light on the
Children are not simply tiny adults, but an estimated 80 to 90% of current drugs are prescribed to children without paediatric—specific guidelines.”
applicability of adult data to paediatric cohorts. Challenges that discourage researchers and sponsors from conducting paediatric research can be categorized into two groups: ethical and methodological, and financial. First, ethical and methodological challenges encapsulate issues including informed consent and limitations in data collection. Depending on the circumstance, informed consent is obtained from parents or legal guardians; if possible, assent is obtained directly from the child. This can be an ethically taxing task because young children often lack effective communication skills. Hence, the involvement of adults—such as parents or social workers—is often necessary. Involving these ‘gatekeepers’ is known to complicate the consent process.3 Furthermore, researchers may have difficulty identifying when participation becomes harmful for the child—that is, deciding when it is ethically necessary to discontinue the research. For example, the cries of an infant may have a variety of causes, but a researcher must interpret when they become a sign of pain caused by an intervention. These types of communication challenges also limit how much information can be acquired from the participant regarding aspects of the treatment, such as its effectiveness or ease. This can limit the progression of research, which is of high significance to the researcher. Secondly, financial challenges can impact industries that focus on the development of diagnostic and therapeutic tools.
When there is a small market (in this case, the paediatric patient population) for a potential product, commercial, or industry sponsors may be reluctant to fund the necessary research. Rare paediatric diseases are appropriately named ‘orphan diseases,’ since the cost of developing treatments cannot be recuperated by the estimated amount of sales. In part due to these challenges, adult data is often applied to paediatric populations. For example, treatments are assumed to perform similarly in children as in adults— with slight allometric adjustments—unless there is proof to the contrary. Children are not simply tiny adults, but an estimated 80 to 90% of current drugs are prescribed to children without paediatric-specific guidelines.4 As an example, adjustments in drug dosages are often based on body weight rather than age, because the impact of age on pharmacodynamics and drug toxicity profiles are understudied.5 Historically, applying adult data to children has had mixed results: many cases have met with success, but other cases have had benign or even harmful results.5 Considering the financial burden and time investment associated with developing treatments, even neutral outcomes can be considered detrimental.3 Moreover, it is possible that incorrect dosages preclude children from reaping the full benefit of the treatment.4 The most prominent objective of a doctor is not to treat the disease but in fact primum non-nocere: above all, do no harm! Treatments that have only been tested in adults present paediatric
physicians with an ethical dilemma: refuse to treat a child based on evidence from adult populations, or treat the child. Naturally, physicians rely on their clinical experiences and professional judgment and perform a risk assessment.4 This in itself is subject to errors and is not a completely objective process. Although there is considerable overlap in the pathophysiology of adults and children, there are also surprising and important differences.6 There is no way to confidently predict when a drug tested in adults is both beneficial and safe in children until it is formally studied. Will the gaps in knowledge between adult and paediatric research be filled in the near future? The answer lies in the hands of policymakers, granting agencies, and researchers. The current trend is promising as many translational researchers aim to fill these gaps and government institutes encourage their efforts. For example, the National Institute of Health requires full inclusion of children in clinical research unless exclusion is justified. Another noteworthy example is the work of the Canadian Laboratory Initiative on Paediatric Reference Intervals at SickKids Hospital in Toronto, which is establishing age-specific reference intervals for serum analyte concentrations.7 These ranges are used as a diagnostic reference tool by physicians to interpret blood results, since diagnostic references based solely on adult data are highly unpredictable.7 With these efforts in progress, it is clear that robust evidence and scientific reasoning must be prioritized in order to overcome the challenges of paediatric research and to create a more personalized medical approach for patients.
References 1. Berlin CM. Advances in paediatric pharmacology, therapeutics, and toxicology. Adv Pediatr 2001;8:439-464. 2. Christensen ML. Best Pharmaceuticals for Children Act and Paediatric Research Equity Act: Time for Permanent Status. J Pediatr Pharmacol Ther. 2012;17(2):140–141. 3. .Fargas-Malet M, McSherry D, Larkin, et al. research with children: methodological issues and innovative techniques. J Child Res.2010;8(2) 175–192. 4. Field MJ, Berman RE, editors. The Ethical Conduct of Clinical Research Involving Children. National Academies Press: Washington (D.C); 2004. 5. Cella M, Knibbe C, Danhof M, et al. What is the right dose for children? Br J Clin Pharmacol.2009;70(4):597-603. 6. Stephenson T. How children’s responses to drugs differ from adults. Br J Clin Pharmacol.2005;59(6):670-673. 7. Jung B, Adeli K. Clinical laboratory reference intervals in paediatrics: The CALIPER initiative. Clin Biochem 2009;42(16-17): 1589-1595.
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Is Interactive By Anna Badner
eer review is at the heart of scientific publishing. It is the primary mechanism for evaluating articles prior to publication and serves as a quality control system for completed research. In its current form, peer review involves the assessment of submitted manuscripts by independent experts in the field. This process is double blind, where both the reviewer and the author are anonymous, or single blind, with only reviewer anonymity. Although peer review is widely accepted as an effective means of research validation, it is not without disadvantages and has been widely scrutinized within the scientific community. For these reasons, the IMS Magazine decided to review the history of peer review, comment on current limitations, and describe the innovative steps taken to improve the process.
assessed by a selected group of members familiar with the subject matter. By 1854, the Society established a monthly periodical entitled Proceedings of the Royal Society, which included the publication of these peer review reports. It is interesting to note that, to date, the Proceedings of the Royal Society continues to publish in physical (Proceedings A) and biological (Proceedings B) science. Following public exposure, mainly at the hands of the Royal Society, peer review practice was gradually adopted by other academic communities and later by independent journals. Yet, it was not until after World War II, with increased subject specialization and technological advances, that peer review became recognized as an important standard in scientific
Through interactive collaboration, peer review can be more consistent, less biased.â€?
The History of Peer Review Philosophical Transactions, one of the first scientific journals, was founded by Henry Oldenburg in 1665. Although an official journal of the Royal Society of London, article selection and review was largely at the hands of the editor. It was not until 1752, when the Society took over editorial responsibility, that manuscripts were
publishing. While some journals were quick to adapt, others, such as the Lancet, were resistant and did not implement peer review until 1976. Moreover, without the establishment of evidence-based guidelines and regulation, peer review quality was, and continues to be, prone to bias, inconsistency, and consequently, ineffectuality.
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The Good, the Bad, and the Ugly In general, with present day competition and pressure to publish, peer review functions as a critical filter for manuscript publication. Although important, the process also has several limitations, with referee bias as a leading example. A recent Journal of the American Medical Association (JAMA) study demonstrated that author, as well as institutional prestige, influenced manuscript acceptance, when comparin g recommendations in single blind versus double blind review. A similar bias exists against studies with negative results, as journals are not willing to publish manuscripts that fail to reproduce or refute the work of others. This is especially problematic, as it leads to exaggerated effects in later meta-analyses. Related to referee bias is the issue of review inconsistency. Plenty of studies on peer review have reported low inter-rater reliability, highlighting the poor level of agreement between reviewers when evaluating manuscripts. In one study of review reproducibility, the authors determined that agreement between reviewers was only slightly greater than would be expected by chance alone, comparable to a coin toss. While diversity of opinion may be beneficial, considering that referees have unique expertise and specialization, this inconsistency presents a major barrier to measuring the quality of science. Moreover, a poorly defined evaluation criteria involving the assessment of novelty, soundness, and significance (which are largely open to interpretation), may also decrease interrater reliability. The implementation of
standardized assessment forms has been just one of many suggestions to increase referee agreement and improve overall review consistency. Expanding on the limitations, peer review is also slow, costly, and without incentives. The presence of progressively complex data, in a competitive environment, requires considerable time to review. This time could be spent securing grants and completing research, presenting a significant cost to reviewers. Therefore, with little incentive, referees are increasingly likely to decline participation in favor of spending their time more productively. So, it is not surprising that there is a growing demand for qualified and committed reviewers. With these issues in mind, metrics of academic recognition, such as the R-index, have been proposed to encourage referee participation. Yet, it is unclear if these measures can be adopted by the whole academic community.
Innovation in Peer Review: Interactive Collaboration Beyond standardized assessment forms and academic recognition, journals are looking to replace the traditional system of peer review with a more modern approach. Interactive collaboration during peer review aims to provide timely, consolidated, constructive, and fair feedback. One of the most successful examples of this practice has been through the online open-access journal, eLife. Funded by the Howard Hughes Medical Institute, the Max Planck Society, and the Wellcome Trust, eLife was established
in 2012 with the goal of revolutionizing scientific publishing. Uniquely, eLife assigns a reviewing editor to serve as one of the referees, who initiates online discussion once the independent reviews have been received. In this process, the referees and their comments are made known to each other. Following discussion, the reviewers generate a unified decision letter with directive comments. The consolidated decision letter is meant to provide clear guidelines for manuscript improvement that, if followed, will ensure publication. The success of this system was further evaluated in a recent F1000Research study, where the authors found that having editors assist with peer review significantly shortened decision times, without affecting submission acceptance or rejection. Other publishing companies, like Elsevier, have also been experimenting with alternative review. In a trial, three Elsevier journals, Cell, Neuron, and Molecular Cell, used the Mendeley reference manager for anonymous referee collaboration. While there were concerns of increased workload for referee and editors, the overall responses were positive and the interactions were thought to improve overall review quality. The current results are promising and will hopefully gain momentum in the next few years. Since its conception in the 18th century, peer review has remained largely unchanged. Now, with significant technological advances and ease of communication, it is time to fix the broken system. Through interactive collaboration, peer review can be more consistent, less
biased; through open discourse with colleagues, referees can be recognized for their efforts. Most importantly, these innovations in peer review can produce better revisions and yield better publications. References 1.
Csiszar A. Peer review: Troubled from the start. Nature. 2016;532(7599): 306-8. 2. Spier R. The history of the peer-review process. Trends Biotechnol. 2002;20(8): 357-8. 3. Kronick DA. Peer review in 18th-century scientific journalism. JAMA. 1990;263(10): 1321-2. 4. Shema H. The Birth of Modern Peer Review. Scientific American. [Cited 2016 Dec 4] Available from https://blogs.scientificamerican. com/information-culture/the-birth-of-modern-peer-review/ 5. Benos DJ, Bashari E, Chaves JM, et al. The ups and downs of peer review. Adv Physiol Educ. 2007;31(2): 145-52. 6. Okike K, Hug KT, Kocher MS, et al. Single-blind vs Double-blind Peer Review in the Setting of Author Prestige. JAMA. 2016;316(12): 1315-6. 7. Dirnagl U, Lauritzen M. Fighting publication bias: introducing the Negative Results section. J Cereb Blood Flow Metab. 2010;30(7): 1263-4. 8. Ioannidis JP. Why most published research findings are false. PLoS Med. 2005 Aug;2(8):e124. 9. Lindsey D. Assessing precision in the manuscript review process a little better than a dice roll. Scientometrics 1988; 14: 75-82. 10. Bornmann L, Mutz R, Daniel HD. A reliability-generalization study of journal peer reviews: a multilevel meta-analysis of inter-rater reliability and its determinants. PLoS One. 2010;5(12): e14331. 11. Rothwell PM, Martyn CN. Reproducibility of peer review in clinical neuroscience. Is agreement between reviewers any greater than would be expected nby chance alone? Brain. 2000;123 (Pt 9): 1964-9. 12. Strayhorn J Jr, McDermott JF Jr, Tanguay P. An intervention to improve the reliability of manuscript reviews for the Journal of the American Academy of Child and Adolescent Psychiatry. Am J Psychiatry. 1993;150(6): 947-52. 13. Smith R. Peer review: a flawed process at the heart of science and journals. J R Soc Med. 2006;99(4): 178-82. 14. Cantor M, Gero S. The missing metric: quantifying contributions of reviewers. R Soc Open Sci. 2015;2(2): 140540. 15. Schekman R, Patterson M, Watt F, et al. Launching eLife, Part 1. Elife. 2012;1: e00270. 16. Schekman R, Watt F, Weigel D. The eLife approach to peer review. Elife. 2013;2: e00799. 17. Giordan M, Csikasz-Nagy A, Collings AM, et al. The effects of an editor serving as one of the reviewers during the peer-review process. Version 2. F1000Res. 2016; 5:683. 18. Carniol K, Pham J, LeMasurier M. Experimenting with collaborative peer review. Elsevier Connect. [Cited 2016 Dec 4] Available from https://www.elsevier.com/reviewers-update/story/innovation-in-publishing/experimenting-with-collaborative-peer-review
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FEINSTEIN By Alexandra Mogadam and Melissa Galati
espite the demanding nature of the clinician-scientist lifestyle, the beauty of the profession stems from those “Aha” moments—the moments that occur in either the clinic or the lab that change the trajectory of work being done in the other realm. Dr. Anthony Feinstein, a psychiatrist at Sunnybrook, had one of those moments 16 years ago when he encountered a particularly interesting patient—a frontline journalist who suffered from post-traumatic stress disorder (PTSD). Over the years, Dr. Feinstein’s medical education and career have taken him around the globe. His journey began in South Africa, where he obtained his medical degree at the University of Witwatersrand in 1980. Following his interest in neuroscience, he started a neurosurgery residency in Johannesburg, South Africa, but changed his path a year later to pursue psychiatry. While he was initially interested in solely practicing medicine as a psychiatrist, during his residency he was encouraged to pursue research in addition to clinical work: “I wanted to be a clinician, and along the way you meet people who change the course of your life. I’ve had a couple in my life… I had a mentor in England who was a well-known neuro-psychiatrist by the name of Maria Ron… She taught me how to write and got me interested in research. She got me to love research.” Dr. Feinstein credits his mentor for
changing the trajectory of his career. He completed his residency and subsequently embarked on a PhD with Dr. Ron, focusing on multiple sclerosis (MS). While the bulk of his work today still centres on MS, he has been inspired to study the stress and emotional health of frontline journalists as well. This topic has been a consistent thread of work over the last 16 years of his career and is something that he is still passionate about today. His studies ask questions about how journalists cope with the pressures of frontline reporting, how this affects them in the long-run, and what motivates reporters to pursue such a career given the dangers involved. This work, widely different from his other research, was inspired by a patient—a war journalist— who suffered from PTSD when returning home in 2000. Upon reviewing the literature, Dr. Feinstein was astonished to learn that not a single publication existed on war and journalism at that time. “To step into a research field and not find anything… I mean, I didn’t believe it!” Dr. Feinstein recalls. “It seemed to me such a big clinical issue given what my patient had been through.” He quickly wrote a grant to an organization called the Freedom Forum, based out of Washington DC, which was accepted soon after. His initial work on war journalism spawned several interesting findings. Of particular interest was his discovery that there are no differences in PTSD or moral
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injury between genders. Dr. Feinstein describes ‘moral injury’ as experiencing the loss of one’s moral compass, something that has traditionally been investigated and written about in returning war veterans. This lack of difference between genders in psychological burden is unlike what is found in the general population, where women tend to experience higher levels of anxiety, depression, and PTSD than men. “I think that’s because the women who choose this [field] are a very select group of women. It’s a self-selection process… The very fact the group [of women] does this work comes with a degree of innate resilience.” Since his studies on Western journalists, Dr. Feinstein has also studied Mexican media coverage of local drug wars. Similarly, he has investigated the burden of reporting in Syria, Kenya, Iran, and, most recently, journalists following the refugee crisis in Europe. These reporters investigate and write about conflicts within their own countries: drug wars, terrorism, geopolitical instabilities, and human crises. This is unlike the Western journalists in Dr. Feinstein’s original project, who return home to safety after their investigation is complete. Through his diverse work on frontline reporting, Dr. Feinstein has revealed that cultural factors are important determinants of the psychological wellbeing of news writers covering conflict. In these international projects, Dr. Feinstein works closely with collaborators native to the subject country and states
FACULTY SPOTLIGHT cornerstone to change,” concludes Dr. Feinstein. Besides the traditional academic channels of knowledge dissemination, Dr. Feinstein has written for a lay audience and produced a documentary—Under Fire: Journalists in Combat. When asked about his experience in translating his research from paper to film, Dr. Feinstein was enthusiastic: “I have to tell you, it was tremendous fun... There’s something about seeing your stuff on the big screen… I ended up with a Hollywood agent for a few months!” Under Fire was very well received, and was even short-listed for an Oscar. In light of the emotional pressures of his clinical work, we wondered how Dr. Feinstein maintains a balance in his own life: “I’m a clinician-researcher. Part of my week is seeing patients, but the other part is doing research. That’s a wonderful balance because I try to get my research to address clinical questions. The clinical work can get heavy, but then you step out of it for a bit and spend time meeting with your research team, writing papers, analyzing data, or working on a grant. So it’s a very nice balance.”
MBBCh, MPhil, PhD, FRCPC Director, Neuropsychiatry Sunnybrook Health Sciences Centre Associate Scientist, Sunnybrook Research Institute, Professor, Department of Psychiatry, Faculty of Medicine, University of Toronto Member, Institute of Medical Science
When asked if he might have the chops to be a frontline journalist himself, Dr. Feinstein laughed, “No, definitely not.”
that establishing trust is critical in these studies.
Dr. Feinstein’s diverse research interests and pursuits demonstrate that careers are subject to changes in trajectory that are not always foreseen. His story is a reminder to be open to guidance from mentors, as well as to have the courage to recognize and pursue the unexpected and curious opportunities that fall into our laps. Inspired by one person’s story, Dr. Feinstein established a new area of research and made it his niche; he was confident in his curiosity, and he let it guide him to where he stands today.
Dr. Feinstein adds that once a study is completed, the data generated are always returned back to the country in which the study was conducted so that the findings can be used to inspire change. He notes that his initial paper on Western journalists, published in the American Journal of Psychiatry in 2002, was influential in new policy development, and changed the way Western news
Although he doesn’t pursue journalism in his spare time, Dr. Feinstein has many other hobbies and interests outside of work. He enjoys watching chess tournaments and the Toronto Blue Jays. He also loves music and plays the violin.
organizations prepare and look after their staff. In his recent study on Iranian reporters, Dr. Feinstein’s team found that there was a significant correlation between symptoms of depression, PTSD, and psychological distress and barbiturate abuse. Despite challenges with implementing policy changes in the countries under study, Dr. Feinstein remains hopeful that local journalists will use the data to raise awareness on the psychological burden of frontline journalism. “I think education is the
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Dr. Michael Richards By Samia Tasmim
Photo credit Meital Yerushalmi
rowing up in a household that greatly valued the arts, Dr. Michael Richards learned to appreciate art at an early age. His brothers are talented painters and composers, and his father is an acclaimed artist who was tasked with painting the portrait of the Queen in 2012. Dr. Richards himself served as his father’s assistant during their tour of Buckingham Palace, which he describes as a “surreal” experience. Dr. Richards himself plays the piano, and when he can find the time, he frequents museums and art galleries. Dr. Michael Richards undoubtedly has a knack for the “fun” things in life, but at the same time, I was curious as to how he
decided to pursue an MD and subsequent PhD. In hindsight, the path Dr. Richards followed appears quite simple: during his life sciences undergraduate studies at the University of Toronto, he realized he liked science “quite a bit.” Unlike his brothers who also started with life sciences but later decided on different career paths, he discovered his passion for science and immediately considered entering the research field. In his own words, he “held research as a noble goal.” Everything seemed to be going well, but a major complication was that he loved interacting with people, and he sought more daily interactions than what he felt could be possible from a career in research. In Dr. Richards’ words, “I thought, how could I
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combine people and social activities with science? Medicine seemed like a sneakily good fit!” At this point, it is crucial to mention Dr. Agnes Wong, Dr. Richards’ mentor and supervisor of 11 years. Dr. Wong is currently the Ophthalmologist-inChief at the Ophthalmology and Vision Sciences Department at the Hospital for Sick Children. She supervises Dr. Richards in both his PhD studies and clinical duties, and Dr. Richards claims that meeting her at the start of medical school was a turning point, even though he didn’t realize it at the time. “She’s been a great influence,” he said; when they met, there was an instant connection.
At each step he just kept an open mind and explored what he liked and actually wanted to do.”
“We clicked. We hit it off personalitywise,” he said, smiling. Dr. Richards is very open-minded, and at the time he was exploring ideas and options. At that every stage in his career “[Dr. Wong] was there to bounce ideas off of.” He wasn’t set on ophthalmology for residency from the get-go, but eventually he discovered that ophthalmology was the right fit for him. “It’s delicate surgery combined with interesting medicine and neurology—and it involved patients who are awake and talkative and able to share their narrative,” he said of his choice of ophthalmology. In contrast, in many other fields, patients are more often systemically unwell or unconscious, which changes the nature of the patient-doctor interactions.
is part of the Clinician-Investigator Program (CIP) run by the Royal College of Physicians and Surgeons of Canada. He said of the program, “The CIP program provides structure, funding, and agreed upon objectives” for research, and it is also a way for people to stay in touch with both their clinical and research work concurrently, allowing for progress to be made in both these fields. This is in contrast to the MD/PhD program where students must complete their medical training and research one at a time. In fact, the CIP allows students to spend one day as a clinician and four days as a researcher, and based on Dr. Richards’s love for research and medicine, it is undoubtedly a perfect match for him.
Dr. Richards’ research in paediatric ophthalmology focuses on amblyopia— also known as “lazy eye.” Amblyopia is a decrease in vision caused by abnormal visual experience in early childhood, such as instances when the vision in one eye is blurry or when the eyes are misaligned. As a result, the area of the brain responsible for visual perception does not develop properly, even though the eye itself may be healthy. For his PhD thesis, Dr. Richards is studying multisensory integration, i.e., how the interaction between auditory stimuli and vision shapes the perception of our surroundings. It is a new way of looking at amblyopia, which has classically been thought of as a purely visual disorder. Dr. Richards is also interested in finding out why people with amblyopia are less susceptible to some illusions, including the McGurk Effect. Speech perception depends on the integration of visual and auditory information, and when there’s a mismatch, our brains can create an illusory sound from combining information from both sensory modalities, thus creating the McGurk Effect.
It’s remarkable that Dr. Richards finds the time to also act as the CIP representative for the IMS Students’ Association (IMSSA) as well. He recognizes that CIP students are all very busy individuals, so he acts as a liaison in communicating between CIP students and the broad student population at the IMS. He mainly wants to ensure that members can enjoy themselves, meet some new people, and make a few friends. IMSSA is a community hub for students. The IMS has a lot of different research themes and people working in various locations. This sometimes makes it is difficult to find fellow students and budding scholars with whom to interact. The best part of the IMS experience for Dr. Richards is that he gets to meet great people, including a broad range of faculty members.
Clinical duties and research each require quite a bit of attention. Dr. Richards
Towards the end of our interview, I asked Dr. Richards about his future goals. “In the short term, like 5 years, I will be done my PhD and my second clinical fellowship in paediatric ophthalmology, and I would like to be a practicing clinician-scientist, researching paediatric eye diseases in a way that aligns with and complements my own clinical practice.”
Dr. Richards became contemplative when asked about his long-term goals, “September 2001 was my first year at U of T!” he recalled, and he mentioned that a lot of changes have taken place in these 15 years. “It is very hard to predict the future, but I hope to maintain an open mind and open heart and take each opportunity and challenge as it comes, and learn and grow from that.” Reflecting on his somewhat philosophical response, he smiled and added, “I think sometimes young students at an earlier stage in their career might think that I meticulously planned this all out!” But in reality, at each step he just kept an open mind and explored what he liked and actually wanted to do. For Dr. Richards it was “a journey of selfdiscovery and trying to achieve some concrete goals.” As a parting note, I asked Dr. Richards if he could share some advice for graduate students at the early stages of their degrees, and his response was something I could instantly relate to: “Of course you are going to work hard and do your best and try to impress people, but don’t get too hung up on feeling that you don’t know what you’re doing…you don’t really (fully) know how a process works until you’ve done it… and then you look back and you say ‘okay, now I know what it’s about!” I also asked about his suggestions for graduate students nearing the end of their degree. He said, “Keep an open mind and be true to yourself and the things that you like. Don’t do something because you think it will make another person happy; because it really is your schooling, your career, and your life choices.” And he added, “Don’t worry too much about false starts either! If you change your mind, that’s okay too!”
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THE HEALTH TECHNOLOGY CAREER NICHE By Marmendia R. Meester, MSc
echnological innovation in health care is a hot market. We are now able to track and share our heart function through a smartwatch, study implants to redirect neuronal signals in the spinal cord after a spinal injury, attempt gene editing to prevent Malaria and HIV spread, and begin designing a pill to scan our gut for colon cancer. One thing
is for sureâ€”a larger skilled workforce is needed to accommodate this rise of health care technology innovation and commercialization. Health technology entrepreneurship is a multidisciplinary field, undervalued by the millennial generation of (bio)medical graduates. Job prospects in health care
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and academia are highly competitive; consequently, graduate students need to become more aware of alternative career possibilities before they set foot into Convocation Hall. According to IBISWorld, Canada expects a 14% increase in job availability in research and development in the biotechnology industry over the next five years.
FUTURE DIRECTIONS Professor John Bell is a senior scientist at the Ottawa Hospital Research Institute, and is spearheading the development and commercialization of oncolytic virus therapy for metastatic cancers. He agrees that a tremendous opportunity lies ahead for biomedical graduates who work hard, seize opportunities, adapt to change and are open to learning new ways of tackling challenging problems. “It is clear that North America is moving towards a knowledge based economy and there will be a demand for scientists with expertise in, and knowledge of, biological systems.” Dr. Bell has been successful in bioengineering and the commercialization of oncolytic viral immunotherapy that has shown astonishing results in treating cancer in select patients suffering from melanoma, breast, colorectal, and pancreatic cancers. He cofounded Jennerex Biotherapeutics Inc., which is now owned by the Korean firm SillaJen. When asked about the skillset required for graduates to succeed in health care biotechnology, Bell replied: “It may be important for graduate students to expand their skill base beyond what is traditional for an academic career. For example, gaining an understanding of project management, quality, and regulatory issues as they pertain to product commercialization could position a trainee to be able to move into industry and ultimately to a strategic leadership position. In my career, I have found great value in ‘team science’ and certainly to commercialize discoveries and work in the industrial setting, it is critical to be able to work within teams of individuals with complementary skills.” Cory Blumenfeld, Chief Operations Officer at DashMD, very much agrees. “I wouldn’t have gotten to this stage without the help of others. This community is all about helping each other.” Cory is a U of T graduate alumnus at the Institute of Health Policy, Management, and Evaluation and co-founded DashMD: a health care app to improve patient self-care after they have been discharged from a hospital. “The major challenge is to find the right people for your team. Group dynamics are essential—you need to organize and understand each other’s roles in a way that complements your skills. Don’t spread yourself thin, it’s better to be focused.” While working on his Master’s thesis,
Cory found there were many challenges to face when it comes to sustaining a health innovation product. “We did not know [3 years ago] that there was an option to become a health care innovator. Many discoveries are being kept within the containment of the labs, where they remain in the research field; whereas these ideas might be very valuable [with widespread commercialization].” Academia is still very traditional in the sense that innovative concepts generally do not move beyond the research organization. “How do we allow all these organizations, which traditionally do not innovate, to commercialize their ideas?” Now that resources are available, there is no longer an excuse to neglect introducing an innovative mindset in the core of academia and health care. “There are governmental innovation funding programs,” says Blumenfeld. Cory Blumenfled and Zack Fisch Rothbart themselves, as start-up founders of DashMD, benefited from ‘The Next 36’ accelerator program. “Force yourself to be out there, at the right place, at the right time. There are start-up mixers, accelerators, and incubators all around Toronto. You can’t be afraid of putting yourself out there, and taking advantage of all these opportunities.”
Yet, Viraj strongly believes that you do not need to become a multi-disciplinary scholar to be an innovator. “I did my own prototyping and proof-of-concept analyses without formal training. With the internet, all the knowledge resources are available. All you have to do is to invest your time and energy to work on it.” Mane added: “Biology and medicine innovations are very lucrative, but you have to set your mind and passion to it, and devote your life to it. You should live within the highrisk innovation ecosystem because you want to, not because you’re forced to.” With that mindset, Viraj has now obtained a US patent to apply his medical device to stabilize electrolytes in whole blood of patients exhibiting hyperbilirubinemia, a concept that he developed along with haematologist Dr. Edward Wong. Together with students from Ryerson University, he will soon start prototyping and working towards clinical application, and is happy to provide his students with hands-on experience in product validation, licensing, and approaching companies. “As life sciences graduate students, you are being exposed to a demanding analytical field,” he adds, “you’re able to construct your thoughts, analyze a concept, and produce an end-product—qualities that employers appreciate in graduate students.”
Within the GTA, the MaRS Discovery District is a major example of a medical innovation accelerator. The MaRS Innovation platform is a Torontobased community that facilitates entrepreneurship and commercialization in health care technology. Viraj Mane was involved in assessing the market potential of early-stage health technology commercialization for 3-4 years at MaRS and others, until he joined Ontario Genomics. “Find a way to contribute to a field you want to build expertise in. When you have an idea, invest your time and energy to work on it.” Inspired by an article on phototherapy for infant hyperbilirubinemia in a medical journal sticking out of his wife’s purse, Viraj thought of a similar principle to be applied as an extracorporeal medical device to treat the disease in adults. “My idea was rejected when I reached out to a genomics clinic, where I heard that a curative treatment already exists.” says Mane, “I learned my limitation as a lab researcher, without specific [clinical] field experience.”
“It’s what researchers do!” Cory Blumenfeld emphasizes, “There is a need for partnerships between health care institutions and research institutions that can provide that expertise. We [life science graduate students] know where to find the field experts, and how to acquire information. We have to change the traditional mindset; there is more than academia. You can be an entrepreneur, and you can innovate.” Are you curious about exploring career opportunities in health innovation and entrepreneurship? On February 22nd 2017 the HIT (Health. Innovation. Technology.) Unconference is offering a unique mix of talks, workshops, demonstrations, and a panel discussion. Speakers and panelists include chief executives and founders, such as Cory Blumenfeld, that range from earlystage start-ups to established technology companies with media coverage. Visit www.HITUnconference.org for more information and register for a free ticket.
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Ori Rotstein Lecture I N T R A N S L AT I O N A L R E S E A R C H
Photo credit Grace Jacobs
By Lindsay Caldarone and Aravin Sukumar
ince 2012, the Institute of Medical Science (IMS) has hosted the annual Ori Rotstein Lecture in Translational Research for incoming trainees. This lecture series was named in recognition of Dr. Ori Rotstein for his longstanding contributions as the Director of the IMS from 2001-2011. Dr. Rotstein transformed the IMS into the largest graduate unit in the Faculty of Medicine and the fifth largest graduate department at the University of Toronto. Dr. Rotstein is the Director of the Keenan
Centre for Biomedical Science, Surgeonin-Chief at St. Michael’s Hospital, and Professor and Associate Chair of Surgery at the University of Toronto. His research program is committed to understanding how traumatic brain injury affects the immune system of patients at high risk of organ injury and death. Dr. Rotstein’s lab uses cellular and animal models in conjunction with clinical sampling to develop novel therapeutic approaches and prevent poor outcomes, reflecting the IMS mandate to translate research from the
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“bench-to-bedside.” The annual lecture highlights breakthrough achievements by renowned clinician-scientists who emulate the essence of translational research by impacting patients’ health. This year, Dr. Peter Liu presented the keynote lecture entitled “Evolution of Biomarker Discovery: Challenges, Opportunities, and Approaches.” Ironically, the night prior to his lecture, Dr. Liu was on-call in Ottawa and unable to attend the traditional
ORI ROTSTEIN LECTURE lecture. In Ottawa, he holds the positions of Chief Scientific Officer and VP of Research at the Ottawa Heart Institute. He is also a Professor of Medicine at both the University of Toronto and the University of Ottawa, and he was the inaugural Director of the Heart and Stroke/Richard Lewar Centre for Excellence at the University of Toronto. He has over 350 peer reviewed publications in high-impact journals and has received numerous awards. His main research focus is heart failure (HF) and cardiac inflammation where he aims to identify novel biomarkers and interventions for cardiovascular disease. Both locally and internationally, he is a proven medical leader with a strong emphasis on knowledge translation; for example, he was instrumental in implementing the C-CHANGE guidelines for cardiovascular disease prevention and treatment. Dr. Liu began his talk with words of wisdom for future clinician-scientists: “You must be equally good at PCR as CPR.” In other words, it is important to excel in both the research and clinical aspects of the clinician-scientist role. Dr. Liu believes that the new generation of researchers must be able to “adapt to change” to create novel solutions for current health challenges. Dr. Liu does this himself by applying a personalized medicine approach to his research on HF.
HF is a significant burden on the
explored and lacks an established therapy. Dr. Liu believes that using biomarkers to diagnose DHF at an early stage would enable more accurate diagnosis and could improve patient outcomes. In the clinic, an ideal biomarker can be used to distinguish between acute and chronic syndromes, stratify risk, enable treatment decisions, monitor treatment response, or enable early detection. To identify a tissue-specific protein biomarker associated with DHF, Dr. Liu and colleagues connected with Dr. Anthony Gramolini, a proteomics expert at the University of Toronto. Drs. Liu and Gramolini analyzed a proteome using gel-free liquid chromatography-mass spectrometry on three cell populations: tissues from multiple mouse models of HF; tissue explants from patients undergoing heart transplantation; and human atrial and ventricular myocytes derived from induced pluripotent stem cells and human embryonic stem cells. They identified differentially expressed proteins in wildtype versus HF groups across all three models, including insulin growth factor binding protein 7 (IGFBP7).2 IGFBP7 levels in human serum were subsequently revealed to have prognostic value for DHF.3 IMS students were captivated as Dr. Liu explained his journey in translating the initial IGFBP7 discovery to commercial use. Recounting his obstacles, pitfalls, and
You must be equally good at PCR as CPR.”
healthcare system, affecting approximately 26 million people worldwide—600,000 of those in Canada. Dr. Liu admits that he is “embarrassed” by the current treatment approach to HF, which lacks clear understanding of its pathophysiology and treatment effects. The most common form of HF is systolic heart failure (SHF), which is characterized by a reduction of the ejection fraction—the percentage of blood pumped from the left ventricle into the circulation. Patients can also develop HF with preserved ejection fraction, referred to as diastolic HF (DHF).1 DHF is less
ultimate success in bringing his research to the market, Dr. Liu emphasized the necessity of teamwork. He explained that a “robust” scientific and medical context postulated a need for HF biomarkers on an industrial scale; however, this had to be brought to the public using an efficient commercial assay developed in the private sector. Roche, the world’s largest diagnostic company, showed interest in these biomarkers. Together with Genome Canada, Dr. Liu’s group patented their biomarker discoveries and filed for a joint patent on seven candidate biomarkers for
HF. To date, two biomarkers have been licensed for commercial kit development. Dr. Liu also emphasized the importance of “crosstalk” throughout his lecture with regards to working in different scientific disciplines. Crosstalk is essential to the “mutual learning” required to partner with the private sector. He stressed that the transition from a research project to a commercialized product is difficult, but also shared key lessons to make this transition easier for students: be openminded, network as much as possible to find partners, identify a need for your product, stay true to your own values, and—before initiating anything—make sure your idea is protected. The panel discussion was moderated by Dr. Rotstein and also included Dr. Brian Courtney (Scientist, Schulich Heart Research Program, Sunnybrook Research Institute), Dr. Milica Radisic (Professor, Institute of Biomaterials and Biomedical Engineering, Department of Chemical Engineering and Applied Chemistry, University of Toronto), and Dr. Douglas Lee (Associate Professor, Department of Medicine, University of Toronto and Senior Scientist at the Institute for Clinical Evaluative Sciences). Despite coming from a variety of backgrounds, similar themes emerged throughout the panelists’ discussion: communication, accepting failure, and escaping one’s comfort zone— in terms of both research innovation and interdisciplinary networking—are vital to progressing from an idea to a commercial product. Interdisciplinary communication is at the heart of translational research. The 2016 Ori Rotstein Lecture in Translational Research brought this message to life by guiding students on an insightful journey of scientific discovery, clinical relevance, and ultimately impacting patients. References 1. Bhatia RS, Tu JV, Lee DS, et al. Outcome of Heart Failure with Preserved Ejection Fraction in a Population-Based Study. N Engl J Med. 2006; 355:260-9 2. Chugh S, Ouzounian M, Lu Z, et al. Pilot study identifying myosin heavy chain 7, desmin, insulin-like growth factor 7, and annexin A2 as circulating biomarkers of human heart failure. Proteomics. 2013; 13:2324-2334 3. Barroso MC, Kramer F, Greene SJ, et al. Serum insulin-like growth factor-1 and its binding protein-7: potential novel biomarkers for heart failure with preserved ejection fraction. BMC Cardiovasc Disord. 2016; 16:199
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SKETCH YOUR SCIENCE
Winnie Qian, MSc Candidate, IMS
S K E T C H YO U R
SCIENCE Sketch Your Science! At the recent St. Mikeâ€™s Hospital IMSSA event, IMS students showed off their artistic skills by capturing the essence of their research projects visually. A sample of their creations are shown here.
Gene Therapy Pratiek Matkar, PhD Candidate, IMS 38 | IMS MAGAZINE WINTER 2017 MATERNAL AND CHILD HEALTH
Cubist Kidney Fibrosis Claudia Watorowski, MSc Candidate, LMP
READ How to keep up with the scientific literature (Article in Science)
When Breath Becomes Air by Paul Kalanithi
Keeping up-to-date with the literature can be time-consuming and is often put aside by scientists in favour of more urgent tasks. Science recently interviewed seven senior scientists who offered creative ways to go about literature review—a great read if you’re looking for a better method to keep track of what’s happening in your field, including lots of unique tools and ways to use them.
This memoir from a neurosurgeon battling stage IV lung cancer is a moving account of the life of Dr. Kalanithi, as well as the time leading up to his death. From the perspective of both doctor and patient, it explores the age-old question of why life is worth living.
LISTEN Raw Talk (Podcast)
Inquiring Minds (Podcast)
Started in the fall of 2016 (originally called ‘Raw Data’), this thoughtprovoking podcast was created by some of the IMS’s own graduate students: Richie Jeremian, Jabir Mohamed, Ekaterina An, Alexandra Mogadam, Melissa Galati, and Romina Nejad. Every Friday, they interview IMS faculty members on their fascinating research and how they ended up where they are today. Favourite episode: #4 with Dr. Albert Wong.
Interviews with movers and shakers in science and tech about how their science influences policy and politics. This podcast is hosted by scientist Indre Viskontas and science educator Kishore Hari. Favourite episode: #155 with Chris and Evan Hadfield.
Looking for a quick overview highlighting top science research each week? Nature Podcast is the perfect pick. Two to four studies are presented each week in an engaging and accessible format.
FOLLOW Samantha Yammine (@science.sam on Instagram)
Science Alert (@sciencealert on Instagram)
Samantha Yammine, a PhD student studying stem cell biology at the University of Toronto, uses her social media platform to highlight women in science, explain her own fascinating discoveries, and explore how science influences our day-to-day lives. Check out her #FeatureFriday and #ScienceSunday posts!
With frequent posts about anything and everything science—from outer space to insects to plants—this account has something for everyone. It even includes science memes and jokes to brighten your day!
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READ IT ONLINE
http://imsmagazine.com www.facebook.com/imsmagazine @IMSMagazine
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The winter issue of the IMS Magazine for 2017, with a feature on Maternal and Child Health.