Issue 38 by The Meducator

DECEMBER 2020 | ISSUE 38

OPINION A N E X A M I N AT I O N O F SOCIAL DETERMINANTS O F M E N TA L H E A LT H I N G E N D E R M I N O R I TY YO U T H

MEDUSTORY A H I S T O RY O F C O R O N A VIRUSES

RESEARCH INSIGHT VA R I AT I O N I N H E A LT H O U TC O M E S A S S O C I AT E D WITH CHILDHOOD M A LT R E AT M E N T: S O C I A L A N D P H Y S I O LO G I CA L F A CT O R S

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table of CONTENTS

table of contents

DECEMBER 2020

| DECEMBER 2020

ISSUE 38

01 INTRODUCTION 02 MEDPULSE 04 MEDBULLETINS 06 PATHOPROFILE 08 BIOTECH BLUEPRINT 10 MEDUSTORY 12 VIEWPOINTS 14 OPINION 16 RESEARCH INSIGHT INTERVIEW SPOTLIGHT 20 DR. SHEILA SINGH 22 DR. SUZANNE ARCHIE 25 CONTRIBUTORS COVER ARTIST JEFF ZHANG TOC ARTIST CARYN QIAN

M E D U CATO R

Welcome to Issue 38 of The Meducator! The interdisciplinary field of health sciences is ever-evolving, with the ongoing pandemic being no exception. It has shaped the way that health sciences is viewed and learned by pushing us to new limits where an abundance of information still remains unknown. While the unknown may seem uncomfortable, it is important to embrace change and emphasize collaboration and patience during these tumultuous times. As displayed in Jeff Zhang’s cover illustration of individuals selfisolating, we all have a part to play in reducing the spread of the virus —the whole is greater than the sum of its parts. We hope that you are staying home, social distancing, and taking measures to help protect yourself and those around you. Our mandate of facilitating critical discourse within the health sciences continues to be front and centre in Issue 38, which showcases an exciting array of student exploration and inquiry. Editors Matthew Lynn and Hannah Silverman provide an overview of the many bioapplications of spider silk, and its implications for tissue engineering. Dr. Sheila Singh, a principal investigator at the Stem Cell and Cancer Research Institute at McMaster University, reflects on her discovery of brain tumour-initiating cells and the future landscape of neuro-oncology. Dr. Suzanne Archie, the Clinical Director of the Cleghorn Early Intervention in Psychosis Program at St. Joseph’s Healthcare, discusses the necessity of teaching youth the relationship between cannabis and psychosis. Through their review of the literature on socioemotional adjustment in children, Madeline Komar identifies respiratory sinus arrhythmia as a potential screening tool for maltreated adolescents. Finally, Ling Yang highlights the impact of media, healthcare, and research representation on the mental health of gender minorities. As you explore this issue, we hope you are inspired to listen to and learn from new perspectives. In continuation with our recent COVID-19 Mini Issue, Issue 38 features the second installment of an all-new article, MeduStory. MeduStory shines a spotlight on an important topic within the health sciences, highlighting its evolution and global impact. In this installment, Aisling Zeng and Adrian Wong provide a brief history of the first human coronaviruses and how they have contributed towards understanding the current COVID-19 pandemic. Due to the unpredictable nature of COVID-19, we would like to remind you that the information presented in this issue regarding this topic is merely a representation of the current body of knowledge, and is subject to change.

Stay curious. Push boundaries. Wear a mask.

| DECEMBER 2020

Sincerely,

M E D U CATO R

Tackling this pandemic requires collaboration between healthcare providers, policymakers, research teams, and everyday citizens. Similarly, this issue of The Meducator illustrates the work of many. In particular, we would like to thank our Managing Editors, Aaron and Sophie; Creative Directors, Peri and Wendy; Video Manager, David; Subcommittee Advisor, Zahra; MeduCollab Directors, Michal and Shadi; and MeduPromo Director, Catherine, for their leadership and initiative. Finally, we would also like to express our gratitude to you, our reader, for your continued support of our publication.

introduction

INTRODUCTION ISSUE 38

dear reader,

KARISHMA MEHTA

Bachelor of Health Sciences (Honours) Class of 2022

DANIEL RAYNER Bachelor of Health Sciences (Honours) Class of 2022

MEDPULSE

Systemic Racism in Canadian Healthcare

AUTHORS: RIDA TAUQIR & SHADI SADEGHIAN ARTISTS: BEVERLY NG & PERI REN

CANADA

Joyce Echaquan was an Atikamekw woman who died on September 28, 2020, and many have attributed her death to negligence and medical racism. Echaquan was given medication despite her history of drug allergies and concerns about being over-medicated. Furthermore, recordings of her interactions with her healthcare team revealed the hospital staff using racial slurs and demeaning her presence in the hospital. Prime Minister Justin Trudeau referred to the incident as “the worst form of racism.” More information regarding the details of this incident are to be uncovered in an inquest to be conducted by lawyer and coroner Géhane Kamel, who is in charge of a committee on mortality in Indigenous communities. Overall, Echaquan’s death has raised dialogue about the systemic racism inherent in the Canadian healthcare institution, and the need to implement culturally-competent care. Specifically, Canadian scholars of public health are calling for the implementation of legislation and policies to end anti-Indigenous racism.

UNITED STATES table of contents

A Pocket-Sized Ultrasound

Butterfly iQ is a handheld ultrasound device crafted by Jonathan Rothberg that aims to improve access to healthcare. Although less powerful than an industrial machine, Butterfly iQ poses many benefits: the device is portable, reasonably priced, and encourages medical imaging to become more routine in clinical settings. In fact, the pocketsized device is being distributed to 53 countries in efforts to help the “4.7 billion people around the world lacking access to medical imaging.” Additionally, Butterfly iQ has proven to be highly productive in Western medicine as COVID-19 overwhelms the healthcare system; physicians report that they can efficiently diagnose, triage, and monitor patients despite reduced access to hospital resources.

Measuring Dissociation Within the Brain - US

There is limited research surrounding dissociative symptoms and disorders that stem from childhood trauma. Effectively, patients experiencing dissociation tend to receive insufficient care, including inaccurate diagnosis, prognosis, and treatment. However, researchers at McLean Hospital in Massachusetts have discovered that dissociation is associated with functional connections between brain regions. Notable regions include the frontoparietal control network and the default mode network, both of which are located on the cortical surface. The team hopes to use these findings to devise an objective diagnostic tool that identifies and measures the severity of trauma-related dissociation.

Nobel Prize for Discovering Hepatitis C

The 2020 Nobel Prize in Physiology or Medicine has been awarded to American researchers Harvey Alter and Charles Rice as well as the UK’s Michael Houghton, for their efforts in discovering the Hepatitis C virus. Currently, approximately 70 million individuals are infected with Hepatitis C, resulting in around 400,000 deaths per year. This research endeavor started when Alter noticed that individuals receiving blood transfusions would fall ill with liver inflammation that was not attributable to Hepatitis A or Hepatitis B. Houghton was able to isolate this flavivirus and sequence its genome, and Rice injected genetically engineered Hepatitis C into an in vivo model which was shown to cause hepatitis. Due to this discovery, blood screening for this virus has become common practice, allowing for early detection and treatment.

UNITED KINGDOM Virtual Reality Rehab

Neurorehabilitation lacks engagement, accessibility, and interactiveness. These factors can hinder the success of treatment. Isabel Van De Keere has revolutionized neurorehabilitation by developing Immersive Rehab —a customizable virtual reality (VR) approach to rehabilitation. This method increases the range of available exercises, improves data collection of patients’ progress, increases accessibility of neurorehabilitation, and enhances patient experience. The company’s next steps are to host clinical trials in Canada, the US, and Europe in efforts to certify VR as a legitimate medical solution.

INDONESIA Reducing DNV Spread With Bacteria

Indonesia, cases of Dengue virus (DNV) Prevalent year-round year-roundin in Indonesia, cases of Dengue virus infectioninfection have increased 700-fold 700-fold over the past An (DNV) have increased over 45 theyears. past 45 research has recently the incidence of years. An center Indonesian researchdiscovered center hasthat recently discovered DNV the canincidence be decreased by can distributing mosquitoes carrying that of DNV be decreased by distributing Wolbachia bacteria. most insect species aremost natural carmosquitoes carryingWhile Wolbachia bacteria. While insect riers for are Wolbachia, the species of mosquitoes that carry DNV species natural carriers for Wolbachia, the species of mos(Aedes that aegypti) not.(Aedes As such, this strain of bacteria quitoes carryare DNV aegypti) are not. As such, was this artificially culturedwas fromartificially fruit flies cultured into Aedes aegypti mosquistrain of bacteria from fruit flies into toes, decreasing DNV replication and transmission. A possible Aedes aegypti mosquitoes, decreasing DNV replication and explanation for this effect is the intra-organismal transmission. A possible explanation for this effect competition is the intrabetween Wolbachia and DNV within the host mosquito, well organismal competition between Wolbachia and DNV as within as the increased immunity from Wolbachia the host mosquito, as wellofasthe thehost increased immunity of the infection. host from Wolbachia infection.

KUWAIT

NIGERIA Diversifying Africa’s Biobank

Researchers from the Middle East, Finland, and Canada have conducted analyses of genomic data from two Kuwaiti Arab groups in an effort to better understand the prevalence of certain inherited metabolic diseases. Most genomic studies to date have focused on European/Caucasian populations, highlighting the necessity for such endeavors. In response to the complications caused by consanguinity in many Arab populations, interest was sparked in understanding the effects of inbreeding on the genomic level. It was discovered that from the 821 variants of the 251 genes identified, 95% were associated with metabolic disorders. Furthermore, 11 genes found in Arab cohorts were identified as novel risk variants for metabolic problems.

M E D U CATO R | A P R I L 2015

The African population contains the most genetically diverse DNA; however, less than 3% of African DNA is involved in human-genome research. Effectively, the potential of health research, drug discoveries, and medical breakthroughs is severely limited. A Nigerian startup founded by Dr. Abasi Ene-Obong, 54gene, is challenging these blindspots in genomic research. The startup aims to collect highly curated genetic information from volunteers across Africa to diversify the continent’s biobank —a biorepository that collects, stores, and distributes biological material for use in research. 54gene’s mandate also strives to improve Africa’s overall health outcomes by partnering with companies dedicated to sharing discoveries with the continent. Additionally, 54gene’s recent partnership with Illumina Incorporation, a health technology company specializing in DNA sequencing technologies, will help Africa overcome its barriers in accessing precision-based medicine.

introduction

Novel Genetic Defects in Middle Eastern Cohorts

References can be found on our website: meducator.org

MEDBULLETIN ALZHEIMER’S

M E D U CATO R | D EC E M B E R 2 0 2 0 M E D U CATO R | A P R I L 2019

medbulletin section title

A THERAPEUTIC DISCOVERY

4 6

MATERNAL GENE REPAIR MICROBIOTA β-THALASSEMIA:

EFFECTS BRAIN DEVELOPMENT A NEW ROADON TOFETAL A CURE

YIMING ZHA N G

PAR NIK A G O D K HIND I

Alzheimer’s disease (AD), a neurodegenerative disorder commonly characterized by a progressive impairment of memory and other cognitive abilities, is responsible for 60-80% of all dementia cases. AD is caused by excessive β-Amyloid (βA) deposits that form harmful plaque buildup around the brain and disrupt neural cell functions. Symptoms gradually increase in severity, beginning with minor cognitive impairment and escalating to confusion, behavioral changes, difficulty speaking or moving, and death.¹ Despite affecting over 24.2 million individuals worldwide, AD has no direct cure and treatments only aim to mitigate damage for as long as possible.2 Most medications for AD perform two functions: they inhibit acetylcholinesterase from breaking down acetylcholine, the neurotransmitter responsible for nerve impulse transmission, and they reduce βA deposits in the brain. As a result, these therapies improve cognitive function, delaying symptoms temporarily.3

The microbiota comprises trillions of bacteria, archaea, viruses and eukaryotic microbes that reside within and on the body. These resident microorganisms impact health and support many bodily functions throughout life, such as protecting us from pathogens, training our immune system, and assisting in metabolism.1 Maternal challenges, including immune system activation and psychosocial stress, are known to lead to neurobehavioural abnormalities in mice offspring.2,3 Previous research has shown that microbiota can mediate the impact of these environmental stressors to ensure proper fetal development. However, little is currently known about the mechanism by which this occurs, nor is it clear whether the microbiome has an influence on the offspring neonatally or postnatally.3,4

While traditional therapeutics focus primarily on amyloid plaques or neurofibrillary tangles, both of which involve βA deposits, one study by Price et al. has argued that that the discovery of AD involving neuroinflammation and lipid metabolism can lead to the development of novel therapeutics. Experiments in murine models have demonstrated that both the homozygous and heterozygous mutations can reduce the effectiveness of the triggering receptor expressed on myeloid cell-2 (TREM2), a lipoprotein-binding receptor. Activation of TREM2 leads to a subsequent activation of microglia, the primary innate immune cell in the central nervous system, causing them to play an active role in the degradation of βA deposits.4 This can significantly increase the risk and severity of AD. Direct cranial injection of AL002a, a TREM2-activating murine IgG1 antibody, was also correlated with reduced βA deposition by upwards of 40%. As such, researchers could potentially develop a treatment that does not directly target the βA peptide. Overall, they hypothesize that direct targeting and promotion of TREM2 function may lead to a new and potent therapeutic response to AD.5

Recent research by Vuong et al. has found that certain maternal gut bacteria create metabolic byproducts that can influence embryonic brain development. Embryos of pregnant mice, that were either germ-free or had their microbiota depleted by antibiotics, were experimentally shown to have different brain structures from those of embryos of mothers with healthy microbiota.5 In particular, embryos of germ-free mothers had thinner axon bundles and shorter, smaller axons between the cortex and thalamus, which is responsible for processing and relaying information in the brain.6 Upon examining the adult offspring of microbiota-deficient mothers, Vuong and colleagues found that the mice had abnormal responses to heat, sound, and pressure, indicating that sensory pathways were predominantly affected.5 Furthermore, maternal gut microbes (the Clostridium genus of bacteria, in particular) affected the levels of metabolites in maternal blood and embryonic brain tissue, suggesting that interactions between the microbiome and nervous system began prenatally.5 These findings contribute to the growing amount of research on the mechanism underlying the impact of the maternal microbiome on the developing brain. Moreover, understanding how metabolites reach the fetus might help identify potential pathways for developing future clinical interventions.

Alzheimer’s Association. What is Alzheimer’s disease? [Internet]. 2020. Available from: https://www.alz.org/alzheimers-dementia/what-is-alzheimers [cited 2020 Oct 16].

Mayeux R, Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb Perspect Med. 2012;2(8):a006239. Available from: doi:10.1101/cshperspect.a006239.

Hansen RA, Gartlehner G, Webb AP, Morgan LC, Moore CG, Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer’s disease: A systematic review and meta-analysis. Clin Interv Aging. 2008;3(2): 211-25. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2546466/ [cited 2020 Oct 16].

Shreiner AB, Kao JY, Young VB. The gut microbiome in health and in disease. Curr Opin Gastroenterol. 2015;31(1): 69-75. Available from: doi:10.1097/MOG.0000000000000139.

Kim S, Kim H, Yim YS, Ha S, Atarashi K, Tan TG, et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature. 2017;549: 528-32. Available from: doi:10.1038/nature23910.

Jašarević E, Howard CD, Morrison K, Misic A, Weinkopff T, Scott P, et al. The maternal vaginal microbiome partially mediates the effects of prenatal stress on offspring gut and hypothalamus. Nat Neurosci. 2018;21(8):1061-71. Available from: doi:0.1038/ s41593-018-0182-5.

Ferretti P, Pasolli E, Tett A, Asnicar F, Gorfer V, Fedi S, et al. Mother-to-infant microbial transmission from different body sites shapes the developing infant gut microbiome. Cell Host Microbe. 2018;24(1):146-54. Available from: doi:10.1016/j. chom.2018.06.005.

Vuong HE, Pronovost GN, Williams DW, Coley EJL, Siegler EL, Qiu A, et al. The maternal microbiome modulates fetal neurodevelopment in mice. Nature. 2020;586: 281-6. Available from: doi:10.1038/s41586-020-2745-3.

Habas C, Manto M, Cabaraux P. The cerebellar thalamus. Cerebellum. 2019;18(3):635-48. Available from: doi:10.1007/ s12311-019-01019-3.

Bachiller S, Jiménez-Ferrer I, Paulus A, Yang Y, Swanberg M, Deierborg T, et al. Microglia in neurological diseases: A road map to brain-disease dependent-inflammatory response. Front Cell Neurosci. 2018;12:488. Available from: doi:10.3389/fncel.2018.00488.

Price BR, Sudduth TL, Weekman EM, Johnson S, Hawthorne D, Woolums A, et al. Therapeutic Trem2 activation ameliorates amyloid-beta deposition and improves cognition in the 5XFAD model of amyloid deposition. J Neuroinflammation. 2020;17(1):238. Available from: doi:10.1186/s12974-020-01915-0.

RACIAL BIAS IN MEDICAL EDUCATION

MICROGLIA

MORE THAN JUST AN IMMUNE CELL

MAKING IMPORTANT CHANGES A IS L IN G Z EN G

3. 4. 5. 6. 7. 8. 9.

van Vreeswijk C, Sompolinsky H. Chaos in neuronal networks with balanced excitatory and inhibitory activity. Science. 1996;274(5293): 1724-6. Available from: doi:10.1126/science.274.5293.1724.

Werneburg S, Feinberg PA, Johnson KM, Schafer DP. A microglia-cytokine axis to modulate synaptic connectivity and function. Curr Opin Neurobiol. 2017;47: 138-45. Available from: doi:10.1016/j.conb.2017.10.002.

Kato G, Inada H, Wake H, Akiyoshi R, Miyamoto A, Eto K et al. Microglial contact prevents excess depolarization and rescues neurons from excitotoxicity. eNeuro. 2016;3(3): ENEURO.0004-16.2016. Available from: doi:10.1523/ENEURO.0004-16.2016.

Badimon A, Strasburger HJ, Ayata P, Chen X, Nair A, Ikegami A et al. Negative feedback control of neuronal activity by microglia. Nature. 2020;586: 417-23. Available from: doi:10.1038/s41586-020-2777-8.

Haas HL, Selbach O. Functions of neuronal adenosine receptors. Naunyn Schmiedebergs Arch Pharmacol. 2000;362(4-5): 375-81. Available from: doi:10.1007/s002100000314.

Araque A, Navarrete M. Glial cells in neuronal network function. Philos Trans R Soc Lond B Biol Sci. 2010;365(1551): 2375-81. Available from: doi:10.1098/rstb.2009.0313.

| DECEMBER 2020

Van Ryn M, Hardeman R, Phelan SM, Burgess DJ, Dovidio JF, Herrin J, et al. Medical school experiences associated with change in implicit racial bias among 3547 students: A medical student CHANGES study report. J Gen Intern Med. 2015;30(12): 1748– 56. Available from: doi:10.1007/s11606-015-3447-7. Ohio State University. Understanding Implicit Bias. [Internet]. 2015. Available from: http://kirwaninstitute.osu.edu/research/ understanding-implicit-bias/ [cited 2020 Nov 21]. Paul D, Ewen S, Jones R. Cultural competence in medical education: Aligning the formal, informal and hidden curricula. Adv Health Sci Educ Theory Pract. 2014;19:751-8. Available from: doi:10.1007/s10459-014-9497-5. Louie P, Wilkes R. Representations of race and skin tone in medical textbook imagery. Soc Sci Med. 2018;202:38. Available from: doi:10.1016/j.socscimed.2018.02.023. McFarling UL. Dermatology faces a reckoning: Lack of darker skin in textbooks and journals harms care for patients of color [Internet]. Stat. 2020. Available from: https://www.statnews.com/2020/07/21/dermatology-faces-reckoning-lack-of-darkerskinin-textbooks-journals-harms-patients-of-color/ [cited 2020 Nov 21]. Page S. A medical student couldn’t find how symptoms look on darker skin. He decided to publish a book about it [Internet]. Washington Post. 2020. Available from: https://www.washingtonpost.com/lifestyle/2020/07/22/malone-mukwende-medical-handbook [cited 2020 Sep 17]. National Rosacea Society. Rosacea may be underdiagnosed in skin of color. [Internet]. 2018. Available from: https://www. rosacea.org/blog/2018/december/rosacea-may-be-underdiagnosed-in-skin-of-color [cited 2020 Nov 21]. Browning DJ, Rosenwasser G, Lugo M. Ocular rosacea in blacks. Am J Ophthalmol. 1986;101(4):441-4. Available from: doi:10.1016/0002-9394(86)90644-6. Kamara-Sesay E. Rosacea in Skin of Colour [Internet]. Black Skin Directory. 2020. Available from: https://www.blackskindirectory.com/bsd-learningjournal/2020/4/19/uxmvv9t8cwi20qh4xwwsu1exoqd8o2 [cited 2020 Nov 21].

A recent study by Badimon et al. provides evidence for one possible mechanism of microglial action.4 Removal of microglia in murine models was shown to both increase the excitability of neurons and decrease the level of adenosine, an inhibitory neurotransmitter. This suggests that release of adenosine could be the mechanism through which inhibition occurs.4,5 Furthermore, adenosine triphosphate (ATP) was also found to be the origin of this pathway and is released upon neuronal activation. Released ATP is converted into adenosine diphosphate (ADP), which attracts microglia to neuronal synapses prior to being converted into adenosine by microglial surface enzymes.4 Additionally, the proximity of microglia to the synapse in this process suggests inhibition to be a localized effect impacting only grey matter, where most synapses are found.4 These findings once again challenge the established neuron-centric dogma of neuronal signalling, adding microglia to a growing list of cell types that play a role in neural signalling.6 More importantly, the ability of microglia to synthesize adenosine from ATP precursors presents a new target for treatments of a range of diseases where neural hyperactivity is a key component, such as epilepsy.

M E D U CATO R

There have been advancements in medical education that have begun to take greater consideration toward the implicit biases in teaching medicine. As mortality rates among African Americans have been shown to be higher in cases of skin cancer, often due to late diagnosis, the need for more diversity in medical reference texts has gained recognition.4,5 Malone Mukwende, a third year medical student at the University of London, published a book in 2020 to help health professionals distinguish differences in skin conditions between Caucasian and African American individuals.6 Additionally, rosacea, a common skin condition that causes redness, presents differently in African Americans and may be overlooked by medical professionals.7,8 To provide a more comprehensive source of education about such skin conditions, Diya Ayodele, an aesthetician, founded the Black Skin Directory in 2018. This resource uses both de-identified images from African American patients with skin conditions such as rosacea, and descriptions of signs and symptoms, to provide a more holistic understanding of these diseases on a different skin pigment.9 While racism still remains to be a significant societal issue, initiatives such as these are steps forward in the pursuit of equitable healthcare.

JIA HUI DU

The circuitry of the central nervous system (CNS) can be summarized as a system of excitatory and inhibitory signals working collectively to facilitate bodily function. Signalling occurs through the release of various neurotransmitters, whose subsequent binding to target receptors alters the target neuron’s membrane potential, making it predisposed to firing a subsequent action potential.¹ While these processes are primarily attributed to neurons, there is growing evidence of the involvement of other cell types in signalling. Among these are microglia, which are the resident macrophages of the CNS responsible for active immune defense, “pruning” of neuronal synapses, and reduction of plaque deposits.2 Despite some evidence suggesting that microglia protect neurons from overactivity with an inhibitory function of sorts, the particular mechanism remains unclear.3

medbulletin

A recent study from the Mayo College of Medicine found that experiences in medical school, such as formal curriculum training, play a significant role in shaping implicit biases in students.1 Implicit biases entail the attitudes or stereotypes that impact actions and beliefs unconsciously, which may affect the medical curriculum.2 One of the implicit biases that has been particularly well-examined over the past two decades is race, with numerous studies emphasizing the need to integrate culturally-considerate educational activities and information into the current healthcare system, along with cultural competence training to improve interpersonal quality of care. Although a majority of these studies have focused on the implicit racial bias against African Americans, it is also applicable to other ethnic minorities.1,3 6

5 5

doi:10.35493/medu.38.6

ATHEROSCLEROSIS Pathoprofile 1.

pathoprofile

M E D U CATO R

D E C E M B E R 2020

10.

Song P, Fang Z, Wang H, Cai Y, Rahimi K, Zhu Y, et al. Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta-analysis, and modelling study. Lancet Glob Health. 2020; 8(5):721-9. Available from: doi:10.1016/ S2214-109X(20)30117-0. Insull W. The pathology of atherosclerosis: Plaque development and plaque responses to medical treatment. Am J Med. 2009;122(1):3-14. Available from: doi:10.1016/j. amjmed.2008.10.013. Bergheanu SC, Bodde MC, Jukema JW. Pathophysiology and treatment of atherosclerosis. Neth Heart J. 2017;25(4):231–42. Available from: doi:10.1007/s12471017-0959-2. Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26(8):1702–11. Available from: doi:10.1161/01. atv.0000229218.97976.43. Zingg J-M, Ricciarelli R, Azzi A. Scavenger receptor regulation and atherosclerosis. Biofactors. 2000;11(3): 189–200. Available from: doi:10.1002/ biof.5520110305. Clauss M, Sunderkötter C, Sveinbjörnsson B, Hippenstiel S, Willuweit A, Marino M, et al. A permissive role for tumor necrosis factor in vascular endothelial growth factor– induced vascular permeability. Blood. 2001;97(5):1321-9. Available from: doi:10.1182/ blood.v97.5.1321. Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res. 2014;114(12):1852–66. Available from: doi:10.1161/ CIRCRESAHA.114.302721. Charo I, Taub R. Antiinflammatory therapeutics for the treatment of atherosclerosis. Nat Rev Drug Discov. 2011;10:365-76. Available from: doi:10.1038/nrd3444. Dadu R, Ballantyne C. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol. 2014;11(10):563-75. Available from: doi:10.1038/ nrcardio.2014.84. Government of Canada. Regulatory Decision Summary - REPATHA - Health Canada [Internet]. 2020. Available from: https://hpr-rps.hres. ca/reg-content/regulatoryde cision-summary-detail. php?linkID=RDS00043 [cited 2020 Nov 15].

AUTHORS: HARGUN KAUR & SHANZEY ALI ARTISTS: ANDY ZHU & ESRA RAKAB

Introduction

Atherosclerosis, characterized by plaque development and subsequent narrowing of arteries, is the precursor to coronary artery disease, heart attacks, and strokes. Known as major adverse cardiovascular events, these conditions are the leading causes of death in the United States, Europe and much of Asia, making atherosclerosis responsible for approximately 31% of all global deaths.1 Atherosclerosis can be conceptualized as an inflammatory response resulting in the formation of arterial wall lesions through the accumulation of cholesterol-rich lipids and fibrous material.2

Pathophysiology

Atherosclerotic lesions can occur due to damage to the endothelium caused by alterations in blood flow at arterial branches, bifurcations, and curvatures. Cardiovascular risk factors which promote the development of atherosclerosis include dyslipoproteinemia, diabetes mellitus, hypertension, smoking, and hypercholesterolemia. Arterial endothelial damage facilitates monocyte entry through cell adhesion and trans-endothelial migration, while also allowing low-density lipoproteins (LDL) to cross the barrier.3 Upon their entry, monocytes differentiate into macrophages which further bind to oxidized LDL (oxLDL) through scavenger receptors.4 Normal artery maintenance turns into atherosclerosis when the aforementioned cardiovascular risk factors promote local, unresolved inflammation. In atherosclerosis, the LDL uptake process is deregulated, resulting in increased cholesterol storage and insufficient export. This increase in oxLDL uptake and subsequent deregulation of enzymes leads to the accumulation of cholesterol esters and encourages foam cell formation.5 Clustering of these foam cells form a fatty streak, the initial atherosclerotic lesion.3 These foam cells release proinflammatory cytokines which recruit additional immune cells —including mast

cells, dendritic cells, and T-cells— to the lesion. Proinflammatory cytokines TNF-α and IL-17 increase the expression of selectin and increase vascular permeability, resulting in further leukocyte migration and lesion development.6 Additional growth factors released by the immune cells recruit vascular smooth muscle cells to the intima and proliferate to produce an extracellular matrix. As the lesion progresses, apoptosis of foam cells and smooth muscle cells can lead to the formation of a necrotic core. The development of a fibrous plaque from smooth muscle cells protects the advanced fibroatheroma from rupturing. Increased activation and expression of matrix metalloproteinases by macrophages can reduce the thickness of the fibrous cap, resulting in increased plaque vulnerability.7 While atherosclerosis may obstruct blood flow, it is unlikely to be fatal without the presence of thrombosis or plaque hemorrhage. The rupturing of the atherosclerotic plaque exposes the thrombogenic interior, resulting in clotting. Rupturing and thrombosis, rather than the hardening of the artery, is the main cause of myocardial infarction and ischemic stroke.7

Treatments

Traditional therapeutic efforts have focused on addressing relevant cardiovascular risk factors. Statins can reduce LDL cholesterol, antihypertensives can treat hypertension, and antithrombotics can reduce the formation of blood clots.8 Several therapeutics, including PLA2 inhibitors and antileukotrienes, are now being developed following the identification of various key antiinflammatory targets.8

It is important to note that statins, despite being successful in lowering levels of atherogenic lipoproteins, are often inadequate for some patients. Maximal doses of the most potent statins are sometimes insufficient in achieving desired levels of LDL cholesterol; additional interventions may also be needed to further lower the risk for cardiovascular disease (CVD). Additionally, some patients are unable to tolerate statin therapy due to adverse effects including myalgia and rhabdomyolysis. Recent metaanalyses have also indicated that statin therapy is associated with an increased incidence of diabetes mellitus. To tackle these problems, various other treatments are being researched for clinical use.9

pathoprofile

Among these is a therapeutic target identified as proprotein convertase subtilisin/kexin type 9 (PCSK9), a hepatic protease involved in LDL receptor (LDLR) degradation. Gain-of-function mutations in PCSK9 have been shown to lead to high LDL cholesterol levels due to increased LDLR degradation, whereas loss-of-function variants lead to low LDL cholesterol levels, and subsequently lower the risk of CVD. Furthermore, statin therapy has been shown to increase PCSK9 levels through negative feedback, which decreases its efficacy in lowering LDL cholesterol. Accordingly, inhibition of PCSK9 with monoclonal antibodies in conjunction with statin therapy has been shown to produce a 50-60% decrease in LDL cholesterol levels, as compared to statin monotherapy. PCSK9 inhibitors have also been well tolerated with a low incidence of adverse effects in short-term trials.9 These have also recently received approval for use in Canada.10

EDITED BY: ALBERT STANCESCU & MEERA CHOPRA

REVIEWED BY: DR. GEOFF WERSTUCK Dr. Geoff Werstuck is a Professor in the Departments of Medicine and Biochemistry and Biomedical Sciences at McMaster University, with his research affiliated with the Thrombosis and Atherosclerosis Research Institute (TaARI) in Hamilton, Ontario. Dr. Werstuckâ&#x20AC;&#x2122;s research primarily investigates the molecular mechanisms that link diabetes to increased risk for cardiovascular disease.

M E D U CATO R | D E C E M B E R 2020

doi:10.35493/medu.38.8

Spider Silk in Tissue Engineering Biotech Blueprint

AUTHORS: HANNAH SILVERMAN & MATTHEW LYNN ARTIST: MANREET DHALIWAL

Introduction The biomedical applications of spider silk can be traced back to ancient Roman times, where silk fibre meshes were used to treat skin lesions.1 Today, spider silk is commonly used as a suturing material in eye, intraoral, and lip surgeries due to its strength and extensibility.2 However, new applications for spider silk have been identified in the field of tissue engineering, with potential uses ranging from meshes and coatings to scaffolding for tissue regeneration.3 These applications take advantage of spider silk’s biocompatibility and high tensile strength to promote cardiac tissue regeneration, peripheral axon myelination, bone regeneration, and cartilage growth.3 In this article, the latest large-scale production methods and several promising applications of spider silk are reviewed.

biotech blueprint

Large-Scale Production Methods Farming spiders for large-scale silk production is not feasible due to their territorial and cannibalistic behaviors.4 As a result, silk-production systems generally utilize other organisms including bacteria (e.g. Escherichia coli), mammalian and insect cell lines, and even transgenic “spider-goats” that produce silk proteins in their milk.5-7 Currently, the most common method for producing spider silk uses recombinant E. coli bacteria which express the genes for spider silk proteins.6 Since these bacteria have shorter doubling times and do not require very sophisticated laboratory setups, this production method can be easily scaled-up.6 However, the use of E. coli bacteria and other similar methods of artificial silk production must also utilize costly, patented manufacturing technologies to assemble silk fibres once secreted.6 Because of this barrier, the only natural fibre currently produced on a large scale for commercial use is produced by the silkworm, Bombyx mori.7 The similarity in high molecular weights and repetitive structures of silkworm proteins (i.e. FibH) and spider silk proteins (i.e. MaSp1) has prompted researchers to investigate the effects of replacing the FibH gene in B. mori with a synthetic gene containing the MaSp1 gene sequence under the FibH promoter.7 This process successfully produced MaSp1-containing silk, though it had significantly different mechanical properties from regular spider silk.7 Although this study only replaced one gene segment to yield a hybrid spider silk fibre, the results introduce a potential approach for future production methods of purified spider silk.7

Peripheral Nerve Axon Regeneration A large body of research has focused on the use of spider silk in axon regeneration following peripheral nerve injury and tumor infiltration.8 Since donors for nerve transplants are rare and autologous transplantation can induce complications, artificial nerve grafting has become a logical solution to support the regeneration and remyelination of peripheral nerve axons.8 However, artificial grafts made from non-resorbable materials can often lead to long term complications and chronic pain if not removed.8 Moreover, other graft materials, though resorbable, cannot viably support the full length of the axon, disqualifying them for use for peripheral nerve regeneration procedures.8,9 Spider silk’s unique characteristics resolve the issue of biocompatibility and it has been successfully used to regenerate full peripheral nerve axons in large animals.3,8,10 Furthermore, when effectively adhered to the silk graft, Schwann cells proliferated and remyelinated peripheral axons, an essential step in the conduction of peripheral nerve impulses.9-11 These studies highlight spider silk’s ability to enhance peripheral nerve regeneration and restore electrophysiological function, introducing it as a viable alternative that minimizes patient trauma.11

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Bone and Cartilage Regeneration

It is estimated that at least 1 in 3 women and 1 in 5 men will suffer from an osteoporotic fracture, due to weak and brittle bones, in their lifetime.12 Bone is naturally composed of both inorganic (e.g. calcium phosphate) and organic materials (e.g. collagen).3 Though collagen has previously been studied for bone tissue engineering, it generally lacks mechanical stability when processed in vitro and loses integrity over time.13 Spider silk has since gained interest in the field of bone regeneration due to its ability to bind and facilitate mineralization of calcium phosphate, which is necessary for bone growth and regeneration.14 One study found that spider silk functionalized with bone sialoprotein is able to accelerate calcification, allow good adhesion, improve differentiation of human mesenchymal stem cells, and promote bone remodelling and osteoblast differentiation.15 Silk has also been studied for its potential applications in inducing the proliferation of chondrocytes for cartilage regeneration.16 Chondrocytes in articular cartilage help mechanically distribute loads across joints by secreting extracellular matrix to maintain and sustain the cartilage.17 Scheller et al. found that the growth and proliferation of chondrocytes was similar when grown on spider silk and natural collagen.16 Compared to collagen, spider silk has a relatively higher mechanical stability and tensile strength, as well as a similar chondrocyte regeneration rate. Thus, it may one day be used to treat osteoarthritis and other joint disorders.3

Heart Muscle Tissue Regeneration Cardiovascular disease (CVD) is the second leading cause of death in Canada, with patients reporting a myocardial infarction (MI) having a death rate four times higher than healthy individuals.18 Of all human organs, the heart is the least regenerative, meaning its capacity for repair and regeneration is extremely limited, particularly following an episode of MI.19 Thus, a solution to improve tissue regeneration or compensate for the loss of cardiomyocytes is needed. Research surrounding the application of spider silk protein eADF4(κ16) as a scaffold for cardiac tissue engineering shows promising results.20,21 Not only can cardiomyocytes bind to and proliferate effectively on this fibre, but spider silk also provides the benefits of high tensile strength, low immunogenicity, and biodegradability —key considerations for scaffold implantation.21 Importantly, cardiomyocytes grown on eADF4(κ16) can effectively contract with natural frequency and rhythm without affecting their response to extracellular modulators (e.g. hormones).20 Additionally, the biocompatibility and flexibility of spider silk allow for its effective application as a coating for carbon nanotubes used in tissue engineering. This use of carbon nanotubes allows for increased electrical activity, while the spider silk coating provides an extracellular matrix which is soft and can facilitate cell adhesion.22 Together, the silk-coated nanotubes can have a variety of applications, such as being a cardiomyocyte scaffold for regenerative purposes or a component of a biosensor.22 Ultimately, the use of spider silk provides a promising range of applications in regenerating cardiomyocytes and restoring heart function, which could help lower the burden of CVD and MI once tested and perfected.

Future Directions

PEER-REVIEWED BY: DR. KYLA SASK Dr. Kyla Sask is an Assistant Professor in the Department of Materials Science and Engineering, and an Associate Member of the School of Biomedical Engineering at McMaster University. Her research is aimed at understanding mechanisms of protein and cell interactions on material surfaces for developing advanced medical devices and implants. Dr. Sask has previously worked at Interface Biologics Inc. as an Associate Research Engineer, focusing on developing anti-thrombotic and anti-infective polymers for medical devices.

biotech blueprint

Despite the many bioapplications of spider silk, in vivo studies of spider silk-based materials are still relatively limited. Studies exploring the characteristics and safety of spider silk show its ability to stimulate angiogenesis without amplifying inflammation —a vital quality in wound healing.3 Meanwhile, in vivo studies of rats confirm the non-toxic degradation of silk proteins by macrophages; a process that can be adjusted via genetic engineering depending on the persistence of the application.23,24 Following recent developments, further applications for spider silk are continuing to surface, including its use in coating breast implants, epidermal wound healing, and incorporation into films, foams, and hydrogels.3 Currently, scalability poses the largest barrier to the wide-spread clinical use of spider silk. However, as researchers continue to explore new production methods, the age of silk-based therapeutics may not be far off.3

EDITED BY: AARON WEN & ROHAN AANANTH

1. 2. 3.

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12. 13.

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regeneration. Int J Mol Sci. 2018;20(1):71. Available from: doi:10.3390/ijms20010071. Kornfeld T, Vogt P, Bucan V, Peck CT, Reimers K, Radtke C. Characterization and Schwann cell seeding of up to 15.0 cm long spider silk nerve conduits for reconstruction of peripheral nerve defects. J Funct Biomater. 2016;7(4):30. Available from: doi:10.3390/jfb7040030. Allmeling C, Jokuszies A, Reimers K, Kall S, Choi CY, Brandes G, et al. Spider silk fibres in artificial nerve constructs promote peripheral nerve regeneration. Cell Prolif. 2008;41(3):408-20. Available from: doi:10.1111/j.1365-2184.2008.00534.x. Osteoporosis. Impact Report 2018 [Internet]. 2018. Available from: https://osteoporosis.ca/our-mission/impact-report-2018/ [cited 2020 Nov 4]. Riesle J, Hollander AP, Langer R, Freed LE, Vunjak-Novakovic G. Collagen in tissue-engineered cartilage: Types, structure, and crosslinks. J Cell Biochem. 1998;71(3):313-27. Available from: doi:10.1002/(sici)1097-4644(19981201)71:3<313::aidjcb1>3.0.co;2-c. Hardy JG, Torres-Rendon JG, Leal-Egaña A, Walther A, Schlaad H, Cölfen H et al. Biomineralization of engineered spider silk proteinbased composite materials for bone tissue engineering. Materials. 2016;9(7):560. Available from: doi:10.3390/ma9070560. Gomes S, Leonor IB, Mano JF, Reis RL, Kaplan DL. Spider silkbone sialoprotein fusion proteins for bone tissue engineering. Soft Matter. 2011;7:4964. Available from: doi:10.1039/ c1sm05024a. Scheller J, Henggeler D, Viviani A, Conrad U. Purification of spider silk-elastin from transgenic plants and application for human chondrocyte proliferation. Transgenic Res. 2004;13(1):51-7. Available from: doi:10.1023/b:trag.0000017175.78809.7a.

17. Akkiraju H, Nohe A. Role of chondrocytes in Cartilage formation, progression of osteoarthritis and cartilage regeneration. J Dev Biol. 2015;3(4):177-92. Available from: doi:10.3390/ jdb3040177. 18. Canada. Heart Disease in Canada [Internet]. 2017 Feb 10. Available from: https://www.canada.ca/en/public-health/services/publications/diseases-conditions/heart-disease-canada. html[cited 2020 Nov 4]. 19. Laflamme MA, Murry CE. Heart regeneration. Nature. 2011;473(7347):326-35. Available from: doi:10.1038/nature10147. 20. Petzold J, Aigner TB, Touska F, Zimmermann K, Scheibel T, Engel FB. Surface features of recombinant spider silk protein eADF4(C16)-made materials are well-suited for cardiac tissue engineering. Adv Funct Mater. 2017;27(36):1701427. Available from: doi:10.1038/s41598-020-65786-4. 21. Kramer JPM, Aigner TB, Petzold J, Roshanbinfar K, Scheibel T, Engel FB. Recombinant spider silk protein eADF4(C16)-RGD coatings are suitable for cardiac tissue engineering. Sci Rep. 2020;10:8789. Available from: doi:10.1038/s41598-02065786-4. 22. Hou J, Xie Y, Ji A, Cao A, Fang Y, Shi E. Carbon-nanotube-wrapped spider silks for directed cardiomyocyte growth and electrophysiological detection. ACS Appl Mater Interfaces. 2018;10(8):67938. Available from: doi:10.1021/acsami.7b14793. 23. Fredriksson C, Hedhammar M, Feinstein R, Nordling K, Kratz G, Johansson J et al. Tissue response to subcutaneously implanted recombinant spider silk: An in vivo study. Materials. 2009;2:1908-22. Available from: doi:10.3390/ma2041908. 24. Müller-Herrmann S, Scheibel T. Enzymatic degradation of films, particles, and nonwoven meshes made of a recombinant spider silk protein. ACS Biomater Sci Eng. 2015;1:247-59. Available from: doi:10.1021/ab500147u.

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Newman J, Newman C. Oh what a tangled web: The medicinal uses of spider silk. Int J Dermatol. 1995;34(4):290-2. Available from: doi:10.1111/j.1365-4362.1995.tb01600.x. Omenetto FG, Kaplan DL. New opportunities for an ancient material. Science. 2011;329(5991):528-31. Available from: doi:10.1126/science.1188936. Salehi S, Koeck K, Scheibel T. Spider silk for tissue engineering applications. Molecules. 2020;25(3):737. Available from: doi:10.3390/molecules25030737. Yip EC, Rayor LS. Maternal care and subsocial behaviour in spiders. Biol Rev Camb Philos Soc. 2013;89(2):427-49. Available from: doi:10.1111/brv.12060. GenomeAlberta. The intricacies of spinning spider silk strands out of goat milk [Internet]. 2015 Jan 6. Available from: https:// genomealberta.ca/livestock/the-intricacies-of-spinning-spidersilk-strands-out-of-goat-milk.aspx [cited 2020 Nov 4]. Teulé F, Cooper AR, Furin WA, Bittencourt D, Rech EL, Brooks A, et al. A protocol for the production of recombinant spider silk-like proteins for artificial fiber spinning. Nat Protoc. 2009;4(3): 34155. Available from: doi:10.1038/nprot.2008.250. Xu J, Dong Q, Yu Y, Niu B, Ji D, Li M, et al. Mass spider silk production through targeted gene replacement in Bombyx mori. PNAS. 2018;115(35): 8757-62. Available from: doi:10.1073/ pnas.1806805115. Radtke C, Allmeling C, Waldmann K-H, Reimers K, Thies K, Schenk HC, et al. Spider silk constructs enhance axonal regeneration and remyelination in long nerve defects in sheep. PLoS ONE. 2011;6(2):e16990. Available from: doi:10.1371/journal. pone.0016990. Resch A, Wolf S, Mann A, Weiss T, Stetco A-L, Radtke C. Co-culturing human adipose derived stem cells and Schwann cells on spider silk—a new approach as prerequisite for enhanced nerve

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table of contents

AUTHORS: ADRIAN WONG & AISLING ZENG ARTISTS: ANDY ZHU & NINGLU WENG

The First Human Coronaviruses

In 1965, David Tyrrell and Malcolm Bynoe discovered a new virus, which they named B814, in a specimen taken from a British schoolboy infected with the common cold.1,2 Within the next two years, two more viruses —229E and OC43— were discovered by independent teams.1,3,4 Examination by microscopy of B814 and 229E demonstrated that they were morphologically and biologically similar to avian infectious bronchitis virus.⁵ In 1968, researchers proposed the existence of a category of viruses currently known as the “coronaviruses,” including B814, 229E, and OC43. This name was a reference to the projections that were found on all of these viruses, reminiscent of the sun’s corona.⁶

SARS-CoV

In November 2002, a new form of pneumonia of unknown origin was discovered in Guangzhou, China, before it spread throughout Guangdong province. This disease, referred to as severe acute respiratory syndrome (SARS), spread to Hong Kong in February 2003 and then to 29 countries around the world, eventually resulting in 8098 infections and 774 deaths.1,7 The cause of this illness was found to be a coronavirus named SARS-CoV, which was slightly different phylogenetically from known human coronaviruses but closely related to coronaviruses found in bats and civets. To date, however, the exact origin of SARS-CoV remains unknown.⁷

MERS-CoV

In June 2012, MERS-CoV, short for Middle Eastern Respiratory Syndrome-Coronavirus, was discovered in Saudi Arabia when a man suffering from severe respiratory symptoms was admitted to a hospital.13 It is believed that the virus originated from bats but was transmitted to humans via infected dromedary camels, which are often used for transport. Although MERS-CoV has been relatively localized, with 80% of the over 2560 reported cases being from Saudi Arabia. However, it also has one of the highest mortality rates among coronaviruses â&#x20AC;&#x201D;it is lethal in approximately 35% of cases.14

NL63/HKU1

In 2004, a novel coronavirus was discovered in a 7-month-old infant who had been admitted to the hospital for bronchitis and conjunctivitis.â ¸ This virus, later named NL63, was found to predominantly infect infants and immunocompromised individuals, leading to symptoms common to other human coronaviruses such as fever, cough, and respiratory problems.9 A year later, researchers in Hong Kong isolated another novel coronavirus from a 71-year-old man suffering from pneumonia symptoms.10 The virus, termed HKU1, is most prevalently seen in the winter and spring, and more commonly infects children.11,12

SARS-CoV-2/COVID-19

introduction

In early December 2019, a physician reported patients with SARS-like symptoms in Wuhan, China. The cause of these cases was found to be another novel coronavirus, termed SARS-CoV-2, which results in a disease titled coronavirus disease 2019 (COVID-19).13 On January 30, 2020, as cases continued to rise at an alarming rate, the World Health Organization declared a public health emergency of international concern.15 Since then, COVID-19 has brought about a global pandemic, with over 57 million confirmed cases, more than 1 million deaths, and far-reaching consequences to the physical and mental health of countless others.16

M E D U CATO R | A P R I L 2015

EDITORS: JERRY DU & PARNIKA GODKHINDI References can be found on our website: meducator.org

doi:10.35493/medu.38.12

VIEWPOINTS

Should CRISPR be used as a medical intervention tool for biological disorders? AUTHORS: MICHAL MOSHKOVICH & YIMING ZHANG ARTIST: BEVERLY NG

viewpoints table of contents

INTRODUCTION

When Chinese scientist He Jiankui was sentenced to three years in jail for using CRISPR-Cas9 to modify the HIV resistance of a pair of prenatal twin girls, he inadvertently reignited the controversy surrounding gene-editing technologies.¹ Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) is a gene-editing tool that allows researchers to manipulate the body’s natural repair system by splicing out targeted DNA strands and replacing them with new, customized strands. From medical application to biological manipulation, CRISPR’s potential only increases as research develops. However, to date, clinical use of CRISPR-Cas9 is frowned upon internationally, and public opinion remains largely divided.² Many European nations agreed in the 1997 Oviedo Convention to completely prohibit clinical germline modifications, while the United States has implemented complicated legal processes that severely limit embryonic research.² Whether the usage of gene editing tools will be made accessible for the public once available is an ongoing international debate. This Viewpoints piece will provide two perspectives on the consequences of public access to future clinical gene editing technologies such as CRISPR-Cas9. 1. Hunt K. What is CRISPR and why is it Controversial? [Internet]. 2020. Available from: https://www.cnn. com/2020/10/07/health/w hat-is-crispr-explainer-scn-trnd/index.html [cited 2020 Oct 23]. 2. Charo R. A. The Legal and Regulatory Context for Human Gene Editing. [Internet]. 2016. Available from: https://issues.org/the-legal-and-regulatory-context-for-human-gene-editing/ [cited 2020 Oct 23]. 3.

Reardon S. World Health Organization panel weighs in on CRISPR-babies debate. [Internet]. 2019. Available from: https://www.nature.c om/articles/d41586-019-00942-z [cited 2020 Oct 24].

4. Kozubek J. How Gene Editing Could Ruin Human Evolution. [Internet]. 2017. Available from: https:// time.com/4626571/crispr-gene-modif ication-evolution/ [cited 2020 Oct 23]. 5. Cavaliere G. Genome editing and assisted reproduction: curing embryos, society or prospective parents?. Med Health Care Philos. 2018;21:215-25. Available from: doi:10.1007/s11019-017-9793-y.

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Vigliotti VS, Martinez I. Public health applications of CRISPR: How children’s health can benefit. Semin Perinatol. 2018;42(8):531-6. Available from: doi:10.1053/j.semperi.2018.09.017.

7. King D. Editing the human genome brings us one step closer to consumer eugenics. [Internet]. 2017. Available from: https://www.theguardian.com/commentisfree/2017/aug/04/editing-human-genome-consumer-eugenics-designer-babies [cited 2020 Oct 31]. 8.

Irvine A. Paying for CRISPR Cures: The Economics of Genetic Therapies. [Internet]. 2019. Available from: https://innovativegeno mics.org/blog/paying-for-crispr-cures/ [cited 2020 Oct 24].

9. Nuffield Council on Bioethics. Genome Editing and Human Reproduction. [Internet]. 2018. Available from: https://www.nuffieldbioethics.org/wp-content/uploads/Genome-editing-and-human-reproduction-FINAL-website.pdf [cited 2020 Oct 24]. 10. Dohn MR. Preventing an era of ‘new eugenics’: An argument for federal funding and regulation of gene editing research in human embryos. Richmond Journal of Law and Technology. 2018;25(2):33. Available from: https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3309259 [cited 2020 Oct 24]. 11. Klitzman R. Designer babies are on the way. We’re not ready. [Internet]. 2019 August 16. Available from: https://www.cnn.com/2019/08/16/opinions/gene-edit-dangers-opinion-klitzman/index.html. [cited 2020 Oct 29]. 12. Stamell K. Why gene editing isn’t the answer. J R Soc Med. 2017;110(7):280-2. Available from: doi:10.1177/0141076817706278. 13. Sherkow JS. CRISPR, Patents, and the public health. Yale J Biol Med. 2017;90(4):667-72. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PM C5733839/ [cited 2020 Oct 29]. 14. Phan S. Wealth gap widening for more than 70% of global population, researchers find. [Internet]. 2020. Available from: https://www.theguardian.com/global-development/2020/jan/22/wealth-gapwidening-for-more-than-70-per-cent-of-global-population-researchers-find [cited 2020 Nov 2]. 15. Carroll D, Charo RA. The societal opportunities and challenges of genome editing. Genome Biol. 2015;16:242. Available from: doi:10.1186/s13059-015-0812-0.

IN FAVOUR OF PUBLIC ACCESS TO GENE EDITING TECHNOLOGIES

CRISPR-Cas9 carries the ability to eradicate life-threatening diseases on a genomic scale. Studies using CRISPR-Cas9 to knock out genes associated with schizophrenia have already clarified scientists’ understanding of disease-relevant mutations, with further research aiming to completely eliminate certain disorders.³ In fact, gene editing tools are currently undergoing trials for the treatment of non-lethal genetic diseases such as autism spectrum disorder.³ The opposition may argue that while the natural process of evolution does not directly remove genetic disorders from the genome, there is no risk of adverse generational byproducts of genetic alterations —thus relying on risk-bearing artificial practices to achieve similar results is unnecessary.⁴ However, though byproducts are a reasonable concern, this argument fails to acknowledge the more precise control that genome editing tools have compared to natural evolutionary changes. CRISPR-Cas9 could create a faster, more efficient method of eliminating genetic predisposition to specific diseases. For example, the technology could act as a guaranteed method of assisted reproduction for couples who wish to protect their offspring from inherited genetic diseases. Scientists are currently researching practical applications of gene-editing tools on infertility cases as well.⁵ Furthermore, CRISPR-Cas9 offers a reliable antiviral strategy for afflicted children suffering from fatal diseases. Historically, such technologies had been used to splice out certain genes and cure children of influenza, a disease with a previous 99% mortality rate for those under the age of five.⁶ Overall, gene-editing technology offers protection and treatment for less fortunate individuals, providing a muchdeserved chance to overcome such genomic factors outside of their control. This gene-editing technology also has the potential to improve quality of life and increase life expectancy. For instance, an individual born deaf would face burdens in all aspects of their life, yet would not be classified as “diseased,” thus there would be no urgency for genetic treatment to

prevent death. Still, gene editing treatment for such a patient would be greatly desired by both the individual and their family. Given current successes in developing cures for deafness in murine models, tools such as CRISPR-Cas9 could potentially deactivate similar mutations in human cases as well, while improving societal health quality overall.⁷ However, when diving into the field of psychology, one must question whether neurodevelopmental and psychological disorders, such as autism and anxiety, should be genetically altered to protect quality of life. Who is to say that myopia or hyperopia should not be eradicated as well? Currently, clinical practitioners are still in need of a statement concerning ethical boundaries, regulation, and treatment qualification. While society will always fear uncertainty, by allowing public use, researchers believe that gene editing therapies will have the potential to help millions of people worldwide.⁸ From disease elimination to quality of life enhancements, CRISPR-Cas9 offers much-needed improvements to public health and society as a whole.

AGAINST PUBLIC ACCESS TO GENE EDITING TECHNOLOGIES

Furthermore, some researchers express extensive concern about the generational consequences that may result from this technology. Dana Carroll, a researcher at the Department of Biochemistry at the University of Utah’s School of Medicine, worries about the “intrinsic uncertainty about downstream effects” from CRISPR-Cas9.¹⁵ Negative effects, such as unintentional increases in certain genetic diseases from unrelated genomic modification, could harm humanity’s future generations.As future generations are not present for this decision, despite bearing the brunt of risk and reward, ethical concerns act as a major hurdle in the practical acceptance of gene-editing tools. Scientists and society cannot predict all of the future consequences of gene-editing and thus, the potential for error exists.¹⁵ As this innovative technology develops, further modifications may improve the effectiveness of gene editing. What remains in question are the limits, regulations, and ethical considerations that must be set in order to discern whether gene manipulation should be authorized for public use —a notion that many scientists argue is far too complicated to implement at the present time.¹⁵ While CRISPR-Cas9 remains a groundbreaking discovery in healthcare and medicine, society must first address the ethical and practical implications it bears before taking any leaps in public accessibility.

introduction viewpoints

Despite the benefits previously outlined, there are ethical and practical concerns associated with the public use of CRISPRCas9. One such concern involves the potential for CRISPR-Cas9 to become a tool which promotes eugenics, a theory of progressive genomic augmentation, as natural adaptations are already the “apotheosis of engineering excellence,” states Dr. Lisa Feldman Barrett, Professor of Psychology at Northeastern University.⁹ Many believe that the public use of gene editing would only cause ignorance of the regulatory limitations initially imposed on the practice, and this would lead the public down a slippery slope of gene manipulation.¹⁰ Fear is enrooted in the belief that gene editing technologies will go beyond their initial goal of curing medical disorders, and rather transition into cosmetic, superficial, or dangerous methodologies. The normalization of “designer babies,” embryos whose physical flaws are removed prenatally, is a major concern that could lead to social stigmas against non-CRISPR-Cas9 babies.¹¹

improves the health of society at large, it comes with a notable flaw. Being a new, expensive technology, CRISPR-Cas9 will likely only be available at highly specialized facilities at a price similar to modern gene-editing therapies, such as Novartis’ $475,000 USD tisagenlecleucel treatment for leukemia.¹³ One must take note of the the worst-case situation: those with greater financial resources will be able to upregulate certain genes and increase their overall health quality, inducing physiological benefits that are inaccessible to the majority of society. As the wealth gap grows over the years, a future of biological superiority awaits.¹⁴ Former microbiologist, David King, is one of many that share this concern, with the belief that “once you start creating a society in which rich people’s children get biological advantages [...] human equality goes out the window.”⁷

A major hurdle in healthcare is the disparities in its access resulting from socioeconomic inequalities, whereby wealthier nations have greater access to higher-quality medications and treatments, including CRISPR-Cas9.¹² Although gene editing has enormous potential to become a preventative treatment which MM E DE U 2 0B 1E 5R 2 0 2 0 D CU ACTAOT R O R | |A DP ER CI LE M

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ARTIST ANNISA SIU

OPINION

Gender Minority Youth tableopinion of contents

Why They are Troubled: An Examination of Social Determinants of Mental Health

| DECEMBER 2020 M E D U CATO R

Bachelor of Health Sciences (Honours), Class of 2021, McMaster University yangl60@mcmaster.ca doi:10.35493/medu.38.14

ABSTRACT Gender minority (GM) youths are disproportionately challenged by mental health and body image issues as a result of social discrimination and impediments. Media portrayal of gendered body ideals can have detrimental effects on GM youths’ body image. To alleviate the effects of media-induced dysphoria and eating disorders , diversifying media representation of gender-nonconforming individuals and fostering a more fluid representation of gender are potential first steps. Additionally, despite the importance of healthcare professionals for GM youths, the quality of care that they receive is insufficient. Education sessions on transgender health issues and trauma-informed care can significantly improve the quality of care. As for academia, transgender individuals have historically been discriminated from studies and sexual orientation was oftenconflated with gender identity. In order to conduct culturally-sensitive research, surveys and questionnaires need to improve the language used. Overall, these factors should be examined together to help inform appropriate solutions.

INTRODUCTION

LING YA N G

In the United States, gender minority (GM) youth are four times more likely to have at least one mental illness compared to their cisgender counterparts.1 45% of transgender youth have attempted suicide in their lifetime, compared to a national average of 0.6% overall.2,3 In contrast to cisgender individuals, GMs are people who identify with a gender different from their sex assigned at birth, which can include those who are transgender, non-binary, gender non-conforming, as well as two-spirit.4 Consequently, GMs face prejudice and discrimination in their daily lives —including increased incidence of bullying, parental abuse, and health disparities.4-6 This piece aims to examine and discuss social influences on mental health in GM youth, specifically the influence of the media, access to health care, and representation in research.

MEDIA PORTRAYAL OF THE IDEALIZED BODY

Media portrayals of idealized bodies are often exaggerated and gendered. Gender binaries are prominent in the portrayal of role models, such as superheroes, where men are shown as powerful and muscular, while women are portrayed as beautiful and thin.7,8 Unrealistic media representation of the idealized

body has a strong influence in shaping adolescents’ body perceptions —especially when social grooming behaviors, such as viewing and commenting, are involved.7-9 GM youth are more likely to identify with media portrayals that are incongruent with their bodies which can lead to gender dysphoria, suicidal ideations, and self-injury.10 Due to body dissatisfaction, GM youth are at an increased risk of developing eating disorders (ED) compared to their cisgender peers.11-13 Transgender youth may also use weight manipulation tactics to align their bodies with their gender, avoid menstrual periods, and delay the progression of puberty.11,12 There have been several recent efforts using mass media campaigns to build self-esteem and positive body image in women. For instance, companies such as Dove and Lane Bryant employed models of diverse body types.14 Public reception of these efforts has been generally positive as people were hopeful that these shifts in advertising practices could improve future generations’ body perceptions.14 However, these body positive advertising efforts did not reach 2SLGBTQQIA+ groups. Instead, there have been continuous criticism for the homogenous representation

of “musclar, shirtless, hairless, and youthful” gay men.15 A more fluid representation of body types can help GM youth recognize their bodies as being accepted and celebrated.

responses using open-ended questions.29 Sharing personal experiences in an unfamiliar setting hinges on trust and rapport.

ACCESS TO HEALTHCARE

We must acknowledge the interconnectedness between media influence, access to healthcare, and representation in research in shaping mental health in GM youth. Despite a myriad of challenges that GM youth face, there are concrete measures that can help improve their mental health outcomes. This can be initiated by diversifying media depictions to improve body image, improving culturally-sensitive care, and bettering research approaches to encourage GM participation.

GM youth experience a higher prevalence of mental health issues —including depression, anxiety, suicidality, trauma, and victimization.16,17 Accessing mental health support can help improve their psychological states; transgender university students report less drug and alcohol concerns after accessing support.18 GM with dysphoria may have difficulties in forming intimate relationships and participating in recreational activities, and the associated stigmas may discourage individuals to not seek medical care.16 This highlights an increased need for GM youth to seek gender affirmative treatments.17,19

Youth have indicated that providers display a lack of ability to deliver patient-centered care to transgender individuals.22,24 Studies have shown that training on transgender health issues significantly improved GM youth’s experiences in healthcare settings, indicating the salience of medical education about GM health issues.26-28

LITERATURE REPRESENTATION

Surveys and questionnaires need to improve the language used in order to conduct culturally-sensitive studies. Several preliminary guidelines have been recommended, such as inclusivity of diverse identities and sexual behaviors, soliciting feedback from GM members, and allowing participants to contextualize

Ruth Repchuck is pursuing a PhD in sociology at McMaster University. She is a Research Coordinator at the Offord Centre for Child Studies. Her research interests include mental health, gender and sexuality, and occupations and organization.

EDITED BY: ALBERT STANCESCU & MEERA CHOPRA 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32.

Lipson SK, Raifman J, Abelson S, Reisner SL. Gender minority mental health in the US: Results of a national survey on college campuses. Am J Prev Med. 2019;57(3):293-301. Available from: doi:10.1016/j.amepre.2019.04.025. Toomey RB, Syvertsen AK, Shramko M. Transgender adolescent suicide behavior. Pediatrics. 2018;142(4):e20174218. Available from: doi:10.1542/peds.2017-4218. American Foundation for Suicide Prevention. Suicide Statistics [Internet]. 2019. Available from: https://afsp.org/suicidestatistics/ [cited 2020 Nov 4]. Reisner SL, Greytak EA, Parsons JT, Ybarra ML. Gender minority social stress in adolescence: Disparities in adolescent bullying and substance use by gender identity. J Sex Res. 2015;52(3):243-56. Available from: doi:10.1080/00224499 .2014.886321. Grossman AH, D’augelli AR, Salter NP. Male-to-female transgender youth: Gender expression milestones, gender atypicality, victimization, and parents’ responses. J GLBT Fam Stud. 2006;2(1):71-92. Available from: doi:10.1300/ J461v02n01_04. Connolly MD, Zervos MJ, Barone II CJ, Johnson CC, Joseph CL. The mental health of transgender youth: Advances in understanding. J Adolesc Health. 2016;59(5):489-95. Available from: doi:10.1016/j.jadohealth.2016.06.012. Franchina V, Coco GL. The influence of social media use on body image concerns. International Journal of Psychoanalysis and Education. 2018;10(1):5-14. Available from: http://www.psychoedu.org/index.php/IJPE/article/view/218 [cited 2020 Nov 4]. Kaplan T, Rauch J, Miller M. Gender differences in movie superheroes’ roles, appearances, and violence. Ada: A Journal of Gender, New Media, and Technology. 2016;10. Available from: doi:10.7264/N3HX19ZK. Kim JW, Chock TM. Body image 2.0: Associations between social grooming on Facebook and body image concerns. Comput Hum Behav. 2015;48:331-9. Available from: doi:10.1016/j.chb.2015.01.009. Hunt QA, Morrow QJ, McGuire JK. Experiences of suicide in transgender youth: A qualitative, community-based study. Arch Suicide Res. 2020;24(sup2):S340-55. Available from: doi:10.1080/13811118.2019.1610677. Coelho JS, Suen J, Clark BA, Marshall SK, Geller J, Lam PY. Eating disorder diagnoses and symptom presentation in transgender youth: A scoping review. Curr Psychiatry Rep. 2019;21(11):107. Available from: doi:10.1007/s11920-0191097-x. Avila JT, Golden NH, Aye T. Eating disorder screening in transgender youth. J Adolesc Health. 2019;65(6):815-7. Available from: doi:10.1016/j.jadohealth.2019.06.011. Duffy ME, Henkel KE, Joiner TE. Prevalence of self-injurious thoughts and behaviors in transgender individuals with eating disorders: A national study. J Adolesc Health. 2019;64(4):461-6. Available from: doi:10.1016/j.jadohealth.2018.07.016. Mabry-Flynn A, Champlin S. Leave a Comment: Consumer Responses to Advertising Featuring “Real” Women In: Vickery J, Everbach T. (eds.) Mediating Misogyny. Palgrave Macmillan, Cham; 2018. p.229-245. Nölke AI. Making diversity conform? An intersectional, longitudinal analysis of LGBT-specific mainstream media advertisements. J Homosex. 2018;65(2):224-55. Available from: doi:10.1080/00918369.2017.1314163. Chodzen G, Hidalgo MA, Chen D, Garofalo R. Minority stress factors associated with depression and anxiety among transgender and gender-nonconforming youth. J Adolesc Health. 2019;64(4):467-71. Available from: doi:10.1016/j. jadohealth.2018.07.006. Olson-Kennedy J, Warus J, Okonta V, Belzer M, Clark LF. Chest reconstruction and chest dysphoria in transmasculine minors and young adults: Comparisons of nonsurgical and postsurgical cohorts. JAMA Pediatr. 2018;172(5):431-6. Available from: doi:10.1001/jamapediatrics.2017.5440. Bartholomew TT, Gundel BE, Sullivan JW, Pérez-Rojas AE, Lockard AJ. Pretreatment counseling experiences, stressors, and support differences between transgender and cisgender university students seeking mental healthcare. J Clin Psychol. 2019;75(6):933-57. Available from: doi:10.1002/jclp.22742. Newcomb ME, Hill R, Buehler K, Ryan DT, Whitton SW, Mustanski B. High burden of mental health problems, substance use, violence, and related psychosocial factors in transgender, non-binary, and gender diverse youth and young adults. Arch Sex Behav. 2020;49(2):645-59. Available from: doi:10.1007/s10508-019-01533-9. Wright T, Candy B, King M. Conversion therapies and access to transition-related healthcare in transgender people: A narrative systematic review. BMJ Open. 2018;8(12):e022425. Available from: doi:10.1136/bmjopen-2018-022425. Rodriguez A, Agardh A, Asamoah BO. Self-reported discrimination in health-care settings based on recognizability as transgender: A cross-sectional study among transgender US citizens. Arch Sex Behav. 2018;47(4):973-85. Available from: doi:10.1007/s10508-017-1028-z. Kidd SA, Veltman A, Gately C, Chan KJ, Cohen JN. Lesbian, gay, and transgender persons with severe mental illness: Negotiating wellness in the context of multiple sources of stigma. Am J Psychiatr Rehabil. 2011;14(1):13-39. Available from: doi:10.1080/15487768.2011.546277. Avery AM, Hellman RE, Sudderth LK. Satisfaction with mental health services among sexual minorities with major mental illness. Am J Public Health. 2001;91(6):990. Available from: doi:10.2105/ajph.91.6.990. Heard J, Morris A, Kirouac N, Ducharme J, Trepel S, Wicklow B. Gender dysphoria assessment and action for youth: Review of health care services and experiences of trans youth in Manitoba. Paediatr Child Health. 2017;23(3):179-84. Available from: doi:10.1093/pch/pxx156. Santos TC, Mann ES, Pfeffer CA. Are university health services meeting the needs of transgender college students? A qualitative assessment of a public university. J Am Coll Health. 2019:1-8. Available from: doi:10.1080/07448481.201 9.1652181. Click IA, Mann AK, Buda M, Rahimi-Saber A, Schultz A, Shelton KM, et al. Transgender health education for medical students. Clin Teach. 2020;17(2):190-4. Available from: doi:10.1111/tct.13074. Bakhai N, Shields R, Barone M, Sanders R, Fields E. An active learning module teaching advanced communication skills to care for sexual minority youth in clinical medical education. MedEdPORTAL. 2016;12:10449. Available from: doi:10.15766/mep_2374-8265.10449. Hansen H, Riano NS, Meadows T, Mangurian C. Alleviating the mental health burden of structural discrimination and hate crimes: The role of psychiatrists. Am J Psychiatry. 2018;175(10):929-33. Available from: doi:10.1176/appi. ajp.2018.17080891. Staples JM, Bird ER, Masters TN, George WH. Considerations for culturally sensitive research with transgender adults: A qualitative analysis. J Sex Res. 2018;55(8):1065-76. Available from: doi:10.1080/00224499.2017.1292419. Maingi S, Bagabag AE, O’mahony S. Current best practices for sexual and gender minorities in hospice and palliative care settings. J Pain Symptom Manag. 2018;55(5):1420-7. Available from: doi:10.1016/j.jpainsymman.2017.12.479. Simons JD, Beck MJ, Asplund NR, Chan CD, Byrd R. Advocacy for gender minority students: recommendations for school counsellors. Sex Educ. 2018;18(4):464-78. Available from: doi:10.1080/14681811.2017.1421531. Sevlever M, Meyer-Bahlburg HF. Late-onset transgender identity development of adolescents in psychotherapy for mood and anxiety problems: Approach to assessment and treatment. Arch Sex Behav. 2019;48(7):1993-2001. Available from: doi:10.1007/s10508-018-1362-9.

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Transgender individuals have historically been underrepresented in research. Previous works have conflated sexual orientation with gender identity and there is a paucity of literature on GM youth in various settings for mental health treatment, including palliative care and school counselling.29-31 More research is needed to advance knowledge of unique mental health issues in GMs. However, the invasive and insensitive ways that some research is conducted may discourage GM participation. Sevlever and Meyer-Bahlburg reported two cases of GMs undergoing psychiatric treatment for mood disorders.32 The investigators misgendered and incorrectly named one of the participants throughout the paper, focused primarily on parental recounts of participant experiences, and published unnecessarily intimate content.32 Such representations of GM experiences may discourage future participation in research.

REVIEWED BY: RUTH REPCHUCK

introduction opinion

Despite the importance of competent care for GM youth, the accessibility and quality of care they receive is unsatisfactory. Barriers to accessing healthcare or medication such as puberty blockers have been commonly reported.20 In addition, GM youth often face unfair treatment from healthcare professionals.21-23 In a 2017 study assessing the experiences of transgender youth in the healthcare system, all 174 youth experiencing gender dysphoria reported negative experiences with healthcare professionals, including discrimination from psychiatric providers who ascribed their mental illnesses to their identity.24 In a university setting, transgender students reported that campus health services were not meeting their needs; oftentimes repeatedly being misgendered, addressed by their incorrect name, and asked inappropriate and irrelevant questions about their gender.25

CONCLUSION

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ARTIST MADELINE CHAN

RESEARCH INSIGHT

Variation in health outcomes associated with childhood maltreatment: Social and physiological factors

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CW: su*cide mention, s*lf-h*rm mention

doi:10.35493/medu.38.16

MADELINE KOMAR

Honours Psychology, Neuroscience & Behaviour (Mental Health Specialization), Class of 2022, McMaster University komarm1@mcmaster.ca

INTRODUCTION Chronic childhood stress predicts poor physical health in adulthood, increased participation in risky health behaviours, and worse mental health.1 Child maltreatment refers to emotional, physical, and sexual abuse as well as experiences of neglect, all of which cause chronic stress.2

Adverse childhood experiences are significantly associated with risky health behaviours such as illicit drug use, cigarette smoking, and reckless self-endangerment, as well as more frequent mental health problems including alcoholism and depression.1,4,5 However, risky health behaviour and mental health outcomes vary among adults who experienced child maltreatment, which may be the result of differing socioemotional adjustment during childhood.5 Examining how social situations and physiological features interact over the course of development to produce different health behaviours among maltreated children is essential for effective intervention programs. RESEARCH DESIGN The objectives of this review are to demonstrate the relationship between poor socioemotional adjustment and risky health behaviours among maltreated children by exploring the connection between parasympathetic nervous activity and socioemotional adjustment. Additionally, this review further explores if respiratory sinus arrhythmia (RSA) moderates the relationship between childhood maltreatment and poor socioemotional adjustment. Research article selection began with a brief review of the works produced by researchers at the Child Emotion Lab at McMaster University. The Child Emotion Lab examines the relationships between personality traits (primarily shyness), early life environment, and social behaviour. From there, other articles were selected using Google Scholar, PubMed, and Scholars Portal. Given the interdisciplinary nature of the research, a broad array of keywords were used, including “respiratory sinus arrhythmia”, “childhood maltreatment”, “socioemotional adjustment”, “early adversity”, “self-regulation”, “mental health”, “resilience”, and “emotional flexibility”.

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MEASURING SOCIOEMOTIONAL ADJUSTMENT Socioemotional adjustment refers to the quality of an individual’s interaction with their environment. Researchers studying socioemotional adjustment examine how children’s traits affect the social situations they experience, and how social situations evoke a variety of responses in different children. For example, a child with a negatively reactive temperament tends to interpret neutral stimuli as threatening, and has disproportionately intense reactions of distress or anger. This temperamental style contributes to aggressive responses with little provocation, which hinder the development of positive social relationships. Researchers gauge socioemotional adjustment in children by examining social outcomes such as peer rejection, reputation, and social network strength.6 For the purposes of this review, poor socioemotional adjustment refers to lacking positive social engagement and exhibiting intense negative reactivity.

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Negative physical health outcomes among survivors of childhood maltreatment can be explained using the biological model of allosteric load. Allosteric load refers to the cumulative effect of having a chronically active physiological stress response, for instance, “wear and tear” of major organ systems.3 Exposure to stressors triggers the physiological stress response causing the sympatho-adrenomedullary and hypothalamicpituitary-adrenal (HPA) axis to release chemical signals that help prepare the body for fight, flee, or freezing responses.1 Blood vessels constrict to increase blood pressure, heart and respiration rates increase to maximize oxygen supply, lipolysis breaks down adipose tissue to increase blood sugar, and the immune system is suppressed.1 Normally, the HPA axis is inhibited via a negative feedback loop and the child can relax once the threat has passed.1 Maltreated children however, are exposed to more stressors over longer periods of time, resulting in chronic activation of the physiological stress response systems. Since the physiological stress response is energetically costly, chronic activation strains bodily organs to increase allosteric load. The effects of the additional allosteric load accumulate over time, contributing to poorer health outcomes in adulthood. The concept of allosteric load can be used to explain the positive correlation between levels of chronic stress in childhood and the prevalence of physical health problems

such as heart disease, cancer, chronic bronchitis, and diabetes in adulthood.1 Risky health behaviours during adolescence may exacerbate the strain caused by allosteric load.1,3

research insight

ABSTRACT Maltreated children tend to experience worse health in adulthood. The physiological model of allosteric load helps to explain why maltreated children often experience adverse physical health outcomes including stroke, cancer, and diabetes in adulthood. However, since mental health and health behaviours vary depending on one’s social environment, understanding mental health and risky health behaviours among people who experienced childhood maltreatment requires integrating biological and psychosocial analyses. Among older survivors of childhood maltreatment, variation in mental health and health behaviours corresponds to variation in socioemotional adjustment. This variation in socioemotional adjustment corresponds to variation in parasympathetic nervous system functioning as measured by respiratory sinus arrhythmia (RSA).Clinicians could potentially use RSA as a screening tool to identify maltreated children whose poor socioemotional adjustment puts them at greater risk of adverse health outcomes in adulthood.

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Bucci M, Marques SS, Oh D, Burke Harris N. Toxic stress in children and adolescents. Adv Pediatr. 2016;63:403-28. Available from: doi:10.1016/j.yapd.2016.04.002.

Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM, Edwards V, 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(4):245-58. Available from: doi:10.1016/s0749-3797(98)00017-8.

McEwen BS. Central effects of stress hormones in health and disease: Understanding the protective and damaging effects of stress and stress mediators. Eur J Pharmacol. 2008; 583(2-3):174–85. Available from: d o i : 1 0 . 1 0 1 6 / j . e j p h a r. 2 0 0 7 . 1 1 . 0 7 1 .

Topitzes J, Mersky JP, Reynolds AJ. Child maltreatment and adult cigarette smoking: A long-term developmental model. J Pediatr Psychol. 2009; 35(5): 484–98. Available from: doi:10.1093/jpepsy/jsp119.

Haskett ME, Nears K, Ward CS, McPherson AV. Diversity in adjustment of maltreated children: factors associated with resilient functioning. Clin Psychol Rev. 2005;26:796-812. Available from: doi:10.1016/j.cpr.2006.03.005.

Gülay H, Önder A. A study of social– emotional adjustment levels of preschool children in relation to peer relationships. Educ. 2012; 41(5): 514-22. Available from: doi: 10.1080/03004279.2011.609827.

Yoon S, Howell K, Dillard R, Shockley McCarthy K, Napier T, Pei F. Resilience following child maltreatment: definitional considerations and developmental variations. Trauma Violence Abuse. 2019;15:24-8. Available from: doi: 10.1177/1524838019869094.

Taussig HN. Risk behaviors in maltreated youth placed in foster care: a longitudinal study of protective and vulnerability factors. Child Abuse Negl. 2002;26(11):1179-99. Available from: doi:10.1016/s0145-2134(02)00391-5.

Karatekin C, Ahluwalia R. Effects of adverse childhood experiences, stress, and social support on the health of college students. J Interpers Violence. 2020;35(1-2):150-72. Available from: doi:10.1177/0886260516681880.

10. Afifi TO, MacMillan HL. Resilience following child maltreatment: A review of protective factors. Can J Psychiatry. 2011;56(5):266-72. Available from: doi:10.1177/070674371105600505. 11. Gratz KL. Risk factors for deliberate selfharm among female college students: the role and interaction of childhood maltreatment, emotional inexpressivity, and affect intensity/reactivity. Am J Orthopsychiatry. 2006;76(2):238-50. Available from: doi:10.1037/0002-9432.76.2.238. 12. Waugh CE, Thompson RJ, Gotlib IH. Flexible emotional responsiveness in trait resilience. Emotion. 2011;11(5):1059-67. Available from: doi:10.1037/a0021786. 13. Kashdan TB, Rottenberg J. Psychological flexibility as a fundamental aspect of health. Clin Psychol Rev. 2010;30(7):865–78. Available from: d o i : 1 0 . 1 0 1 6 / j . c p r. 2 0 1 0 . 0 3 . 0 0 1 .

RISKY HEALTH BEHAVIOURS AND VARIATION IN SOCIOEMOTIONAL ADJUSTMENT Socioemotional adjustment varies among children exposed to maltreatment. Positive social engagement is generally associated with improved health among maltreated youth.7 For maltreated youth placed in the foster care system, differences in the quality of peer relationships among the youth accounted for up to 19% of the variance in their likelihood to engage in risky behaviours, including unsafe sex, substance abuse, and suicidal behaviours approximately one year later.8 Similar effects have been observed in college students, suggesting that having a strong social network and positive social engagement protects against adverse health outcomes among people with a history of maltreatment throughout their life.9 Maltreated youth with balanced life outlooks engage in risky health behaviours less often than their more negatively reactive peers.5,10 Specifically, higher levels of negative emotional reactivity were positively correlated with frequent self-harming behaviour among female survivors of childhood maltreatment.11 The ability to respond flexibly to emotional stimuli, rather than react with blanket negativity, has been positively associated with resilient functioning in a variety of contexts.12,13 THE PARASYMPATHETIC NERVOUS SYSTEM AND SOCIOEMOTIONAL ADJUSTMENT The parasympathetic nervous system has a calming, inhibitory influence on the body. Under normal conditions, this system helps maintain homeostasis by inhibiting the sympathetic nervous system, preventing a chronic stress response. For example, the inhibitory influence of

the parasympathetic nervous system keeps heart rate low in the absence of danger. When a threat is detected, the parasympathetic nervous system withdraws its inhibitory effect, allowing heart rate to increase. The sympathetic nervous system activates, increasing the heart rate further.1,14 RSA is used to index parasympathetic nervous system activity. Through indexing parasympathetic nervous system functioning, RSA informs researchers about one’s ability to respond flexibly to social situations.14 Baseline RSA is positively associated with executive functioning, emotional regulation, and attentional shifting.15-17 The parasympathetic nervous system influences heart rate via the 10th cranial nerve and RSA measures how heart rate varies with respiration. Thus RSA indirectly indexes PNS activity.14,17 High baseline RSA reflects effective parasympathetic nervous system functioning and the ability to respond flexibly to stress, while low baseline RSA reflects a lack of flexibility because there is more lability for change in the event of encountering environmental stressors. Because high levels of baseline RSA suggest more parasympathetic activation, parasympathetic nervous system functioning should decrease in response to environmental stressors. Since the parasympathetic nervous system is operating at a relatively low level among children with low baseline RSA, a smaller increase in arousal occurs in response to a stressor (see Figure 1).14-16,18 RSA AS A PREDICTOR OF SOCIOEMOTIONAL ADJUSTMENT IN MALTREATED CHILDREN Differences in baseline RSA correspond to differences in negative reactivity and social network quality. Baseline RSA is negatively associated with negative reactivity throughout development. One study measured baseline

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14. Porges SW. Orienting in a defensive world: Mammalian modifications of our evolutionary heritage: A polyvagal theory. Psychophysiology. 1995;32(4):301– 18. Available from: doi: 10.1111/ j.1469-8986.1995.tb01213.x.

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15. Marcovitch S, Leigh J, Calkins SD, Leerks EM, O’Brien M, Blankson AN. Moderate vagal withdrawal in 3.5-yearold children is associated with optimal performance on executive function tasks. Dev Psychobiol. 2010;52(6):603–8. Available from: doi:10.1002/dev.20462. 16. Skowron EA, Cipriano-Essel E, Gatze-Kopp LM, Teti DM, Ammerman RT. Early adversity, RSA, and inhibitory control: Evidence of children’s neurobiological sensitivity to social context. Dev Psychobiol. 2013;56(5):964– 78. Available from: doi:10.1002/dev.21175. 17. Hassan R, Poole KL, Schmidt LA. Revisiting the double-edged sword of self-regulation: Linking shyness, attention shifting, and social behavior in preschoolers. J Exp Child Psychol. 2020;196. Available from: doi:10.1016/j.jecp.2020.104842. 18. Thayer JF, Lane RD. A model of neurovisceral integration in emotion regulation and dysregulation. J Affect Disord. 2000;61(3):201-16. Available from: doi:10.1016/S0165-0327(00)00338-4.

FIGURE 1. Higher baseline RSA indicates higher baseline parasympathetic nervous system activation. People with higher baseline RSA then have more room to maneuver when responding to threats; the magnitude of the difference between their baseline state and their state of emergency is greater for people who have low baseline RSA (A>B). Thus, people with high baseline RSA have more flexibility to respond to environmental stressors.

RSA among a sample of maltreated adolescent girls, and used baseline RSA to predict levels of neuroticism over one year. Neuroticism is a personality trait associated with blanket negative reactivity; neurotic individuals tend to interpret neutral stimuli as negative and struggle to regulate their emotions. This study found that baseline RSA predicted neuroticism trajectories over the course of the year, such that neuroticism increased among girls with low baseline RSA, and remained low and stable among girls with high baseline RSA.19

19. Hassan R, MacMillan HL, Tanaka M, Schmidt LA. Psychophysiological influences on personality trajectories in adolescent females exposed to child maltreatment. Dev Psychopathol. 2020;32(4):1390-401. Available from: doi:10.1017/S0954579419001342. 20. Geisler FCM, Kubiak T, Siewert K, Weber H. Cardiac vagal tone is associated with social engagement and selfregulation. Biol Psychol. 2013;93(2):279-86. Available from: doi:10.1016/j.biopsycho.2013.02.013. 21. Gordis EB, Feres N, Olezeski CL, Rabkin AN, Trickett PK. Skin conductance reactivity and respiratory sinus arrhythmia among maltreated and comparison youth: Relations with aggressive behavior. J Pediatr Psychol. 2010;35(5):547â&#x20AC;&#x201C;58. Available from: doi:10.1093/jpepsy/jsp113. 22. Fanti KA, Henrich CC, Brookmeyer KA, Kuperminc GP. Aggressive behavior and quality of friendships. J Early Adolesc. 2008;29:826-38. Available from: doi:10.1177/0272431609332819. 23. Bolger E, Patterson CJ. Developmental pathways from child maltreatment to peer rejection. Child Dev. 2001;72(2):549-68. Available from: doi:10.1111/1467-8624.00296.

REVIEWED BY: DR. LOUIS SCHMIDT & RAHA HASSAN Raha Hassan is a Ph.D. candidate in the Department of Psychology, Neuroscience and Behaviour. Her research interests center around the relation between childrenâ&#x20AC;&#x2122;s self-regulation and their temperament. Dr. Louis Schmidt is a professor in the Department of Psychology, Neuroscience and Behaviour, as well as a Science Research Chair in Early Determinants of Mental Health. His research interests focus on how temperment and early life experiences can influence the relationship between brain development and behaviour, as well as the processes associated with typical and less typical development.

EDITED BY: NICK TELLER & TAAHA HASSAN

introduction research insight

Baseline RSA has been directly linked to social engagement in the general population, and this relationship likely exists among people who experienced childhood maltreatment.20 However, differences in RSA correspond to differences in aggressive behaviour among maltreated youth aged 6 to 19, as behaving aggressively makes it harder for a child to make friends.21,22 Anti-social maltreated children have pre-established aggressive behaviour patterns by the time they enter school, suggesting that aggressive behaviours contribute to peer rejection, rather than the reverse.23 High baseline RSA may act as a buffer for aggressive behaviour.22 The effects of RSA in moderating aggressive behaviour are especially significant considering aggressive behaviour contributes to peer rejection during childhood and into adolescence.23 Given that adolescent peer relationships buffer against mental illness and risky health behaviours among survivors of maltreatment, RSA may be an effective screening tool to identify children at risk of adverse developmental trajectories.7-10

health-risk behaviours (see Figure 2). RSA should be considered as a tool for predicting socioemotional adjustment in maltreated children. If physicians can identify which maltreated children are most likely to struggle socially, physicians can use targeted interventions to improve socioemotional adjustment among those children, thereby reducing the risk of mental health issues and risky health behaviours. Further research should assess the reliability and validity of RSA in directly predicting future risky health behaviours and mental health outcomes of maltreated children.

CONCLUSIONS Individual differences in parasympathetic activity moderate the effect of childhood maltreatment on socioemotional adjustment. Differences in socioemotional functioning can then partially explain differences in M E D U CATO R | A P R I L 2015 M E D U CATO R | D EC E M B E R 2 0 2 0

FIGURE 2. Proposed model for the impact of childhood maltreatment on adverse health outcomes, variable health risk behaviours and mental health outcomes in adulthood.

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IN T E R V IE W SPOTLIGHT

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DR. S HE IL A S IN G H Photo Credit: Unknown

The Dynamics of Brain Tumors MICHAL MOSHKOVICH1 & SOPHIE ZARB2

Bachelor of Health Sciences (Honours), Class of 2023, McMaster University Bachelor of Health Sciences (Honours), Class of 2022, McMaster University

Dr. Sheila Singh is a Pediatric Neurosurgeon at McMaster Children’s Hospital, a Professor of Surgery and Biochemistry at McMaster University, and a Canada Research Chair in Human Cancer Stem Cell Biology. She is also a Principal Investigator in the Stem Cell and Cancer Research Institute at McMaster University and the Director of the McMaster Surgeon Scientist Program. Her research has been dedicated primarily to applying a developmental neurobiology approach to the study of human brain tumours.

WHAT INSPIRED YOU TO PURSUE A CAREER PATH IN PEDIATRIC NEUROSURGERY AND STEM CELL AND CANCER RESEARCH? So, I think I knew for a long time, since I was a girl, that I wanted to be a doctor and was mostly inspired by family members. My mother was a nurse and my father was a doctor and so the whole sort of caregiving aspect really appealed to me. When I went to medical school, I had an abiding interest in the brain. It started because my father, who is a psychiatrist, had all kinds of books on psychotherapy, and they were the only books that were available in his library. Mostly, they were all Sigmund Freud and stuff like that, so I started reading psychology and became fascinated by how little we know about the brain. When I got to medical school, I knew I wanted to do something related to the

brain and did electives in everything that had the word “neuro” in front of it. So, the reason I chose neurosurgery is because, out of all of the fields which were intellectually interesting and cognitively gratifying, I found only neurosurgery had that sense of activism where you threw yourself into a cause where someone was very sick and you were actually able to do something about it. In neurology, I loved the diagnostic process, the whole localizing the lesion and finding out where the central nervous system was injured based on someone’s presentation. But, it was depressing because, very often, you’d say, “Oh, you have a neurodegenerative disorder for which there’s no known cure and I don’t have any medical treatments for you”. That was too passive for me. So, I think it was really just the difference between passive and active that made me choose neurosurgery because that just suits my personality. When I was a teenager, I was kind of a social activist and I always wanted to pick up a cause and protest so I think neurosurgery suited me personally because of the activism. Having said that, when I chose neurosurgery in medical school, I didn’t pick it lightly; I really tested myself, trying to find out what I enjoyed the most. Once I realized it was neurosurgery, I wanted to make sure that I was able to keep up with the demands of the profession. So, I did enough electives to have experience in it, to know that I enjoyed the pace and the demands of the lifestyle. That’s another important thing: just because you like something, the next question is, am I well suited for this? Then, the final thing is that you know at the end of everything in medical school, this was the only thing I loved. It’s almost as if when you love something like that, then it chooses you, it’s not like you chose it. I couldn’t imagine myself doing anything else.

COULD YOU DESCRIBE THE RESEARCH THAT YOU HAVE BEEN CONDUCTING IN YOUR LAB?

WE WERE WONDERING IF YOU COULD ELABORATE ON THE PATH THAT YOUR RESEARCH TOOK TO BRING YOU TO YOUR GROUNDBREAKING DISCOVERY OF THE BRAIN TUMOUR-INITIATING CELLS.

ARE THERE ANY NEW TECHNOLOGIES ON THE HORIZON THAT MIGHT BE ABLE TO FURTHER AID IN THE ANALYSIS OF BRAIN TUMOR CELLS, ESPECIALLY SINCE YOU HAVE MENTIONED THE DYNAMIC NATURE OF TUMOR GROWTH? I think one thing is recognizing that cancer is a dynamic system. I think modeling how cancers form, and its heterogeneity, both at a cellular and a genetic level, as well as from a spatial and temporal perspective is important. So building model systems that capture how cancers evolve over time or tumor evolution is a theme that’s

WHAT DO YOU BELIEVE ARE THE NEXT STEPS FOR YOUR LAB OR FOR YOU AS A RESEARCHER-SCIENTIST? We’re very excited in the Singh Lab about the prospect and the hope of immunotherapy because there have been some big breakthroughs with harnessing the immune system to treat cancers like blood cancers and melanoma. We’re hoping that some of those approaches can apply to brain cancer. It’s a big challenge because the brain is notoriously known for being an immunosuppressive environment. So, things can hide out in the brain and escape detection by the immune system and that’s possibly why brain cancers do so well. How do you somehow alert the immune system and notify the brain that there is something that needs to be dealt with? Trying to relieve that immunosuppression using things like new versions of checkpoint inhibitors that kind of wake up the immune system and uncover the tumors’ ability to evade immune detection is one option. Another option is developing direct targeted therapies like engineering T-cells to go after a tumor antigen that’s expressed on a brain cancer cell and then deploying them to go and attack the antigen. These are therapies that are not like your traditional chemotherapies, but rather, new therapies that are more specific but also may be more organic because they’re based on your own immune system.

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When I spoke to many other people who made important discoveries or seminal discoveries, what you find is that most of them are serendipitous. So, almost everything that turns into a discovery is something that people have observed before. They’ve just never made the connection of what the observation could imply. So, for me, I wasn’t the first person to visualize these floating spheres of cells in a dish when we placed brain tumor cells into culture without serum. I’m sure I wasn’t the first person to observe that there were lovely cells growing in these spheres. However, I think we may have been the first people to realize what those spheres implied because the sphere is just a floating colony of all the cells that are present in a stem cell hierarchy. So, basically a sphere arises from a single stem cell that divides and then gives rise to all this divergent progeny, all of which clump together and float around in this sphere. As a result, I think we realized, when we saw that, that this meant there were stem cells in brain cancer. So, not that it was a novel observation, but simply that we interpreted it in such a way that led us to that discovery.

But, last year at the most recent Society for Neuro-Oncology meeting, the first technology that seems to be gripping everyone right now is single cell sequencing. So, everyone likes the idea of deconvoluting something down to its most basic building block and trying to understand what’s happening at a single cell level and there’s all kinds of new technologies in that regard. And then the second thing that everyone’s talking about is organoids. Organoids are like complex cellular systems. Imagine that we right now have cultures filled with spheres that are from a patient’s brain tumor, but now imagine if you could build a brain microenvironment using normal brain cells and then sort of graft the tumor into that and try to sort of recapitulate a more realistic model system of how the tumor may grow in the patient. These organoids are cultures where you can mix normal and cancer cells and try to establish a three-dimensional model of what may be happening in the patient. You can do that all in a dish, which is the appeal of it. So, I think those kinds of model systems have everyone excited right now. I don’t think they’re too close yet to what happens in patients, but they’ll get better.

introduction interview spotlight

I set up a lab at the McMaster Stem Cell and Cancer Research Institute in 2007 when I joined here as a pediatric neurosurgeon. It was really quite an amazing fit for me because they started the institute in 2006, and my PhD was involved in the characterization of the population of cancer stem cells and brain cancer. So, it was a perfectly named institute for me. My lab applies a developmental neurobiology and stem cell biology approach to the study of brain cancer. We don’t study cancer in isolation. We study cancer, knowing that it’s a dynamic process, and we’re trying to imagine what could be the conversion that happens in cancer from a normal state to an abnormal state. So, we always study cancer in comparison to normal tissues, which is a slightly different approach. Another mandate of the institute is that we focus on human model systems, which are much more challenging and difficult to develop. We study all human normal neural stem cells in comparison to human brain cancer stem cells. The reason that I think you need an institute to accomplish something like that is because modeling those systems is not only intense in terms of the experience and training required, but it’s also very expensive, so it’s a lot better if you have a group of researchers who can focus in this area and then share infrastructure together. That’s why an open concept model of the institute was also really appealing with a shared lab space. It sort of promotes team-building as well.

been really powerful. This relies on capturing tissue from patients at different time points throughout their treatment. So not just basing all your knowledge on the treatment-naive biopsy of the patient’s cancer at the beginning, but rather trying to survey the cancer through time and understand how the cells evolve and how genetic mutations evolve over time as well. So the whole field of intra-tumoral heterogeneity and apt cancer evolution has been of great interest. There’s been many tools that have been developed for things like lineage tracing where you follow cells through time, or DNA cellular barcoding where you drop a barcode library on cells at the beginning and then observe whatever manipulation you put the cells through. For example, you implant a tumor into a mouse and then you can track all the different barcodes through time and figure out which ones dropped out after therapy. You can try to figure out what cells are actually driving the tumor to recur or relapse. So, those are models and experimental systems that we’ve been using.

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A RT I S T KIEN NAGALES

INTERVIEW SPOTLIGHT

table of contents

DR. SUZANNE ARCHIE

EXPLORING PSYCHOSIS IN YOUTH CANNABIS USERS ERIC ZHANG 1 & NURI SONG 2 Bachelor of Health Sciences (Honours), Class of 2024, McMaster University 2 Bachelor of Health Sciences (Honours), Class of 2022, McMaster University

Over the past two decades, the relationship between marijuana and youth usage has been evolving. Recent research suggests that marijuana use increases risk of psychosis, a state of impaired reality involving hallucinations, delusions, and thought disorganization. To explore such issues, we sat down with Dr. Suzanne Archie, an Associate Professor in the Department of Psychiatry and Behavioural Neurosciences and Clinical Director of the Cleghorn Early Intervention in Psychosis Program at St. Joseph’s Healthcare Hamilton. She is also a psychiatrist at the Peterborough Centre for Addictions Research and a Brain and Behaviour Subunit Planner for the Undergraduate Medical Education Program at McMaster University. Her research interests include early intervention for youth marijuana use and ethnic diversity in pathways to care for first episodes of psychosis. Presently, Dr. Archie is leading a knowledge translation project using video games as a tool for youth to learn about early psychosis intervention.

WOULD YOU BE ABLE TO SHARE MORE ABOUT YOUR BACKGROUND AND WORK? I’m a psychiatrist and I have been doing early intervention in psychosis for about 25 years. Over the years, I noticed that there were a lot of patients who were using cannabis at a very young age, so I became interested in [the] link between [cannabis] use and later development of psychosis. [...] If there was a link, we could help young people understand that, especially since many of them may actually not have a serious addiction, because they haven’t been using it for very long. And if they can understand that, they can get better faster. [...] So I [focused my research on] different knowledge translation strategies for [helping youth understand] the link [between psychosis and cannabis use]. [...] I am also a member of the Peterborough Centre for Addictions Research, [as well as] the Brain and Behavior subunit planner for the Undergraduate Medical Education [Program]. Education and teaching is something that I’m very interested in.

LET’S TALK SPECIFICALLY ABOUT YOUR RESEARCH ON CANNABIS USAGE AND RISK OF PSYCHOSIS. WHAT’S THE RELATIONSHIP BETWEEN THE TWO? WHAT ARE SOME RISK FACTORS FOR DEVELOPING PSYCHOSIS AMONG CANNABIS USERS?

Secondly, there is an increased risk of cannabis use among people who have a genetic vulnerability for schizophrenia and serious mental illness. People who have a vulnerability for schizophrenia may have more cannabinoid type 1 (CB1) receptors in their brains, even before they develop psychosis or use marijuana. [...] People who have that genetic vulnerability use marijuana regularly. Not only do they have an increased risk of developing psychosis, they also have an increased risk of using more frequently. There are studies that show that as the risk for schizophrenia increases, there is an increased risk of using it regularly and more frequently. [...]

Psychosis usually involves three main symptoms. First is a disturbance in perception. [For example], a person will hear sound as though it’s coming from the outside world, but actually it’s coming from a chemical imbalance in their brain, so they may hear it just like you’re hearing my voice now. It can be very difficult for someone experiencing psychosis to actually recognize that the experience is coming from a disorder in their brain as opposed to it really happening. Other people won’t hear what they are hearing so that is one of the ways that people figure out that they’re experiencing things different[ly]. [Secondly], people will come to different kinds of conclusions [or have delusions] because of their perceiving reality differently. So, if a person is seeing shadows, or seeing people and they think that they’re following them, then they’re going to believe that [...] somebody is trying to kill them or harm them. If you understand the perception that a person with psychosis is experiencing, then their belief systems actually do make sense because their beliefs are based on what they’re experiencing. The reason why it seems so odd is because in the regular reality, other people aren’t perceiving things the way they are, but once you kind of understand how they’re perceiving things, then their reality starts to make sense, because often it’s based on a disturbance of perception. [Finally], the other component is thought disorganization and behavior disorganization. The parts of the brain are not processing information properly. The person’s having disordered perceptions, all of that contributes to thought disorganization, and that also can lead to changes in their speech and changes in their behaviors. WHAT IS CBD AND THC AND WHAT ARE THE DIFFERENCES IN THEIR EFFECTS? HOW DO THEIR CONCENTRATIONS CONTRIBUTE TO PSYCHOSIS AND ADDICTION? [...] We know that THC has a dose-dependent effect on mental health symptoms. At low levels, THC can induce relaxation and a sense of calm. At higher levels, it starts to impair concentration and memory —particularly [...] emotionally difficult [and] painful memories— and it can induce a sense of euphoria. Then, at very high [...] intoxication levels, people can develop symptoms consistent with psychosis, such as paranoia. So they become suspicious, they misinterpret reality, they can have perceptual changes [in that] they can hear or see things differently, and their thoughts can become disorganized. [The] medical term

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Thirdly, there’s also the initial age of use. As people use it younger and younger, the risks of developing substance use issues and psychosis issues increase dramatically. The age of regular use has changed over the last 30 years. In the ‘70s and ‘60s the age of regular use was university years — people would use three times a week or more when they were in their early 20s. But when my daughter was born, in the ‘90s and early ‘00s, the age of regular use dropped to high school years. So, people might have been 16 or 17 years of age when they were using three times a week or more. Now, in the last 10 years or so, the age of regular use has dropped even further to about grade 7 or grade 9. We’re talking 13 to 15 years of age. This is concerning, since the brain has a lot of developmental differences between a 14-year-old and a 21-year-old.

WHAT ARE SOME SYMPTOMS OF PSYCHOSIS? HOW CAN SOMEONE REALIZE THAT THEY HAVE GONE THROUGH A PSYCHOTIC EPISODE?

introduction interview spotlight

The relationship is actually complex and multidirectional. I should note that there are a few main risk factors for developing psychosis through cannabis use. First is the concentration of tetrahydrocannabinol (THC) in marijuana. In Canada, marijuana THC content has drastically changed over the years. In the ‘70s and ‘80s, THC, which is the active ingredient in marijuana that’s related to psychosis and addiction, was about 2% for weed. But today in Canada, given the climate that we have here, the THC content has been genetically engineered so that it’s 15% to 30% in order to get a good yield of the crop. In contrast, the cannabidiol (CBD) content, which has medicinal properties but also has antipsychotic and anti-anxiety properties, has remained low at 2%. So, the balance between THC and CBD is off compared to what it was like for centuries, when it was around 2% THC and 2% CBD. Hashish traditionally had 5% THC, and that was considered high in the ‘60s and ‘70s. But of course that’s low today. So in conclusion, THC concentration is an important risk factor, since the higher the THC content, the more likely you are to find it appealing and use it more, which contributes to psychosis risk, especially for young people.

Of course, lots of people use marijuana and have no problems with it. The vast majority of people use marijuana without a lot of risk, but there are populations that are vulnerable. Most of us are not aware of the fact that there may be serious mental illnesses, such as schizophrenia, bipolar illness, or addiction in their families [...].

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[for this is] cannabis-induced psychosis, which can occur up to a month after using marijuana. [However], people can also simply have cannabis intoxication, like other substances of abuse. [In general], if you consume too much, you can induce psychosis [via] alcohol, cocaine, and other substances of abuse as well. CBD, on the other hand, does not have any addictive properties [...]. But, CBD is being studied for being used for post-traumatic stress disorder (PTSD). So there is some evidence that it may be helpful for PTSD and, certainly, I think the US veterans have been using that. CBD has [also] been associated with a number of medicinal purposes, as well. It’s known to be effective for epilepsy, for example, in children who have severe epilepsy. It [and THC are] also helpful for chronic pain as well.

M E D U CATO R

| DECEMBER 2020

table of contents interview spotlight

YOU CREATED A GAME RELATING TO EARLY PSYCHOSIS INTERVENTION, THE BACK TO REALITY SERIES. COULD YOU EXPLAIN WHAT THE GAME IS AND WHAT THE INSPIRATION WAS BEHIND IT?

We created the Back to Reality Series to specifically focus on marijuana and psychosis because we wanted to translate knowledge of the research previously mentioned to youth. I have also done some research on pathways to care for a first episode of psychosis. In this research, we were able to show that Black youth were more likely than other ethnic groups to experience police involvement in their pathways to care for the first episode of psychosis, and were less likely to be involved with family doctors. We thought that it would be important to not just educate youth about the risks, but also educate them about how to seek care in addition to mental health and addictions services. That way, you don’t end up having police involvement in order to get the kind of addiction and mental health care that you need [...]. We felt we needed something that the target audience would be able to use. A study in 2015 showed that 32% of youth who have had an episode of psychosis play video games on a daily basis, [with] 100% of them [having] access to a laptop or computer; 92% play video games on their cell phone and 83% had [a] console. Video games were a good way of reaching youth where they were at. Also, the nice thing about video games is that they can simulate visual and auditory experiences in a format that people can perceive, which helps more effectively communicate what psychosis symptoms can be like. A lot of people don’t understand what it means to have a psychotic episode. They may think that people are imagining it, or that they’re making it up. The game is helpful because it teaches people mental health literacy, so they have a better understanding when doctors use words like “hallucinations” or “depression.” Another great thing noted was that people could see, hear, [and] read about mental health and addictions services in a format that was user-friendly and didn’t involve reading pamphlets. It’s great because you get to know what the services are like a little bit before you actually utilize them [...].

WHERE DO YOU HOPE TO TAKE YOUR RESEARCH IN THE FUTURE? [...] I have a partnership with the Free For All Foundation, which is a charitable organization that works with Black families in the Bradenton area. We’re going to be recruiting about ten to twelve high school students associated with this organization and they are going to be participating in some tutorials. We’ll be using the Back To Reality Series like a homework assignment in order to provide a springboard into discussions about marijuana and psychosis. We’re going to do before-and-after testing to see if we can learn something about educating youth, not just using the video games, but also through the experience of having this discussion in a tutorial led by other young people. [...] The other is a study for young people going through their first episode of psychosis, [where] they will be involved in individual interviews [...] to talk about what their understanding is between cannabis and psychosis. [...] We’re going to get a sense of what their beliefs are about this area. After having them play the game in another session, we’ll see whether it shapes or influences their thoughts, feelings, and beliefs about the relationship and whether they feel that they have learned anything from using the video games [...].

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