Issue 40 by The Meducator

DECEMBER 2021 | ISSUE 40

C E L E B R AT I N G

DO PROSTHETIC LIMBS REALLY HAVE TO COST AN ARM AND A LEG? E X P LO R I N G T H E D E V E LO P M E N T O F A N O P E N - S O U R C E, LO W C O S T O P E RAT I O N A L T RA N S RA D I A L PROSTHESIS P R O TOTY P E

MACHINE LEARNING AND DEPRESSION

P R E D I CT R E S P O N S E S TO D E P R E S S I O N T R E AT M E N T S W I T H N E U R O I M A G I N G D ATA

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ROBOTICS IN SPINAL SURGERY

CURRENT L I M I TAT I O N S A N D F U T U R E D I R E CT I O N S

M E D U CATO R

| DECEMBER 2021

table of contents

PHOTOGRAPHY: ANDY ZHU MAKEUP: MADELINE CHAN NAILS: SOPHIE ZARB MODEL: YIMING ZHANG

table of CONTENTS DECEMBER 2021

01 INTRODUCTION 02 MEDPULSE 04 MEDBULLETINS 06 PATHOPROFILE 08 NEUROABSTRACTS 10 MEDUSTORY 12 VIEWPOINTS

ISSUE 40

CRITICAL REVIEW 14 SPINAL SURGERY 18 MACHINE LEARNING 22 GLOBAL PERSPECTIVE INTERVIEW SPOTLIGHT 25 DR. DAVID LYSECKI 28 LETTER FROM STACEY 29 CONTRIBUTORS

dear reader,

INTRODUCTION ISSUE 40

Welcome to Issue 40 of The Meducator! Entering the 20th year of The Meducator, we are thrilled by all the incredible feats this journal has achieved. Starting small as a black and white publication containing a few article types and printed annually, to now bi-annually showcasing the incredible talents of our editors, graphic designers, and videographers, we have grown as a publication. This year, we have launched a new video initiative, MeduCares, and a new podcast, MeduCurrent, dedicated to featuring healthcare experts and student researchers, respectively, within the McMaster community. This new era of our publication is conveyed in Madeline Chan and Andy Zhu’s inventive photo cover art collaboration featuring our Managing Editor, Yiming Zhang, as a model. The bold colours and use of new creative media help demonstrate how innovation and pushing boundaries make scientific research so inspiring in this day and age. Editors Matthew Ahn and Hannah Silverman start Issue 40 off by exploring novel health-related developments across the globe in MedPulse, highlighting the vast body of research that has persisted through the limitations of the COVID-19 pandemic. Anya Kylas and Rida Tauqir then dive deep into the pathogenesis of tuberculous meningitis, the most lethal form of one of the world’s most devastating infectious diseases. Next, editors Gurleen Bhogal and Aaron Wen highlight the MeduStory of Dr. Sarah Gilbert, a vaccine researcher who developed the Oxford COVID-19 vaccine. Further, in Viewpoints, Allison Fang and Aisling Zeng debate the issue of financial compensation for living organ donors.

introduction

In Issue 40, The Meducator continues its collaboration with the annual NeuroXChange Conference. This issue’s Neuroabstracts examine depressive symptoms and inflammatory markers post-acute myocardial infarction, the connection between social withdrawal, substance use, and mental illness during the pandemic, and, finally, the structure of resilience and adverse childhood experiences in borderline personality disorder. We are also excited to feature two Critical Reviews and one Global Perspective. In a critical review on the use of robotics in spinal surgery, Justin Phung highlights the current role, benefits, and risks of using robotics in the provision of healthcare. Meanwhile, Yifan Wang examines the novel use of neuroimaging data and machine learning in the prediction of responses to depression treatments. Transitioning to a more global perspective, Abdul Nafea Zuberi and colleagues highlight the need for the development of more cost-effective and accessible transradial prosthesis prototypes. We round off this issue with an Interview Spotlight featuring Dr. David Lysecki, a palliative care specialist, and a special note from Dr. Stacey Ritz, the McMaster Bachelor of Health Sciences program’s Assistant Dean, in honour of our 20th anniversary of The Meducator this year.

All the best,

SOPHIE ZARB

Bachelor of Health Sciences (Honours) Class of 2022

| DECEMBER 2021

From the both of us, thank you, and we cannot wait to see what the next twenty years of The Meducator will bring.

M E D U CATO R

Issue 40 is the product of close collaboration between all members of our talented and passionate staff. We cannot express enough gratitude towards our hardworking team, the supportive McMaster community, and you, our engaged readers. We would also like to give special thanks to our executive team, Aisling, Andy, Carolyn, Catherine, Daniel, David, Eric, Jeffrey, Karishma, Madeline, Shanzey, and Yiming, for their incredible student leadership.

MICHAL MOSHKOVICH

Bachelor of Health Sciences (Honours) Class of 2023

MEDPULSE Bunchberry (Canada)

AUTHORS: MATTHEW AHN & HANNAH SILVERMAN ARTISTS: ASHLEY LOW & KAYLA ZHANG Tulip (Afghanistan)

Native BioData Consortium CANADA/NORTH AMERICA | October 2021 In reflecting on reconciliation with the history of Indigenous Peoples in Canada, genomic justice to empower and reclaim genetic data decisions within Indigenous communities is an emerging priority according to Dr. Nadine Caron. Dr. Caron is the co-director of the Centre for Excellence in Indigenous Health at UBC, leader of the Silent Genomes Project, and the first female Indigenous surgeon.1 The creation of the Native BioData Consortium, Silent Genomes Project, and associated projects empowers Indigenous genetic research serving Indigenous genetic research priorities.2 Over the next few years, the digital genome market is expected to grow significantly, opening opportunities to increase Indigenous data ownership and reclamation. As a result, the consortium seeks to not only reclaim Indigenous biological samples, but also the economic opportunity invested in genetic data banks.

Picky Eating In College Students USA | October 2021 Picky eating (PE), or selectively eating a narrow range of foods, is a common phenomenon among children but can also persist into adulthood.3,4 A recent study surveyed American undergraduate students to determine the effects of PE in college students. About 65% of the picky eaters identified in the survey reported eating fewer than 10 foods.4 Picky eaters further reported less fibre and vegetable intake than non-picky eaters, higher levels of social phobia and situational distre ss, and lower quality of life.4 As many young adults start making their own food decisions in college, understanding the behaviours associated with PE in college can help inform intervention strategies at a pivotal time. Can Air Pollution Affect Test Performance? BRAZIL | October 2021 Most of the effects of air pollution on human health are associated with exposure to particulate matter (PM): extremely small airborne particles containing chemicals, metals, dust, and soil.5 While the effects of PM on the respiratory and cardiovascular systems are well-known, its impacts on cognitive performance are less characterized.6 A new study from Brazil examined correlations between PM levels and university entrance exams, and reported that an increase of 10 μg/m3 in PM on the day of the examination decreased students’ scores by 6.1 points.6 The data also suggests that PM levels adversely affected male students and students from poorer households to a greater degree.6 While decreased cognitive performance would not lead to hospitalization, it can reduce productivity at work. This effect creates a cycle of disadvantage as it hits the poorest people of poor countries the hardest —those who need development prospects the most.6

Ipê-amarelo (Brazil)

Rose (USA)

Orchid (Sub-Saharan A First Malaria Vaccine Endorsed by WHO SUB-SAHARAN AFRICA | October 2021 Around half of the world’s population is at risk for malaria, an illness caused by Plasmodium parasites transmitted from infected mosquitos to humans.7 In 2019, 94% of the approximately 229 million malaria cases and 400,000 deaths occurred in Africa.7 On October 6, 2021, the World Health Organization (WHO) made history by recommending the first malaria vaccine.8 RTS,S/AS01, or Mosquirix, was created in 1987 and targets the circumsporozoite protein on the surface of Plasmodium.9 The recommendation came after a pilot program in Ghana, Kenya, and Malawi showed Mosquirix to be safe, feasible, and cost-effective.8 However, among children aged 5-17 months, the vaccine efficacy is 36% after four doses, falling short of current targets of 75% protection.10,11 Nonetheless, Mosquirix has the potential to save tens of thousands of lives in Africa, and offers a “glimmer of hope for the continent” in the fight against malaria.8 References can be found on our website at Meducator.org

Rapid Heart Attack Sensor FRANCE | September 2021

Mental Health Endemic in Afghanistan AFGHANISTAN | October 2021 Amidst the violence and sociopolitical changes in Afghanistan over the past few months, the mental health crisis haunts the nation as a silent, unending disease. Following years of conflict, upheaval and trauma, nearly 1 in 2 Afghans suffer from psychological distress, yet only 3% of individuals seeking health services are appropriately offered mental health support.12 This dramatic inequity arises from the lack of funding to support mental health services and professionals, as well as a social taboo stigmatizing treatments for youth and women.13 As this crisis continues to slowly fracture the bruised Afghan healthcare system, decisive and immediate responses from the international community should work pragmatically to intervene in the delivery of mental health services before arriving at yet another endemic.

Researchers from the University of Notre Dame and University of Florida have developed a new platform for the rapid detection of acute myocardial infarctions (AMI), commonly known as heart attacks.14 The sensor uses a multiplexed ion-exchange membrane platform to detect microRNAs (miRNAs) as biomarkers of AMI.15 miRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression.15 Since miRNA has a high turnover rate, it can be detected earlier and with lower error than the proteinbased gold standards.15 The platform does not require any sample preparation; measurements can be made within minutes of sampling and readout occurs in under half an hour.15 This innovation thus provides a low-cost, portable tool that can speed up diagnosis of one of the leading causes of death worldwide.16 Fleur-de-lis (France) Zoonotic Canine and Feline Vectors for Tropical Diseases SOUTHEAST ASIA | 2021

Rumdul (Southeast Asia)

Africa)

Anti-Seizure Cannabinoids AUSTRALIA | October 2021

Emerging during the COVID-19 pandemic, research on zoonotic viruses remains a critical focus, especially in regions of Southeast Asia (SEA) where limited financial and laboratory resources hinder research efforts. In particular, infectious parasites such as Bartonella henselae, Rickettsia felis and Dirofilaria repens exemplify canine and feline zoonotic vector-borne diseases.17 Among neglected tropical diseases in SEA, conditions such as lymphatic filariasis (elephantiasis) endemically affects nearly 15 million people due to infection from pathogens such as Wuchereria bancrofti. With up to 60% prevalence in felines, B. henselae is reported to cause cat scratch disease and endocarditis in humans, whereas R. felis has been attributed to nonspecific febrile illnesses across SEA. In contrast, D. repens is mosquito-borne and results in heartworm and subcutaneous complications.18 Due to the lack of resources in SEA, many details about the zoonotic nature of these infectious parasites and their alternative vectors remain unknown. For instance, not much is known about the specific mosquito species and the mechanisms of zoonotic transmission that are responsible for D. repens infection. As a result, greater communication and collaboration between regional, medical, and veterinary groups is required to strengthen knowledge and prevention of further zoonotic transmissions or potential disease epidemics.

Phytocannabinoids, such as Δ9-tetrahydrocannabinol and cannabinol (CBD), have been used extensively in clinical treatments against epilepsy. Specifically, CBD has demonstrated efficacy for treating Dravet syndrome —a rare, drugresistant form of epilepsy developed in infancy.19 A recent study from the University of Sydney highlighted three novel cannabinoid molecules that displayed efficacy in treating hyperthermia-induced and electric-shock induced seizures. These three molecules are Cannabigerolic Acid (CBGA), Cannabidivarinic Acid (CBDVA) and Cannabigerovarinic Acid (CBGVA).20 Notably, since the heating process often decarboxylates the acidic compounds into neutral compounds, all three phytocannabinoids are found only in raw cannabis and not in commercial products. In particular, CBGA demonstrates the most potent anticonvulsant effect through potentiating clobazam during hyperthermia-induced and spontaneous seizures, in addition to MES threshold tests. Nevertheless, CBGA as a monotherapy has proconvulsant effects on spontaneous seizures and receptor destabilization to GABAa receptors, which demonstrates the divergent nature of these phytocannabinoids.

Golden Wattle (Australia)

MEDBULLETIN

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| DECEMBER 2021

medbulletin section title

THE HUMAN CODE PROLONGING LIFE GENE REPAIR ANALYZING ANCIENT DNA USING NOVEL NUTRITIONAL COMPOUNDS TO INCREASE LONGEVITY

TECHNIQUES

ME E R A C HO P R A

MEER A CH O PR A

Biological aging is the result of a complex interplay between multiple factors, one of which is mitochondrial dysfunction. The current hypothesis is that as we age, mutations in mitochondrial DNA accumulate, resulting in the overproduction of reactive oxygen species (ROS). 1 These reactive molecules oxidize mitochondrial DNA, proteins, and lipids, resulting in impaired mitochondrial function, which further perpetuates this cycle of damage.²

Sequencing DNA of ancient Homo sapiens gives important archaeological and anthropological insight into human evolution. Researchers sequenced the first ancient genome in 2010, discovered from a 4000-year old hair sample of an early settler of Greenland.¹ Based on the genetic difference between this ancient individual and current groups, phylogenetic trees and dispersal routes can be created, allowing for a more comprehensive understanding of the ancestr y of modern populations.²

To prevent the overproduction of ROS, cells can degrade dysfunctional mitochondria in a process known as mitophag y. Although this mechanism is not completely known, it is thought to function similarly to macroautophag y, in which cellular products are degraded after being engulfed in a phagosome and fused with a lysosome.³ In mice, rates of neurological mitophag y decrease by 70% from 3 to 21 months of life, meaning that aging is related to the decreased capacity to break down dysfunctional mitochondria.⁴ Researchers have accordingly generated a new hypothesis about aging —rather than being the result of mitochondrial dysfunction due to increased ROS production, aging may be caused by a decreased capacity to degrade dysfunctional mitochondria.⁴ Upon further research into nutritional anti-aging compounds, a molecule found in walnuts, Urolithin A (UA), has been shown to increase mitophag y capacity.⁵ In a study on Caenorhabditis elegans , administration of UA increased gene expression of sequences coding for proteins involved in mitophag y, resulting in a 45% increased lifespan compared to control.⁶ UA was also found to upregulate gene expression for sequences related to mitophag y or mitochondrial biogenesis in human skeletal muscle, demonstrating an ability to improve cellular health.⁷ Although more research must be done to further elucidate the long-term impact of UA on human longevity, this molecule shows incredible promise as a tool to delay the effects of aging.

1. 2. 3. 4. 5. 6.

Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016;61(5):654-66. Available from: doi:10.1016/j. molcel.2016.01.028. Stefanatos R, Sanz A. The role of mitochondrial ROS in the aging brain. FEBS Lett. 2018;592(5):743-58. Available from: doi:10.1002/1873-3468.12902. Chen G, Kroemer G, Kepp O. Mitophagy: An emerging role in aging and age-associated diseases. Front Cell Dev Biol. 2020;8:200. Available from: doi:10.3389/fcell.2020.00200. Sun N, Yun J, Liu J, Malide D, Liu C, Rovira II, et al. Measuring in vivo mitophagy. Mol Cell. 2015;60(4):685-96. Available from: doi:10.1016/j.molcel.2015.10.009. D’Amico D, Andreux PA, Valdés P, Singh A, Rinsch C, Auwerx J. Impact of the natural compound Urolithin A on health, disease, and aging. Trends Mol Med. 2021. Available from: doi:10.1016/j.molmed.2021.04.009. Ryu D, Mouchiroud L, Andreux PA, Katsyuba E, Moullan N, Nicolet-dit-Félix AA, et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat Med. 2016;22(8):879-88. Available from: doi:10.1038/ nm.4132. Andreux PA, Blanco-Bose W, Ryu D, Burdet F, Ibberson M, Aebischer P, et al. The mitophagy activator urolithin A is safe and induces a molecular signature of improved mitochondrial and cellular health in humans. Nat Metab. 2019;1(6):595-603. Available from: doi:10.1038/s42255-019-0073-4.

Challenges associated with sequencing the genome of ancient humans have prevented rapid developments in the field of ancient DNA (aDNA) analysis. Since fossils are left in the environment for many years prior to being collected, they may experience degradation, chemical contamination, or colonization by microorganisms.² These conditions result in low percentages of endogenous DNA in fossil samples, creating difficulties for geneticists tr ying to identify sequences belonging to ancient populations. As a result, a recent study by Suchan et al. sought to determine if hybridization capture using Restriction Associated DNA (hyRAD) probes could be used to capture gene sequences of interest when samples are contaminated.³ This procedure involves using restriction enzymes to cleave DNA samples of the target species, then using the digested fragments as probes in aDNA samples.³ To determine the effectiveness of hyRAD, analysis was performed on bone and tooth samples from the 10,000 BC to the 400 CE. For samples with low (0.34%) target DNA content, the hyRAD method was able to increase enrichment of the target sequence by a factor of 146. However, for samples with larger (>30%) target DNA content, hyRAD only slightly increased enrichment.³ hyRAD’s effectiveness in low-content samples suggests that this technique may be used to identify DNA sequences in samples that were previously unable to be analyzed. This advancement in genetic technolog y may pave the way to a better understanding of human ancestr y.

1. 2. 3.

Rasmussen M, Li Y, Lindgreen S, Pedersen JS, Albrechtsen A, Moltke I, et al. Ancient human genome sequence of an extinct Palaeo-Eskimo. Nature. 2010;463(7282):757-62. Available from: doi:10.1038/nature08835. Slatkin M, Racimo F. Ancient DNA and human history. Proc Natl Acad Sci USA. 2016;113(23):6380-7. Available from: doi:10.1073/pnas.1524306113. Suchan T, Kusliy MA, Khan N, Chauvey L, Tonasso-Calvière L, Schiavinato S, et al. Performance and automation of ancient DNA capture with RNA hyRAD probes. Mol Ecol Resour. 2021. Available from: doi:10.1111/1755-0998.13518.

MYOCARDITIS

HUMAN TOUCH

INTRICATE MOLECULAR PATHWAYS UNDERLIE SIMPLE HUMAN SENSES

S URA J BA N SAL

SUR AJ BANSAL

Myocarditis is characterized as a heterogeneous inflammator y disease with diverse etiologies and therapeutic responses.¹ Although normally caused by viral infections, recent cases of inflammator y responses to vaccine exposure have temporally associated hypersensitivity myocarditis with the mRNA COVID-19 vaccination.² Increased attention to myocarditis as a potential adverse complication of immunization is warranted.

The Nobel Prize in physiology or medicine was recently awarded to Drs. David Julius and Ardem Patapoutian for their parallel investigations into skin receptors for temperature and touch. Julius’ extensive classification of TRP proteins and Patapoutian’s identification of pressure-sensitive proteins provide complementar y insight into understanding mechanobiolog y.¹

An investigation by Fox et al. uncovered a greater diffuse distribution of CD68+ cells in the hearts of COVID-19 patients compared to matched control or other myocarditis patients. Their findings indicate that COVID-19-infected hearts contain diffusely infiltrative cells of monocyte or macrophage lineage instead of lymphocytes.³ A concurrent study by Bozkurt et al. suggests that interstitial cells, pericytes, and macrophages in the myocardium contain SARS-CoV-2 RNA by in situ hybridization. This may contribute to capillary endothelial cell or microvascular dysfunction and individual cell necrosis. Thus, macrophages, which mediate both local and systemic responses to viral infections, may activate apoptotic attack complexes to kill nearby myocytes.² Collectively, these studies suggest that COVID-19 incites a derivative of myocarditis that is unlike typical lymphocytic myocarditis.

2. 3. 4. 5.

Mayo Clinic. Myocarditis [Internet]. 2021. Available from: https://www.mayoclinic.org/diseases-conditions/myocarditis/ symptoms-causes/syc-20352539 [cited 2021 Sep 18]. Canadian Paediatric Society. Clinical guidance for youth with myocarditis and pericarditis following mRNA COVID-19 vaccination: Canadian Paediatric Society [Internet]. 2021. Available from: https://www.cps.ca/en/documents/position/clinicalguidance-for-youth-with-myocarditis-and-pericarditis [cited 2021 Sep 18]. Fox SE, Falgout L, Heide RSV. Covid-19 myocarditis: Quantitative analysis of the inflammatory infiltrate and a proposed mechanism. Cardiovasc Pathol. 2021;54:107361. Available from: doi:10.1016/j.carpath.2021.107361. Bozkurt B, Kamat I, Hotez PJ. Myocarditis with Covid-19 mRNA vaccines. Circulation. 2021;144(6):471-84. Available from: doi:10.1161/CIRCULATIONAHA.121.056135. Montgomery J, Ryan M, Engler R. Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. JAMA Cardiol. 2021;6(10):1202-6. Available from: doi:10.1001/jamacardio.2021.2833.

These discoveries uncovered important physiological understandings for converting external stimuli into nerve signals at the molecular level. Taken together, these findings are promising for informing treatment development for neuropathic pain and associated conditions. 1. 2. 3. 4. 5. 6. 7.

Cooney E, Molteni M. Scientists win Nobel in medicine for how we sense temperature and touch [Internet]. 2021. Available from: https://www.statnews.com/2021/10/04/nobel-prize-medicine-2021-temperature-touch-receptors [cited 2021 Oct 26]. Le Page M. Medicine Nobel awarded for explaining how we sense heat and touch [Internet]. 2021. Available from: https:// www.newscientist.com/article/2292196-medicine-nobel-awarded-for-explaining-how-we-sense-heat-and-touch [cited 2021 Oct 26]. Durrani J. Science behind sense of touch and temperature wins medicine Nobel prize [Internet]. 2021. Available from: https:// www.chemistryworld.com/news/science-behind-sense-of-touch-and-temperature-wins-medicine-nobel-prize/4014503. article [cited 2021 Oct 26]. Jara-Oseguera A, Simon SA, Rosenbaum T. TRPV1: On the road to pain relief. Curr Mol Pharmacol. 2021;1(3):255-69. Available from: doi:10.2174/1874467210801030255. Lewis T. 2021 medicine Nobel prize winner explains the importance of sensing touch [Internet]. 2021. Available from: https:// www.scientificamerican.com/article/2021-medicine-nobel-prize-winner-explains-the-importance-of-sensing-touch [cited 2021 Oct 26]. Resnick B. Our amazing sense of touch, explained by a Nobel laureate [Internet]. 2021. Available from: https://www.vox.com/ science-and-health/22710533/nobel-prize-2021-ardem-patapoutian-touch [cited 2021 Oct 26]. Oldach L. Nobel prize in physiology or medicine recognizes discoveries of ion channels [Internet]. 2021. Available from: https:// www.asbmb.org/asbmb-today/people/100421/2021-nobel-in-medicine [cited 2021 Oct 26].

DECEMBER 2021

To identify touch receptors, Patapoutian and his colleagues used pressure-sensitive cells responsible for producing an electrical signal when prodded with a micropipette. Using this information, they identified 270 genes that could encode for touch receptor proteins. By systematically deactivating individual genes, they uncovered PIEZO1, a force-activated cation channel triggered by mechanical pressure and proprio ception.⁵ This led to the discover y of another mechanosensitive ion channel, PIEZO2, which is present in sensor y neurons and responsible for detecting physiological processes like blood pressure, bladder control, and breathing.⁶

These findings cumulatively highlight the potential for rare adverse events, including cardiac injur y, following COVID-19 vaccination.⁵ However, concerns regarding rare adverse complications following immunization should not diminish overall confidence in mRNA COVID-19 vaccines.

Independently, Julius and Patapoutian identified a similar ion receptor termed TRPM8, which opens in response to cold temperatures. Their investigations exploited the activity of these receptors in response to menthol, which triggers their opening. This discovery subsequently sparked a series of investigations into similar ion channels that allow for multiple different temperatures to be sensed.⁴

M E D U CATO R

Furthermore, a case series by Montgomer y et al. recently identified 23 men (aged 20 to 51 years) diagnosed with myocarditis after vaccination.¹ These previously healthy patients presented with acute onset of marked chest pains and elevated cardiac troponin levels within four days of receiving an mRNA COVID-19 vaccine. Among eight patients who under went cardiac magnetic resonance imaging (MRI), findings were consistent with the clinical diagnosis of myocarditis. Additional testing did not identify other etiologies for myocarditis, such as acute COVID-19, ischemic injur y, or underlying autoimmune conditions. Cardiac symptoms resolved within seven days for 16 people.⁵

Julius et al. uncovered the TRPV1 receptor for capsaicin, an active component of chillies which elicits a burning sensation by stimulating the false presence of heat.¹ The TRPV1 receptor is a temperature-sensitive ion channel receptor in cell membranes that opens in response to high temperatures.² These receptors are abundant in pain pathways, making them important targets in the development of analgesics without the drawbacks of traditional opioid treatments.³

medbulletin

CONCERNS OF MYOCARDITIS FOLLOWING MRNA COVID-19 VACCINATION

doi: 10.35493/medu.40.6

Tuberculous Meningitis ANYA KYLAS & RIDA TAUQIR Pathoprofile AUTHORS: ARTISTS: ANDY ZHU & CARYN QIAN 1.

M E D U CATO R

| DECEMBER 2021

pathoprofile table of contents

Galimi R. Extrapulmonary tuberculosis: Tuberculous meningitis new developments. Eur Rev Med Pharmacol Sci. 2011;15(4):36586. Available from: https://pubmed. ncbi.nlm.nih.gov/21608431 [cited 2021 Nov 7]. Méchaï F, Bouchaud O. Tuberculous meningitis: Challenges in diagnosis and management. Rev Neurol (Paris). 2019;175(7-8):451-57. Available from: doi:10.1016/j. neurol.2019.07.007. World Health Organization. Tuberculosis (TB) [Internet]. Available from: https://www.who. int/news-room/fact-sheets/detail/ tuberculosis [cited 2021 Nov 7]. Davis AG, Rohlwink UK, Proust A, Figaji AA, Wilkinson RJ. The pathogenesis of tuberculous meningitis. J Leukoc Biol. 2019;105(2):267-80. Available from: doi:10.1002/JLB.MR0318102R. Lewinsohn DA, Lewinsohn DM. Immunologic susceptibility of young children to Mycobacterium tuberculosis. Pediatric Res. 2008;115(63):1. Available from: doi:10.1203/ PDR.0b013e3181652085. Engelborghs S, Niemantsverdriet E, Struyfs H, Blennow K, Brouns R, Comabella M, et al. Consensus guidelines for lumbar puncture in patients with neurological diseases. Alzheimers Dement. 2017;8(1):3. Available from: doi:10.1016/j. dadm.2017.04.007. Ramachandran TS. Tuberculous meningitis [Internet]. 2017 Dec 7. Available from: https://emedicine. medscape.com/article/1166190 [cited 2021 Nov 7]. Isabel BE, Rogelio HP. Pathogenesis and immune response in tuberculous meningitis. Malays J Med Sci. 2014;21(1):4-10. Available from: htt p s : //pubme d.n cbi.nlm.ni h. gov/24639606 [cited 2021 Nov 7].

INTRODUCTION With a death rate of 20-50%, tuberculous meningitis (TBM) is the most lethal form of one of the world’s most devastating infectious diseases.1-3 Mycobacterium tuberculosis (M.tb), the pathogen responsible for infiltrating cells, does so via parasitizing macrophages.1 In TBM, M.tb travels from the lungs through the lymphatic system and infects the meninges of the central nervous system (CNS).1,2 Through activation of the microglia, the predominantly affected cells in TBM, a pro-inflammatory response is initiated, beginning a cascade of pathological events that result in host damage and poor patient outcomes.⁴ RISK FACTORS Infection with human immunodeficiency virus (HIV) is the most observed comorbidity for patients with TBM, with the severity of disease increasing if HIV is left untreated.2 In fact, HIV positive patients are five times more likely to develop tuberculosis (TB) of the CNS and, overall, extrapulmonary-TB has become significantly more prevalent since the beginning of the HIV/autoimmune deficiency syndrome (AIDS) epidemic.2 Additional predisposing conditions, including diabetes mellitus and silicosis, have also been observed to negatively impact the patient's ability to combat M.tb.2 Moreoever, the use of immunosuppressive drugs, such as corticosteroids, can lead to higher susceptibility of M.tb infections within patient cells, resulting in TBM.1 Children are also more susceptible than adults to all forms of TB and meningitis, and are more likely to develop a severe form of TB.1,2,5 It is suspected that children are more susceptible to TB due to several factors such as their impaired macrophage and dendritic cell function, stemming

from their lack of immunologic maturity.11 Diagnosis in children is also more complex due to the lack of acid-fast bacillus in sputum, which is often observed in adult patients.11 This causes additional concern as prompt treatment is necessary in effectively combating infection.1,3,5 DIAGNOSIS TBM is a rare infectious disease that clinicians have trouble diagnosing due to its unfamiliar nature.1 Magnetic resonance imaging (MRI) is typically the first diagnostic tool used for patients presenting with TBM symptoms, including hydrocephalus, infarction, and basal enhancement.1,2 In brief, any abnormal shift or growth in the CNS is indicative of infection.1,2 Unfortunately, imaging is not always accurate as symptoms may not present in early stages of infection. Furthermore, it is crucial that increased intracranial pressure is identified before conducting the next step in diagnosis, the lumbar puncture, in order to avoid causing herniation of the cerebellar tonsils.1,2,6 There are several characteristics in the cerebrospinal fluid (CSF) that indicate the presence of M.tb, including low glucose, high protein, and high lymphocyte counts.1 The determining factor, however, is the presence of acid-fast bacilli in the CSF, which confirms the diagnosis of TBM.2 As aforementioned, TBM is the most lethal form of TB, with a mortality rate of 40% and 80% in patients presenting with symptoms 2 weeks and 4 weeks post-infection, respectively.1,2,4 Consequently, current diagnostic techniques are imperfect as they lack the sensitivity required for early diagnosis, which is vital for improving chances of survival.1,2,4 MECHANISM PART 1: HEMATOGENOUS SPREAD Initial TB infection is contracted by the inhalation of airborne droplets of M.tb.7 The bacteria crosses the lung epithelium and infects the alveolar macrophages, which secrete various antimicrobial peptides and cytokines.⁵ The body’s natural immune response can fester into active primary TB, allowing M.tb to invade and replicate within the lymphatic endothelial cells (LECs) of the regional lymph nodes.4 Upon entry into LECs, macrophages phagocytose M.tb and carry it across the blood brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) of the CNS.4 Exogenous M.tb are also able to

traverse the BBB and BCSFB by invading the cerebral vascular endothelial cells with the aid of various virulence factors.⁴ Once M.tb reaches the meninges or brain parenchyma, limited local innate immunity promotes its replication.This leads to development of subpial or subependymal metastatic caseous lesions, called Rich Foci.4,5 Rupturing of Rich Foci into the subarachnoid space infects the meninges and initiates the meningeal inflammatory response characteristic of TBM.4,5

CHECK OUT OUR COMPANION VIDEO!

Macrophages

Lymphocytes

Rupturing of the Rich Foci into the subarachnoid space

10.

REVIEWED BY: DR. CHERYL MAIN 11.

| DECEMBER 2021

Dr. Cheryl Main is an Associate Professor in the Department of Pathology and Molecular Medicine at McMaster University. As the Chair of the Specialty Committee for Infectious Diseases with the Royal College of Physicians and Surgeons of Canada, her research focuses on quality assurance, laboratory safety, and educational research in infectious disease. She has published several papers on the management of invasive infectious diseases.

Marx GE, Chan ED. Tuberculous meningitis: Diagnosis and treatment overview. Tuberc Res Treat. 2011;2011:798764. Available from: doi:10.1155/2011/798764. Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. 2016;4(4):CD002244. Available from: doi:10.1002/14651858. CD002244.pub4. Thwaites GE, Bang ND, Dung NH, Quy HT, Oanh DT, Thoa NT, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351(17):1741–51. Available from: doi:10.1056/ NEJMoa04053.

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TREATMENT Following presentation of clinical symptoms, rapid treatment is vital to reduce poor patient outcomes.7 Standard treatment of TBM includes two months of daily antimicrobial therapy, also known as RIPE therapy.7 It consists of rifampin (RIF), isoniazid (INH), pyrazinamide, and either ethambutol or streptomycin, all of which are bactericidal and are capable of entering the CSF upon meningeal inflammation.5,7 Daily treatment with INH and RIF is followed for an additional seven to ten months if M.tb is susceptible to these agents.7 Adjunctive corticosteroid therapy is also recommended as it may help reduce brain

GLOBAL IMPLICATIONS AND FUTURE STEPS As the seventh leading cause of disability and mortality worldwide, both pulmonary and extrapulmonary TB pose a massive threat to global health.5 While diagnostic techniques and treatment efficacy can still be improved, poverty remains the greatest contributor to TB.5 The severe lack of public health infrastructure and the co-epidemic of HIV/AIDS continue to propagate the incidence of TB.5 Thus, it is imperative that a holistic approach addressing these global disparities is considered for the foreseeable future to combat TBM cases.

M.tb

pathoprofile

PART 2: INFLAMMATORY RESPONSE Microglia are the primary CNS cells infected by M.tb.⁴ Upon activation, microglia secrete a multitude of proinflammatory cytokines, including TNF-α, IFN-γ, IL-6, IL-1, IL-1β, CCL2, CCL5, CXCL-10, IL-1α, and IL-12p40.4,8 In particular, TNF-α plays a central role in the pathophysiology of TBM by inducing fever and releasing additional cytokines.⁴ The permeability of the BBB is also disrupted by TNF-α, IL-6, and vascular endothelial growth factor, allowing for an additional influx of inflammatory mediators into the CNS.4,6 The ultimate result is the formation of a thick and gelatinous inflammatory exudate in the basal cistern, subarachnoid space, and potentially, the spinal canal.4,5 As a result, this exudate encases the major cerebral vessels, blocks CSF circulation, and compresses cranial nerves III, VI, and VII, rendering them dysfunctional.4,5 Downstream complications of TBM include tissue damage, hydrocephalus, vasculitis, cranial nerve palsies, ischaemia, and death.4,5,9

tissue damage and cerebral or spinal cord edema, as well as mitigate inflammatory responses within the subarachnoid space and small blood vessels.7,10 This is especially important since TBM morbidity and mortality is largely attributed to the host’s inflammatory response.5,7 For mild cases of TBM in adults, Thwaites et al. suggests 0.3 mg/kg/day of dexamethasone for 1 week, 0.2 mg/kg/day for the following week, and then four weeks of gradual tapering.7,11 A recommended regime for children is 12 mg/day (8 mg/day for children weighing ≤25 kg) of dexamethasone for three weeks, followed by three weeks of gradual tapering.7 In terms of prevention, the Bacillus Calmette-Guerin vaccine, administered neonatally, is effective in preventing TBM and is estimated to avert approximately 30,000 potential cases in children every year.2

EDITED BY: NICK TELLER & TAAHA HASSAN

NEUROABSTRACTS The Relation of Social Withdrawal Subtypes with Substance Use and Mental Health Difficulties in the Context of Social Engagement Over the COVID-19 Pandemic REIHANEH JAMALIFAR1

Department of Psyschiatry and Behavioural Neuroscience, McMaster University

table of contents neuroabstracts

Individual differences in social withdrawal may lead to differences in susceptibility to socioemotional ramifications related to the COVID-19 pandemic (e.g., substance use and mental health difficulties). Social withdrawal can be categorized into three subtypes: conflicted shyness (high shyness and high sociability), avoidant shyness (high shyness and low sociability), and unsociability (low shyness and low sociability). According to the literature, individuals with conflicted shyness are at particularly elevated risk for developing substance use difficulties. The primary purpose of this study was to examine whether changes in levels of social engagement during the pandemic moderated the relation between conflicted shyness and changes in substance use. The findings will help evaluate speculations as to why conflicted shyness is related to high substance use. The secondary purpose of this study was to examine patterns of change in substance use and mental health difficulties (i.e., symptoms of depression and anxiety) over the pandemic in relation to individual differences in social withdrawal.

Contrary to our prediction, no significant correlation was found between conflicted shyness and changes in substance use over the pandemic. Moreover, our regression model revealed that conflicted shyness and changes in social engagement over the pandemic did not significantly interact to predict changes in substance use. Despite the lack of a significant correlation indicated by our study, our findings extend previous research and suggest that there may be other factors underlying the relation between conflicted shyness and substance use. Moreover, unsociability was negatively correlated with changes in depressive symptoms over the pandemic. Hence, individual differences in social withdrawal may have influenced people’s vulnerability to the stressors of the pandemic. This finding also suggests that the mental health of unsociable individuals may benefit from reduced social engagement. Further investigation could lead to the development of new intervention techniques for treating unsociable individuals with depressive symptoms.

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Undergraduate students completed an online survey in which they retrospectively reported their levels of social engagement, substance use, depression, and anxiety during different stages of the pandemic. The Emerging Adult Social Preference Scale-

Revised was used to index social withdrawal subtypes.

EDITORS: ALEXANDER XIANG & SEPEHR BAHARESTAN ARTIST: MANREET DHALIWAL

The Structure of Resilience and Adverse Childhood Experiences in Borderline Personality Disorder TALIA TISSERA1, STEPHANIE PENTA2, JAMES MIRABELLI3, MINA PICHTIKOVA2, HOLLY RAYMOND2, CATHERINE MCCARRON1, KATHERINE HOLSHAUSEN1,2 St. Joseph's Healthcare Hamilton Department of Psychiatry and Behavioural Neurosciences, McMaster University 3 Department of Biochemistry, McMaster University

Resilience refers to one’s ability to adapt to stressors; it moderates the severity of the psychological ramifications of stressors. According to the authors whose works have been referenced, this relation has not been investigated in the population of individuals diagnosed with borderline personality disorder (BPD). Adverse Childhood Experiences (ACEs) are major risk factors for BPD, leading to greater symptom severity and poorer treatment outcomes.

On the other hand, the moderation analysis yielded statistically insignificant results, suggesting that resilience does not moderate the relation between ACEs and BPD. Resilience may diminish the severity of BPD symptoms, suggesting that BPD treatments should incorporate resilience-improving strategies. In lieu of developing a standard measure of resilience, future studies should attempt to replicate this finding using other scales or physiological indicators of resilience. Furthermore, this study was cross-sectional and thus cannot determine a causal link between BPD, resilience, and ACEs. Future studies should investigate the relation between BPD, resilience, and ACEs prospectively to establish a temporal relationship between these factors.

Depressive Symptoms and Inflammatory Markers Following Acute Myocardial Infarction: A Systematic Review

neuroabstracts introduction

The current study hypothesizes that higher resilience would weaken the relation between ACEs and BPD, and vice versa. 45 individuals with a primary diagnosis of BPD completed the following questionnaires after a psychoeducation session and prior to treatment: The Borderline Symptom List-23 (BSL-23), the Childhood Trauma Questionnaire —Short Form (CTQ-SF), and the Brief Resilience Scale (BRS). A linear regression analysis revealed that resilience and ACEs can predict BPD symptoms with significant accuracy. Specifically, it was determined that participants with higher degrees of resilience experienced

milder BPD symptoms, r(43) = -.35, p < .05, and participants with higher exposure to ACEs experienced more severe BPD symptoms, τb = .29, p < .01. To the author’s knowledge, this is the first quantitative study establishing a relation between BPD and resilience.

EMMA A. MENSOUR1, KIERA LIBLIK2,3, LAURA E. MANTELLA2,3, AMER M. JOHRIB2,3 Department of Biomedical and Molecular Sciences, Queen’s University Cardiovascular Imaging Network at Queen’s (CINQ) 3 Department of Medicine, Queen’s University

1st, 2000, and December 31st, 2020 in the PubMED, Cochrane, EMBASE, and Web of Science databases were assessed. A total of 30 documents were considered and found eligible for this review. The inflammatory biomarkers reviewed include tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8, IL-10, IL-17a, IL-18, IL-12p70, interferon (IFN), C-reactive protein (CRP), intracellular adhesion molecule-1 (ICAM-1), endothelin-1 (ET1), platelet factor 4 (PF4), and beta-thromboglobulin (BTG). The studies reviewed suggest sustained, low-grade inflammation is an important component of depression following AMI. TNF-α, CRP, and IL-6 showed significant promise as reliable indicators for depression following AMI. Further investigation of the inflammatory markers detected in patients with post-AMI The present review systematically identifies and critically evaluates depression will extend the pathophysiological understanding of the relevant inflammatory biomarkers of depression in the this condition and potentially lead to the identification of novel high-risk AMI population. Articles published between January therapeutic targets. REVIEWED BY DR. AADIL BHARWANI & DR. DESPINA JOANNE NIFAKIS Peer reviewer biographies can be found on our website: meducator.org

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 1

Among patients with recent acute myocardial infarction (AMI), there is an increased prevalence of depression which is associated with increased morbidity, mortality, and rehospitalization. Yet, depression is frequently underdiagnosed and undertreated in patients following AMI. The paucity of data informing the management and treatment of depression in this population emphasizes the need for further investigation into the pathophysiological relationship between depression and AMI. Depressive symptoms following AMI may arise due to a range of factors, including the activation of the immune system. However, the specific role of inflammation in the etiology of both depression and AMI remains poorly understood.

medustory

SARAH GILBERT AUTHORS: GURLEEN BHOGAL & AARON WEN ARTIST: NATALIE CHU

EARLY LIFE – THE ROOTS1 • •

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Born in April 1962 in Kettering, Northamptonshire Gilbert’s father managed a shoe business and Gilbert’s mother was a primary school teacher Exceeded in early education with great grades, passing O-level exams with six As at Kettering High School Completed a Bachelor of Science in Biological Sciences at the University of East Anglia in Norwich, England Completed a PhD in Genetics and Biochemistry at the University of Hull

ENTRANCE TO VIROLOGY – MALARIA After completing her doctorate at the University of Hull, Gilbert realized her interest lied within a range of topics, from drug design to biological mechanisms of the immune response. She wanted to explore the interplay of scientific disciplines. Although this was something she was hesitant about when mapping out her career, she initially entered virology as a vaccine specialist at the University of Oxford, diving into the genome of malaria and eventually working on malaria vaccines.2

THE DEVELOPMENT OF A UNIVERSAL FLU VACCINE

Prior to the race for the COVID-19 vaccine, Gilbert played a significant role in the development and testing of a universal flu vaccine. Although seasonal influenza vaccines became increasingly accessible throughout the 2000s, several challenges persisted. Vaccines against seasonal influenza were not entirely reliable, and the efficacy was reduced in older and more immunocompromised populations.3 The approach to the development of this universal flu vaccine was unique. Instead of stimulating the production of antigen-specific antibodies, Gilbert’s team worked on harnessing the power of T-cells, which were able to recognize and target essential viral proteins that antibodies could not identify. This created the chance of broad protection against many influenza strains. As of 2019, Gilbert’s influenza vaccine was undergoing two phase II trials through Vaccitech, a company she co-founded in Oxford.4

CONTRIBUTIONS TO THE FIGHT AGAINST COVID-19

ACHIEVEMENTS

Following the 2021 Rosalind Franklin Lecture on “Racing Against the Virus,” Sarah Gilbert was awarded the Humanists UK Rosalind Franklin Medal for her life-saving work on creating the Oxford AstraZeneca vaccine.8 Her involvement in the creation of the vaccine also won her the Royal Society for Arts, Manufactures and Commerce Albert Medal, joining an exclusive list of award winners including Marie Curie, Alexander Graham Bell, and Stephen Hawking.9 Other achievements include the Princess of Asturias Award for Technical and Scientific Research and a Gold Medal from the Royal Society of Medicine (RSM), the highest accolade that can be bestowed by the RSM.10,11 Gilbert’s contribution to medicine and society will surely yield further accolades and achievements in the foreseeable future.

A P R I L 2015

References can be found on our website: meducator.org

Some interesting news appeared in early August when Mattel, the company responsible for producing the Barbie doll, created a Barbie of Sarah Gilbert in honour of her work with the Oxford AstraZeneca vaccine. Gilbert initially remarked that she felt the gesture to be “very strange,” but hoped that it “would inspire young girls to work in science, technology, engineering, and mathematics.” This is not the first time that Mattel has produced Barbie dolls to acknowledge certain influential women. Lisa McKnight, the senior vice-president of Mattel, explained that “to shine a light on the efforts [of those confronting the pandemic], we are sharing their stories… to inspire the next generation to take after those heroes and give back.”12

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THE BARBIE DOLL – RECOGNIZING WOMEN IN STEM

introduction

As COVID-19 emerged in China, Gilbert’s team was ready and quick to act. Prior to the novel virus arising, Gilbert’s team had already contemplated the nature of a disease with global impacts. Gilbert commented, “We had recently started thinking about an appropriate response to Disease X; how could we mobilise and focus our resources to go more quickly than we had ever gone before. And then Disease X arrived.”5 Once the genome of SARS-CoV-2 was published, Gilbert and her team immediately got to work in the lab, creating the vaccine design within a couple of days and giving rise to the Oxford AstraZeneca vaccine. The creation of this vaccine started off highly theoretical, as it was primarily based on designs for “Disease X” —lacking specificity for SARS-CoV-2 antigens. Gilbert recognized how much work it took to develop the vaccine in a short time period, along with the immense pressure of COVID-19 cases rising and overwhelmed communities.6 Now, nearly a year since the Oxford AstraZeneca vaccine was released, Gilbert’s contributions remain ongoing as her team works closely with AstraZeneca to make new vaccine types against variants of SARS-CoV-2.7

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VIEW

POINTS

Should governments offer financial compensation to organ donors and their families as a strategy to increase donation rates?

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2021

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doi: 10.35493/medu.40.12

INTRODUCTION The heightened incidence of organ failure and recent technological developments of organ transplants have conjunctly led to a greater demand for donors.¹ By the end of 2020, 4129 Canadians remained on the organ transplant list, with 805 withdrawing that year due to either clinical improvement, voluntary withdrawal, deteriorating patient condition, or death.² This organ shortage has increased the cost of medical care worldwide, deprived organ recipients of a standard quality of life, and led to thousands of deaths.¹ One proposed solution to address the increasing demand for organ donors is donor compensation.³ The topic is of high ethical and financial debate, and would impact not only the lives of those on the transplant waiting list, but also the healthcare system and how society views individual rights as a whole. IN FAVOR OF FINANCIAL COMPENSATION Major obstacles for living organ donors include the financial costs associated with travel, board, recovery, and medical treatment postoperation.¹ The removal of such disincentives for organ donors is legal under the National Organ Transplant Act (NOTA), but has demonstrated variable results with regards to increasing organ supply.³ Compensation has thus been proposed as an alternate solution. Currently, NOTA prohibits the profitization of any organ transplants, calling for donations to be motivated by altruism. Donor compensation, however, would have benefits for both individuals and the healthcare system as a whole. Regulated compensation by the government would incentivize organ donors and lead to an increase in organ supply. As a result, the stress placed on the organ transplant list would diminish, thereby improving the quality of life of

AUTHORS: ALLISON FANG & AISLING ZENG ARTISTS: ASEEL ABONOWARA & RYAN TSO hundreds of thousands of patients.⁴ Additionally, a study by Meier-Kriesche et al. found that in end-stage renal failure patients, longer transplant wait times are a risk factor for decreased survival post-transplant.⁵ Increased organ supply would thus decrease the average wait time of patients on the waitlist, promoting patient survival rates. Furthermore, the implementation of organ compensation programs in other countries have modeled the success of such a solution. Iran adopted a compensated organ donor system in 1988, and by 1999, completely eliminated the renal transplant waiting list.⁶ 78% of Iranian donors were unrelated to the recipients, and as of recently, Iran has doubled annual kidney transplants from 1186 in 1999 to approximately 2600.⁶,⁷ Additionally, an organ compensation donor model would provide financial benefit to the healthcare system.³,⁸ A costbenefit analysis conducted in the United States by Held et al. found that taxpayers would save $12 billion annually, under the assumption that living and deceased donors receive $45 000 and $10 000 in compensation, respectively.⁸ In the case of renal failure specifically, the high costs of dialysis, averaging about $121 000 annually, coupled with long transplant wait times, led to an estimated lifetime cost of $735 000.⁸ In comparison, the total cost of a transplant, including recovery procedures and medication, is estimated to be $395 000— approximately half the previously calculated cost.⁸ Furthermore, the associated health consequences and costs of long wait times on transplant lists are a major contributor to transplant tourism.⁹ The implementation of a regulated

organ compensation program would help eliminate this pattern. Patients with the financial means often travel to countries with fewer regulations to undergo illegal and dangerous transplant procedures, then return to their home country for followup care.⁹ In a 2011 British Columbia study by Gill et al., all patients of ethnic minority elected to travel for unregulated transplantation after a median wait time of two years and a completed transplant evaluation.10 Since the procedure is illegal, medical records and important procedure notes are often not recorded, hindering the ability of the patient’s physician to perform follow-up care afterwards. Moreover, patients that undergo unregulated procedures are at a higher risk of infection, organ failure, and death.¹¹

As the demand for organs outpaces supply, the organ-desperate patient and the economically struggling individual both present as easy targets for those involved in illegal organ markets. This calls into question the ethical implications of a financial compensation program for organ donation. This calls into question the ethical implications of a financial compensation program and whether it would open the door for human exploitation.¹⁴ While arguments in favor of compensation programs highlight laws and policies that protect against the abuse of the system, it will be impossible to distinguish which donations were financially motivated; a truly ethical system may thus never be feasible.¹²

With the demand for donor organs remaining an ever-present issue, there is no doubt that the controversy surrounding financial compensation systems will be reignited. Limited by a complex debate of ethics and logistics, the topic is largely divided in public opinion. With many countries already operating under a compensation system, only time will tell whether more will follow suit. 1. 2.

3. 4.

5. 6. 7.

8. 9. 10.

11. 12. 13. 14. 15.

16.

17. 18. 19.

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Dr. Lainie Ross, a physician and bioethicist at the University of Chicago, says that in order to understand the argument against financial compensation for organ donation, the principle of autonomy must be examined.¹⁵ While people have the right to make their own decisions about their body from a moral standpoint, limits can be placed on autonomy to protect individuals from misguided decisions.¹⁶ Thus, someone’s choice to donate organs should be challenged if there is an element of coercion due to hardships such as economic status. Additionally, Ross states that organ donation is unique in that it involves a third party: the medical staff responsible for the transplantation. The surgeon also has the right to refuse to operate based on their moral stance if they believe the patient has elected to donate organs solely for monetary gain.¹⁵ These ethical barriers make financial compensation for organ donation a difficult program to implement.

Abouna GM. Organ shortage crisis: Problems and possible solutions. Transplant Proc. 2008;40(1):34-8. Available from: doi:10.1016/j. transproceed.2007.11.067. Canadian Institute for Health Information. e-Statistics on organ transplants, waiting lists and donors [Internet]. 2020. Available from: https://www.cihi.ca/ en/e-statistics-on-organ-transplants-waiting-lists-and-donors [cited 2021 Oct 25]. Harbell JW, Mathur AK. Financial compensation for organ donors. Curr Opin Organ Transplant. 2019;24(2):182-7. Available from: doi:10.1097/ MOT.0000000000000617. Hippen B, Ross LF, Sade RM. Saving lives is more important than abstract moral concerns: Financial incentives should be used to increase organ donation. Ann Thorac Surg. 2009;88(4):1053-61. Available from: doi:10.1016/j. athoracsur.2009.06.087. Meier-Kriesche HU, Port FK, Ojo AO, Rudich SM, Hanson JA, Cibrik DM, et al. Effect of waiting time on renal transplant outcome. Kidney Int. 2000;58(3):13117. Available from: doi:10.1046/j.1523-1755.2000.00287.x. Ghods AJ, Savaj S. Iranian model of paid and regulated living-unrelated kidney donation. Clin J Am Soc Nephrol. 2006;1(6):1136-45. Available from: doi:10.2215/CJN.00700206. Malekshahi A, Morteza-Nejad HF, Taromsari MR, Gheshlagh RG, Delpasand K. An evaluation of the current status of kidney transplant in terms of the type of receipt among Iranian patients. Ren Replace Ther. 2020;6(1):66. Available from: doi:10.1186/s41100-020-00314-8. Held PJ, McCormick F, Ojo A, Roberts JP. A cost-benefit analysis of government compensation of kidney donors. Am J Transplant. 2016;16(3):877-85. Available from: doi:10.1111/ajt.13490. Akoh JA. Key issues in transplant tourism. World J Transplant. 2012;2(1):9-18. Available from: doi:10.5500/wjt.v2.i1.9. Gill J, Diec O, Landsberg DN, Rose C, Johnston O, Keown P, et al. Opportunities to deter transplant tourism exist before referral for transplantation and during the workup and management of transplant candidates. Kidney Int. 2011;79(9):102631. Available from: doi:10.1038/ki.2010.540. Babik JM, Chin-Hong P. Transplant tourism: Understanding the risks. Curr Infect Dis Rep. 2015;17(4):473. Available from: doi:10.1007/s11908-015-0473-x. Harbell JW, Mathur AK. Financial compensation for organ donors. Curr Opin Organ Transplant. 2019;24(2):182-7. Available from: doi:10.1097/ MOT.0000000000000617. Shaikh SS, Bruce CR. An ethical appraisal of financial incentives for organ donation. Clin Liver Dis. 2016;7(5):109-11. Available from: doi:10.1002/cld.548. Adair A, Wigmore SJ. Paid organ donation: The case against. Ann R Coll Surg Engl. 2011;93(3):191-2. Available from: doi:10.1308/147870811X565061a. Hippen B, Ross LF, Sade RM. Saving lives is more important than abstract moral concerns: Financial incentives should be used to increase organ donation. Ann Thorac Surg. 2009;88:1053-61. Available from: doi:10.1016/j. athoracsur.2009.06.087. Engelbrecht SF. Can autonomy be limited - an ethical and legal perspective in a South African context? J Forensic Odontostomatol. 2014;32(Suppl 1):34-9. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5734815/ [cited 2021 Oct 25]. Frey B, Jegen R. Motivation crowding theory: A survey of empirical evidence. J Econ Surv. 2002;15(5):589-611. Available from: doi:10.1111/1467-6419.00150. Gill S, Klarenbach S, Barnieh L, Caulfield T, Knoll G, Levin A, et al. Financial incentives to increase Canadian organ donation: Quick fix or fallacy? Am J Kidney Dis. 2014;63(1):133-40. Available from: doi:10.1053/j.ajkd.2013.08.029. Abolghasemi H, Hosseini-Divkalayi NS, Seighali F. Blood donor incentives: A step forward or backward. Asian J Transfus Sci. 2010;4(1):9-13. Available from: doi:10.4103/0973-6247.59385.

introduction viewpoints

AGAINST FINANCIAL COMPENSATION While the potential benefits of a donor compensation program may appeal to healthcare systems with a high demand for organs, there are ethical and practical concerns that must be considered. Offering financial incentives for organ donation would disproportionately affect those in the lower socioeconomic bracket.¹² Financially vulnerable individuals may turn to donating their organs as a source of income, which could compromise the integrity of the transplant system as a whole. Additionally, donor candidates might be inclined to falsify medical records and information to increase their chances of being selected as an organ donor, putting both their own and the recipient’s health at risk.¹³,¹⁴

Furthermore, there is no guarantee that financial compensation would even close the organ shortage gap. According to the motivation crowding theory, the provision of extrinsic incentives may undermine intrinsic motivation.¹⁷ In this case, payment for organ donation could reduce intrinsic motivation, decreasing the existing number of donations for which no money is given.¹⁸ In certain situations, donors may feel that financial compensation lessens the weight of altruism that is involved in the gift of donation.¹³ For example, a Swedish study by Abolghasemi et al. on blood donation found that in groups of women, the introduction of monetary incentives cut donors by nearly 50%.¹⁹

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CURRENT LIMITATIONS AND FUTURE DIRECTIONS

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ARTISTS: ARIM YOO & YOOHYUN PARK

20 14

CRITICAL REVIEW

ROBOTICS IN SPINAL SURGERY:

doi: 10.35493/medu.40.14

JUSTIN PHUNG

Bachelor of Health Sciences (Honours), Class of 2024, McMaster University phungj3@mcmaster.ca

ABSTRACT Surgical robotics have been introduced in a number of disciplines, with the aim of minimizing tissue disruption, reducing operating personnel radiation exposure, and improving dexterity and efficiency relative to human operation. In spinal surgery, robotic systems are relatively novel, applied to date largely for the placement of pedicle screw instrumentation. Only a few robotic systems have been approved for spinal surgery, and there remain significant barriers to the widespread implementation of surgical robotic techniques. This review provides an overview of robotic systems in spinal surgery and identifies current limitations that must be addressed before clinical use, including clinical merit relative to freehand navigation systems, steep learning curves, and unclear cost-effectiveness.

CONTEXT

With aging populations, studies from the US and England have demonstrated a higher prevalence of degenerative spinal disorders, resulting in greater demands for lumbar spinal surgery.1,2 Spinal surgery is associated with higher rates of complications compared to other orthopaedic procedures; thus, robotics could significantly impact future spinal surgeries by improving safety and producing consistent results.3 Currently, the primary application of robotics is for pedicle screw insertion.3 Pedicle screw instrumentation connected to rod constructs in the thoracolumbar spine is the most commonly used technique, widely applied for degenerative, traumatic, neoplastic, and deformative spinal disorders.4,5 As such, this review will focus on pedicle screw placement with robotic guidance.

M E D U CATO R | DECEMBER 2021

Robot-assisted (RA) spinal surgery allows the physician to insert surgical instruments and screws with the use

EVALUATING EFFECTIVENESS

RA pedicle screw insertion has resulted in higher accuracy, safety, and feasibility of the procedure compared with its conventional alternatives. Two meta-analyses demonstrated that RA pedicle screw insertion operations had lower neurological complication rates and reduced risk of pedicle perforation compared to the freehand placement technique.6 Lieberman et al. also noted RA accuracy rates between 94.5-99%, even in cases involving severe deformity or revision surgeries due to congenital malformations, degenerative disorders, destructive tumors, and trauma.19 It must be noted, however, that no study to date has demonstrated improved screw placement accuracy with robotic guidance vs. freehand navigation guidance, with most prospective series citing accuracy rates in the 90%+ range for both techniques.20 Some current robotic systems include ROSA Spine, the Excelsius GPS, the TiRobot, and the Mazor X.21 To classify pedicle screw accuracy, the Gertzbein and Robbins system is frequently used, with grades A or B considered clinically acceptable and C or D considered unacceptable, often requiring immediate or delayed revision.22 The original model of ROSA Spine attained combined accu-

critical review

Traditionally, pedicle screw fixation was conducted with the freehand technique.6 In expert hands, rates of successful placement were as high as 80-90%, though screw malposition can result in severe and potentially permanent clinical sequelae. Malpositioned screws may be associated with long-term poor construct strength and accelerated degeneration of adjacent spinal segments.7 Over the past two decades, intra-operative 2D-fluoroscopy navigation was introduced into spinal surgery to improve pedicle screw placement accuracy. In these procedures, pre-operative computed tomography (CT) scans were reconstructed to generate a 3D model of the spine.8 Despite the critical role of fluoroscopy in spinal navigation, operating room (OR) staff and the patient are exposed to significant harmful ionizing radiation.3,6 Thus, radiation exposure and operating time are important to consider. Modern image-guidance systems using CT scans have significantly reduced radiation exposure to OR staff. Intra-operative CT or 3D-fluoroscopy systems, in particular, allow real-time imaging of the patient in the surgical prone position (as opposed to supine positioning for a pre-operative CT), eliminating errors due to motion between pre- and intra-operative positioning.9 Intra-operative CT scan-based navigation has resulted in improved pedicle screw placement accuracy compared to 2D-fluoroscopy techniques.10,11

of a rigid robotic arm and drill guide effector.12 RA spinal surgeries have therefore developed alongside navigation techniques including 2D-fluoroscopy, 3D-fluoroscopy, pre-operative CT, and intra-operative CT.13 In most cases, RA pedicle screw placement and novel imaging navigation systems have resulted in improved accuracy and efficiency of the tedious procedure, reducing human variation, fatigue, and radiation exposure for OR personnel.12,14-18

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racy rates of 96.3%, 97.3%, and 98.3% with A and B grades.21 Similarly, the Excelsius GPS attained high levels of accuracy in two retrospective studies. Jain et al. noted 100% of the 66 reviewed post-operative CT screws were categorized as grade A or B, with no major screw-related complications from 643 total screws placed.23 Elswick et al. reported 97.6% grades A and B for their Excelsius GPS study involving 125 screws.24 Finally, a randomized prospective trial comparing the TiRobot with free-hand screw placement had similar conclusions, with 95.3% of scores classifying as grade A and 98.7% as combined grades A and B.14 Evidently, many available robot systems are effective and accurate.

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CURRENT PRACTICAL LIMITATIONS Radiation exposure is one concern that must be addressed in the field of robotic spine surgery. In several studies, the RA technique was reported to provide a 40-70% reduction in intra-operative radiation exposure rates for the patient, the surgeon, and the OR personnel.19 The RA technique reduced the average radiation exposure time to 34 seconds, compared to the freehand fluoroscopic technique with an average exposure time of 77 seconds.19 Nevertheless, an average radiation exposure time of 34 seconds is still substantial, and in current use, navigation with intra-operative CT or 3D-fluoroscopy systems is associated with insignificant radiation exposure to OR personnel as they step out of the room during the scans, whereas robotic guidance requires several orthogonal single X-ray shots in the OR for registration.25,26 Given that pedicle screw insertions are common procedures, the cumulative radiation exposure over one’s lifetime can be carcinogenic. Future studies should investigate methods to facilitate the reduction of radiation exposure for subsequent RA systems. Furthermore, the surgical learning curve could limit widespread clinical application as RA software can be cumbersome and unintuitive.6 However, there have been several studies indicating that screw placement accuracy improves as more procedures are performed. Schatlo et al. reported that the rate of misplaced screws significantly decreased after surgeons completed 25 RA surgeries, while Hu et al. reported similar findings, where screw placement success rate increased after a surgeon’s first 30 patients.27,28 To address this learning curve, practicing under the supervision of an RA-experienced surgeon and engaging in wet lab or cadaver training prior to surgery in patients is suggested.3 The lack of research on clinical outcomes and cost-effectiveness also holds back patient and hospital decisions to undergo RA surgery, specifically due to the novelty of these systems and their questionable benefits

relative to freehand navigation.29 Although evidence suggests intra-operative benefits, little is known about post-operative complications and duration of hospital stay.29 These factors influence patient perspective and can sway their decision to opt for RA surgery. Furthermore, barriers in assessing cost-effectiveness hinder RA spinal surgeries. One particular study by Menger et al. reported savings of $608 546 USD in a year associated with 557 RA thoracolumbar cases.30 However, the cost-effectiveness of the robot cannot be applied to smaller healthcare settings. Further reviews on post-operative outcomes and cost-effectiveness of RA spine surgery are necessary for the progression of robots into clinical settings.

FUTURE PROSPECTS With digital optics continuing to advance in the next decade, high-resolution imaging may serve as an alternative to intra-operative fluoroscopy. 7D Surgical, a Toronto-based company, offers a navigation system that utilizes digital stereoscopic topographical referencing and matches it with pre-operative CT, resulting in rapid image registration and elimination of intra-operative radiation exposure.21 Augmented reality (AR) is also a visualization technique to explore in spinal surgery, although it must currently remain with freehand actuation. Augmedics Xvision System is an AR platform that provides live 3D navigational feedback, reducing radiation exposure to OR personnel.21 Similarly, ImmersiveTouch and MagicLeap provide surgeons with intra-operative virtual headsets that allow real-time 3D visualization during the surgery, mitigating differences between the surgical environment and 2D intra-operative imaging.31 Elmi-Terander et al. achieved an accuracy of 94.1% using an AR surgical navigation system, while Alaraj et al. reported that ImmersiveTouch allowed trainee surgeons

14.

to place screws precisely.32,33 Although accuracy and radiation exposure are critical to assess, future research should evaluate operative time, clinical outcomes, and intra- and post-operative complications.

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CONCLUSION RA spinal surgery could potentially revolutionize the surgical field. Although clinical implementation is feasible, further research must be conducted to clarify the benefits and drawbacks of robotic spinal surgery. Overall, the evidence demonstrates that RA pedicle screw insertion is more accurate than its freehand counterpart, with several models achieving high GR grades. However, radiation exposure to OR personnel and the learning curve that surgeons face when adapting to new technology remain concerning. Further reviews on cost-effectiveness and clinical outcomes should be conducted to inform hospitals and patients of the benefits, especially as novel high-resolution imaging systems develop alongside RA spinal surgery. Comprehensive reports and evaluations in future publications are essential to pave the way for robotics in the field of spinal surgery.

Dr. Daipayan (Deep) Guha is a spinal neurosurgeon at Hamilton Health Sciences and an Assistant Professor of neurosurgery at McMaster University. Some of his research interests include emerging imaging technologies for spinal surgery, the applications of augmented reality (AR) in Neurosurgery, and intra-operative three-dimensional spinal navigation.

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Pannell WC, Savin DD, Scott TP, Wang JC, Daubs MD. Trends in the surgical treatment of lumbar spine disease in the United States. Spine J. 2015;15(8):1719–27. Available from: doi:10.1016/j.spinee.2013.10.014. Sivasubramaniam V, Patel HC, Ozdemir BA, Papadopoulos MC. Trends in hospital admissions and surgical procedures for degenerative lumbar spine disease in England: A 15-year time-series study. BMJ Open. 2015;5(12):e009011. Available from: doi:10.1136/bmjopen-2015-009011. Garg B, Mehta N, Malhotra R. Robotic spine surgery: Ushering in a new era. J Clin Orthop Trauma. 2020;11(5):753–60. Available from: doi:10.1016/j. jcot.2020.04.034. Verma K, Boniello A, Rihn J. Emerging techniques for posterior fixation of the lumbar spine. J Am Acad Orthop Surg. 2016;24(6):357–64. Available from: doi:10.5435/JAAOS-D-14-00378. Gaines RWJ. The use of pedicle-screw internal fixation for the operative treatment of spinal disorders. J Bone Joint Surg Am. 2000;82(10):1458-76. Available from: doi:10.2106/00004623-200010000-00013. Vo CD, Jiang B, Azad TD, Crawford NR, Bydon A, Theodore N. Robotic spine surgery: Current state in minimally invasive surgery. Global Spine J. 2020;10(2 Suppl):34S-40S. Available from: doi:10.1177/2192568219878131. Verma R, Krishan S, Haendlmayer K, Mohsen A. Functional outcome of computer- assisted spinal pedicle screw placement: A systematic review and meta-analysis of 23 studies including 5,992 pedicle screws. Eur Spine J. 2010;19(3):370-5. Available from: doi:10.1007/s00586- 009-1258-4. Weiner JA, McCarthy MH, Swiatek P, Louie PK, Qureshi SA. Narrative review of intraoperative image guidance for transforaminal lumbar interbody fusion. Ann Transl Med. 2021;9(1):89. Available from: doi:10.21037/atm-20-1971. Guha D, Jakubovic R, Gupta S, Fehlings MG, Mainprize TG, Yee A et al. Intraoperative error propagation in 3-dimensional spinal navigation from nonsegmental registration: A prospective cadaveric and clinical study. Global Spine J. 2019;9(5):512-20. Available from: doi:10.1177/2192568218804556. Wood M, Mannion R. A comparison of CT-based navigation techniques for minimally invasive lumbar pedicle screw placement. J Spinal Disord Tech. 2011;24(1):E1-5. Available from: doi:10.1097/BSD.0b013e3181d534b8. Silbermann J, Riese F, Allam Y, Reichert T, Koeppert H, Gutberlet M. Computer tomography assessment of pedicle screw placement in lumbar and sacral spine: Comparison between free-hand and O-arm based navigation techniques. Eur Spine J. 2011;20(6):875–81. Available from: doi:10.1007/ s00586-010-1683-4. Chen H-Y, Xiao X-Y, Chen C-W, Chou H-K, Sung C-Y, Lin FH et al. A spine robotic-assisted navigation system for pedicle screw placement. J Vis Exp. 2020;(159):e60924. Available from: doi:10.3791/60924. Amr AN, Giese A, Kantelhardt SR. Navigation and robot-aided surgery in the spine: Historical review and state of the art. Robot Surg. 2014;1:19–26. Available from: doi:10.2147/RSRR.S54390.

introduction critical review

REVIEWED BY: DR. DAIPAYAN GUHA (MD, PHD, FRCSC)

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Han X, Tian W, Liu Y, Liu B, He D, Sun Y, et al. Safety and accuracy of robotassisted versus fluoroscopy-assisted pedicle screw insertion in thoracolumbar spinal surgery: A prospective randomized controlled trial. J Neurosurg Spine. 2019;30(5):615–22. Available from: doi:10.3171/2018.10.SPINE18487. Hyun S-J, Kim K-J, Jahng T-A, Kim H-J. Minimally invasive robotic versus open fluoroscopic-guided spinal instrumented fusions: A randomized controlled trial. Spine. 2017;42(6):353–8. Available from: doi:10.1097/ BRS.0000000000001778. Kantelhardt SR, Martinez R, Baerwinkel S, Burger R, Giese A, Rohde V. Perioperative course and accuracy of screw positioning in conventional, open robotic-guided and percutaneous robotic-guided, pedicle screw placement. Eur Spine J. 2011;20(6):860–8. Available from: doi:10.1007/s00586-0111729-2. Keric N, Eum DJ, Afghanyar F, Rachwal-Czyzewicz I, Renovanz M, Conrad J, et al. Evaluation of surgical strategy of conventional vs. percutaneous robotassisted spinal trans-pedicular instrumentation in spondylodiscitis. J Robot Surg. 2017;11(1):17–25. Available from: doi:10.1007/s11701-016-05975. Stüer C, Ringel F, Stoffel M, Reinke A, Behr M, Meyer B. Robotic technology in spine surgery: Current applications and future developments. Acta Neurochir Suppl. 2011;109:241–5. Available from: doi:10.1007/978-3-211-996515_38. Lieberman IH, Kisinde S, Hesselbacher S. Robotic-assisted pedicle screw placement during spine surgery. JBJS Essent Surg Tech. 2020;10(2):e0020. Available from: doi:10.2106/JBJS.ST.19.00020. Peng YN, Tsai LC, Hsu HC, Kao CH. Accuracy of robot-assisted versus conventional freehand pedicle screw placement in spine surgery: A systematic review and meta-analysis of randomized controlled trials. Ann Transl Med. 2020;8(13):824. Available from: doi:10.21037/atm-20-1106. Huang M, Tetreault TA, Vaishnav A, York PJ, Staub BN. The current state of navigation in robotic spine surgery. Ann Transl Med. 2021;9(1):86. Available from: doi:10.21037/atm-2020-ioi-07. Vardiman AB, Wallace DJ, Booher GA, Crawford NR, Riggleman JR, Greeley SL, et al. Does the accuracy of pedicle screw placement differ between the attending surgeon and resident in navigated robotic-assisted minimally invasive spine surgery? J Robot Surg. 2020;14(4):567–72. Available from: doi:10.1007/s11701-019-01019-9. Jain D, Manning J, Lord E, Protopsaltis T, Kim Y, Buckland AJ, et al. Initial single-institution experience with a novel robotic-navigation system for thoracolumbar pedicle screw and pelvic screw placement with 643 screws. Int J Spine Surg. 2019;13(5):459–63. Available from: doi:10.14444/6060. Elswick CM, Strong MJ, Joseph JR, Saadeh Y, Oppenlander M, Park P. Robotic-assisted spinal surgery: Current generation instrumentation and new applications. Neurosurg Clin N Am. 2020;31(1):103–10. Available from: doi:10.1016/j.nec.2019.08.012. Mendelsohn D, Strelzow J, Dea N, Ford NL, Batke J, Pennington A, et al. Patient and surgeon radiation exposure during spinal instrumentation using intraoperative computed tomography-based navigation. Spine J. 2016;16(3):343-54. Available from: doi:10.1016/j.spinee.2015.11.020. Klingler JH, Scholz C, Krüger MT, Naseri Y, Volz F, Hohenhaus M, et al. Radiation exposure in minimally invasive lumbar fusion surgery: A randomized controlled trial comparing conventional fluoroscopy and 3D fluoroscopybased navigation. Spine. 2021;46(1):1-8. Available from: doi:10.1097/ BRS.0000000000003685. Hu X, Lieberman IH. What is the learning curve for robotic-assisted pedicle screw placement in spine surgery? Clin Orthop Relat Res. 2014;472(6):1839–44. Available from: doi:10.1007/s11999-013-3291-1. Schatlo B, Martinez R, Alaid A, von Eckardstein K, Akhavan-Sigari R, Hahn A, et al. Unskilled unawareness and the learning curve in robotic spine surgery. Acta Neurochir (Wien). 2015;157(10):1819–23. Available from: doi:10.1007/ s00701-015-2535-0. Huang J, Li Y, Huang L. Spine surgical robotics: Review of the current application and disadvantages for future perspectives. J Robot Surg. 2020;14(1):11–6. Available from: doi:10.1007/s11701-019-00983-6. Menger RP, Savardekar AR, Farokhi F, Sin A. A cost-effectiveness analysis of the integration of robotic spine technology in spine surgery. Neurospine. 2018;15(3):216–24. Available from: doi:10.14245/ns.1836082.041. McDonnell JM, Ahern DP, Ó Doinn T, Gibbons D, Rodrigues KN, Birch N, et al. Surgeon proficiency in robot-assisted spine surgery. Bone Joint J. 2020;102B(5):568–72. Available from: doi:10.1302/0301-620X.102B5.BJJ-20191392.R2. Elmi-Terander A, Burström G, Nachabe R, Skulason H, Pedersen K, Fagerlund M, et al. Pedicle screw placement using augmented reality surgical navigation with intraoperative 3D imaging. Spine. 2019;44(7):517–25. Available from: doi:10.1097/BRS.0000000000002876. Alaraj A, Lemole MG, Finkle JH, Yudkowsky R, Wallace A, Luciano C, et al. Virtual reality training in neurosurgery: Review of current status and future applications. Surg Neurol Int. 2011;2:52. Available from: doi:10.4103/21527806.80117.

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table of contents

ARTIST: KATELYN MOORE

Critical Review

Machine Learning and Depression USING NEUROIMAGING DATA AND MACHINE LEARNING TO PREDICT RESPONSES TO DEPRESSION TREATMENTS

doi: 10.35493/medu.40.18

ABSTRACT Despite the high prevalence of major depressive disorder (MDD), there is a lack of tools for predicting individual patient responses to specific MDD treatments. However, a growing body of literature has been describing the use of machine learning (ML) to improve MDD treatment by using neuroimaging data to generate a model capable of predicting said treatment responses. Studies follow a general ML pipeline, though exact methodologies for sampling, treatment, and imaging vary. Overall, predictions using ML are relatively successful, with reasonable accuracy during crossvalidation. However, generalizability of these algorithms has not yet been demonstrated and, at this stage, studies largely serve as “proof-of-concept”, with many practical issues that still need to be addressed prior to clinical implementation. This review aims to discuss the potential benefits and limitations of ML in predicting patient responses to MDD treatment.

When it comes to MDD treatment, ML provides two key advantages. First, it allows for predictions at the level of the individual rather than solely the identification of gross differences on a group level.6 As such, it has high translational potential to a clinical setting. Second, its multivariate nature makes it more sensitive to subtle, spatially-distributed brain alterations.6 This enables it to detect patterns in massively multivariate data, such as magnetic resonance imaging (MRI), that are far too complicated for humans to interpret. These patterns can be used to predict whether a specific treatment will be successful in decreasing depressive symptoms for a given patient. Models commonly focus on predicting the success of pharmacotherapy and ECT, while significantly less research has applied ML predictions to cognitive behavioral therapy, despite it being a common treatment for MDD.7 The machine learning pipeline typically begins with data preprocessing, which prepares and refines the raw data to make it more suitable for the machine learning model. This generally entails the alignment and normalization of image data, and the filtering-out of noise. However, there is significant variation in the tools used to perform these steps; some studies have also included further preprocessing steps, such as feature selection, where only features that are expected to be meaningful for prediction are included in the model.8 Although these differences are not largely significant, they highlight the lack of a standardized and validated approach to preprocessing imaging data that may be necessary before clinical application is possible. Following preprocessing, models are trained using training data to build an algorithm to make predictions about the success of the drug or intervention. One method of analyzing neuroimaging data is an algorithm called a support vector machine (SVM).6 SVMs seek to define a “hyperplane” in high-dimensional space, which is a decision boundary that separates data into discrete categories, namely whether a depression treatment is successful or not (see Fig. 1). It should be noted that different studies vary in their criteria for a “successful” intervention, with some using symptom reduction measured on the Hamilton Depression Rating Scale (HRSD) and others defining success as complete remission.8,9 While this makes it more difficult to compare studies, these different definitions of success allow for greater application over multiple contexts, depending on the history and severity of MDD a patient experiences. Once a model is trained, it can be used to make predictions on new data.

| DECEMBER 2021

MACHINE LEARNING Machine learning (ML) is a branch of artificial intelligence that uses an algorithmic and data-based approach to develop machines to perform tasks without explicit programming. In ML models, machines are “trained” using a bottom-up approach, where they are given examples from which they learn, automatically improving as further experience is gained to develop a more generalizable algorithm.5 This means that ML can develop models capable of novel and generalizable predictions; this ability has led ML to gain significant traction in

recent decades, with applications ranging from self-driving cars to medical diagnoses.5

M E D U CATO R

Although methods such as psychotherapy, electroconvulsive therapy (ECT), and pharmacotherapy are commonly used to treat depression, these approaches are effective in only 30-50% of patients.3 This is partially due to the broad and heterogeneous nature of depression diagnoses: the DSM-5 does not break down MDD into more narrowly defined disease entities with specific biologies.1 This impedes the personalization of treatment on a patient-specific level.4 Instead, effective treatment is dependent on long-term interactions, where clinicians begin with recommendations based on broader symptom classifications before personalizing the treatment over time through trial and error.3 Although this approach may eventually prove effective for patients, it prolongs disease complications and consumes significantly more resources compared to targeted approaches.2 This review aims to investigate the potential of the application of machine learning to neuroimaging data to predict individualized responses to MDD treatment, while addressing specific and systemic limitations of current research.

Bachelor of Health Sciences (Honours), Class of 2024, McMaster University wang66@mcmaster.ca

critical review

INTRODUCTION Major depressive disorder (MDD) is a highly prevalent disorder characterized by depressed mood, diminished interests, impaired cognitive function, disturbed sleep, and changes in appetite causing clinically significant distress or impairment.1 Affecting 1 in 6 adults, it is estimated by the Global Burden of Disease Consortium to be the fourth leading contributor to global disease burden in individuals aged 10 to 24, and sixth in those aged 25 to 49.2

YIFAN WANG

critical review table of contents

Performance can be evaluated with a range of metrics, but the most commonly reported metrics are accuracy (the proportion of correctly predicted cases), sensitivity (the proportion of correctly predicted responders out of all responders), and specificity (the proportion of correctly predicted non-responders out of all non-responders). Model accuracy varies significantly between investigations, ranging from 62-89%.10,11 This variability is partly due to objective model performance, but can also be attributed to different methodologies for sampling, treatment, imaging, and analysis. The average sensitivity and specificity was estimated to be 77% and 79% respectively in a 2021 meta-analysis conducted by Cohen et al., which demonstrates that models perform fairly successfully overall.7 There were no significant differences resulting from imaging modality: structural and functional MRI studies yielded similar sensitivities and specificities. However, the predictive accuracy of ECT interventions has generally been found to be higher than that of pharmacotherapy.7

M E D U CATO R

PREDICTIVE PERFORMANCE The performance of an ML model is commonly evaluated by first training the model using a training set, after which the generated algorithm is applied to a test set to analyze performance by comparing the prediction to the correct label. Specifically, most studies in this area use leave-one-out crossvalidation, a method where a single participant from both responder and non-responder groups is excluded to use as a test set, while the model is trained on the remaining patients.7 This process is repeated with different participants being excluded at each iteration, until every participant is excluded once. While this cross-validation approach produces high-variability and potentially biased estimations, other approaches are currently difficult to implement due to small sample sizes.3

| DECEMBER 2021

Figure 1: A two-dimensional support vector machine. SVM is an ML algorithm that finds a hyperplane in N-dimensional space (where each dimension corresponds to a feature of the dataset) that most successfully classifies cases, while also maximizing the margin between the data points closest to the hyperplane (support vectors).3

Studies have had widely varying results for brain regions with high predictive importance for MDD treatment. Costafreda et al. found that increased grey matter density in the cingulate gyrus (CgC) predicted an increased probability of clinical remission in response to fluoxetine.8 These findings agree with an earlier functional MRI study by Marquand et al., which also identified

the CgC as a biomarker for successful antidepressant response.12 Grieve et al. conducted a subsequent study using different drugs, yet also found that the CgC predicted non-remitting patients.13 This raises a potential issue: current algorithms could be predicting the overall success of antidepressant treatments in general, rather than being drug-specific. While such predictions may still be helpful, it detracts from their clinical utility where deciding between multiple potential drugs is often required. Many other regions of interest have been identified, such as the amygdala and the hippocampus, with some studies identifying as many as 25 regions of interest.7,14 However, this varies significantly between publications, as regions of high predictive importance identified in some studies have been completely excluded from others.11,15 Overall, there is no clear agreement in the literature that suggests a single region of interest as a potential biomarker. LIMITATIONS While ML seems like a promising technology to assist with the treatment of MDD, it has many limitations that should be addressed. Firstly, training and testing data are often unrepresentative of the actual populations to which ML will be applied. Most current studies seek to obtain a pure estimate of the population mean without influence from other factors like comorbidities or medication effects, which often serve as exclusion criteria. In the general population, however, MDD cases are often comorbid with other psychiatric disorders.16 As such, a model that displays high accuracy within a single study may not necessarily produce successful results in larger, more heterogeneous populations. In fact, the accuracy of these models trend downwards with increasing sample size, despite the fact that ML models generally improve with more data.17 This inflation of accuracy may be due to overfitting, where small sample sizes can cause the model to capture dynamics that are specific to training data, but consequently do not generalize well to new data. As such, before clinical application is possible, the generalizability of ML in broader samples must be proven, especially in MDDafflicted individuals with comorbid conditions that may complicate prediction. Dwyer and colleagues have proposed a validation hierarchy to achieve greater generalizability, where models can be gradually applied to more diverse selections of individuals, such as leave-site-out cross validation (where models are trained in one site and tested in another).3 Another significant limitation with current research is that investigators often use a classification approach. This approach considers the success of a treatment as a discrete variable, separating patients into responder and non-responder groups based on arbitrarily defined boundaries, such as a 50% reduction in HRSD score.9 However, efficacy is a continuous variable, with varying degrees of symptom reduction: most non-ML studies of treatment efficacy do indeed report results continuously.18 As such, a machine learning algorithm using a classification approach will be fundamentally constrained by being an inaccurate representation of the true nature of treatment. Therefore, it could be worth investigating a regression approach, where predictions are made on a continuous scale that estimates the degree of success of a treatment. Finally, there are several challenges that must be addressed

before ML can be used in clinical settings. One issue is that models created by ML are often difficult to interpret, meaning that it is hard to understand how variables are combined to make predictions on both a computational and biological level. In the context of patient care, this lack of transparency could potentially undermine trust in this technology by both clinicians and patients, preventing adoption. However, improvement in this area reduces accuracy, given that the best performing models tend to be the least explainable, and vice versa.19 ML will also likely create ethical issues of accountability: if an ML model makes an incorrect prediction, it is difficult to determine where culpability lies, creating further complications for existing legal and regulatory systems that address medical malpractice. Finally, there are a range of practical issues that also limit the usefulness of ML. These include a lack of clinician experience and training in using ML models, restricted access to neuroimaging, and the high time and computational demand required to implement this technology on a larger scale.

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Otte C, Gold SM, Penninx BW, Pariante CM, Etkin A, Fava M, et al. Major depressive disorder. Nat Rev Dis Primers. 2016;2:16065. Available from: doi:10.1038/nrdp.2016.65. Vos T, Lim SS, Abbafati C, Abbas KM, Abbasi M, Abbasifard M, et al. Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204-22. Available from: doi:10.1016/ S0140-6736(20)30925-9. Dwyer DB, Falkai P, Koutsouleris N. Machine learning approaches for clinical psychology and psychiatry. Annu Rev Clin Psychol. 2018;14:91-118. Available from: doi:10.1146/annurev-clinpsy-032816-045037. Khan A, Faucett J, Lichtenberg P, Kirsch I, Brown WA. A systematic review of comparative efficacy of treatments and controls for depression. PLoS One. 2012;7(7):e41778. Available from: doi:10.1371/journal.pone.0041778. Jordan MI, Mitchell TM. Machine learning: Trends, perspectives, and prospects. Science. 2015;349(6245):255-60. Available from: doi:10.1126/science.aaa8415. Orrù G, Pettersson-Yeo W, Marquand AF, Sartori G, Mechelli A. Using Support Vector Machine to identify imaging biomarkers of neurological and psychiatric disease: A critical review. Neurosci Biobehav Rev. 2012;36(4):1140-52. Available from: doi:10.1016/j.neubiorev.2012.01.004. Cohen SE, Zantvoord JB, Wezenberg BN, Bockting CLH, van Wingen GA. Magnetic resonance imaging for individual prediction of treatment response in major depressive disorder: A systematic review and meta-analysis. Transl Psychiatry. 2021;11(1):168. Available from: doi:10.1038/s41398-02101286-x. Costafreda SG, Chu C, Ashburner J, Fu CHY. Prognostic and diagnostic potential of the structural neuroanatomy of depression. PLoS One. 2009;4(7):e6353. Available from: doi:10.1371/journal.pone.0006353. Gong Q, Wu Q, Scarpazza C, Lui S, Jia Z, Marquand A, et al. Prognostic prediction of therapeutic response in depression using high-field MR imaging. Neuroimage. 2011;55(4):1497-503. Available from: doi:10.1016/j. neuroimage.2010.11.079. Korgaonkar MS, Williams LM, Song YJ, Usherwood T, Grieve SM. Diffusion tensor imaging predictors of treatment outcomes in major depressive disorder. Br J Psychiatry. 2014;205(4):321-8. Available from: doi:10.1192/ bjp.bp.113.140376. Jiang R, Abbott CC, Jiang T, Du Y, Espinoza R, Narr KL, et al. SMRI biomarkers predict electroconvulsive treatment outcomes: Accuracy with independent data sets. Neuropsychcopharmacology. 2018;43(5):1078-87. Available from: doi:10.1038/npp.2017.165. Marquand AF, Mourão-Miranda J, Brammer MJ, Cleare AJ, Fu CHY. Neuroanatomy of verbal working memory as a diagnostic biomarker for depression. Neuroreport. 2008;19(15):1507-11. Available from: doi:10.1097/WNR.0b013e328310425e. Grieve SM, Korgaonkar MS, Gordon E, Williams LM, Rush AJ. Prediction of nonremission to antidepressant therapy using diffusion tensor imaging. J Clin Psychiatry. 2016;77(4):e436-43. Available from: doi:10.4088/ JCP.14m09577. Drysdale AT, Grosenick L, Downar J, Dunlop K, Mansouri F, Meng Y, et al. Resting-state connectivity biomarkers define neurophysiological subtypes of depression. Nat Med. 2017;23(1):28-38. Available from: doi:10.1038/ nm.4246. Redlich R, Nils O, Dominik G, Katharina D, Dario Z, Christian B, et al. Prediction of individual response to electroconvulsive therapy via machine learning on structural magnetic resonance imaging data. JAMA Psychiatry. 2016;73(6):557-64. Available from: doi:10.1001/ jamapsychiatry.2016.0316. Hasin DS, Sarvet AL, Meyers JL, Saha TD, Ruan WJ, Stohl M, et al. Epidemiology of adult DSM-5 major depressive disorder and its specifiers in the United States. JAMA Psychiatry. 2018;75(4):336-46. Available from: doi:10.1001/jamapsychiatry.2017.4602 Flint C, Cearns M, Opel N, Redlich R, Mehler DMA, Emden D, et al. Systematic misestimation of machine learning performance in neuroimaging studies of depression. Neuropsychopharmacology. 2021;46(8):1510-7. Available from: doi:10.1038/s41386-021-01020-7. McGirr A, Berlim MT, Bond DJ, Fleck MP, Yatham LN, Lam RW. A systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials of ketamine in the rapid treatment of major depressive episodes. Psychol Med. 2015;45(4):693-704. Available from: doi:10.1017/ S0033291714001603. Kelly CJ, Karthikesalingam A, Suleyman M, Corrado G, King D. Key challenges for delivering clinical impact with artificial intelligence. BMC Med. 2019;17(1):195. Available from: doi:10.1186/s12916-019-1426-2.

Pedro L. Ballester has a bachelor’s and master’s degree in computer science. He is currently a neuroscience PhD candidate at McMaster University. His research is focused on artificial intelligence and mental health, particularly accelerated brain aging in mood and psychotic disorders. He is a trainee at the Canadian Biomarker Integration Network in Depression (CANBIND) searching for neuroimaging biomarkers of treatment response in depression.

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 1

REVIEWED BY: PEDRO L. BALLESTER

introduction critical review

CONCLUSION The potential of ML to predict treatment response on an individual level could help rectify the current lack of targeted treatment methodologies and significantly improve patient care. However, many limitations still prevent clinical implementation. Future research should focus on improving generalizability, as successful validation across multiple sites or across different investigations would greatly improve the value of ML in realworld applications. Alongside this, researchers should also consider issues of how to make this technology readily available for clinician use, while enhancing transparency to encourage patient adoption.

EDITED BY: SHANZEY ALI

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GLOBAL PERSPECTIVE: ARTIST JEFF ZHANG

Do prosthetic limbs really have to cost an arm and a leg? ARTIST: JEFF ZHANG

Exploring the development of an open-source, lowcost operational transradial prosthesis prototype NOTE FROM THE EDITORS: Those of the disabled community identify themselves in different ways. Some prefer identity-first language as a “disabled person,” while some prefer person-first language as a “person with disability.” To respect the two groups, we have chosen to use both terms in this piece.

doi: 10.35493/medu.40.22

ABDUL NAFEA ZUBERI, ABDULRAHMAN HAJJAJ, ADEEL NIAZ, AHMED ALLAM, HAASHIM SHAHZADA, HASHIM ALI, MOHAMMED NIGM, SAMIUDDIN DANISH MOHAMMED, & YOUSUF KHILJIRAJJAJ Bachelor of Engineering, Class of 2024, McMaster University zubera1@mcmaster.ca

These models were designed to work simultaneously with the aforementioned open-source electronics. Specifically, our prosthetic arm uses an Arduino UNO microcontroller in combination with a Myoware EMG sensor, PCA9685 servo driver board and five SG90 servo motors. Using C++, we coded a program that runs on the Arduino UNO and is constantly checking the sensor for EMG voltage signals coming from a muscle. The EMG sensor is placed on the user’s bicep at the middle of the muscle body and aligned with the orientation of the muscle fibers to increase the accuracy of its readings.6 The program averages out the last 20 values it receives and based on that, sends commands to another function in the code that angles the servos to control which fingers move. Once the code is sent to the servos, a high tensile strength wire previously in tension is put on an increased strain. This strain value is attained using a predetermined scale that analyses tension compared to resulting flexion.

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As we heard the stories of our SMILE mentees, we noticed how many families supported by the organization had a hard time affording high-quality assistive devices. With some prostheses costing as much as $75,000 CAD, many families are unable to afford the immense price tag.1 We saw how this financial barrier prevents many children from receiving these devices, which inspired our group of engineering and health sciences students to start Brachïum.

Our CAD models were made and assembled in an online cloud platform known as Onshape. Onshape has 2D sketching and 3D modelling tools that allow users to create complex parts that can be arranged and exported using the online service. Our models were designed to be assembled using parts that are commonly available in hardware stores for ease of access. Through countless test prints and multiple revisions of the CAD models, we came up with an efficient and functioning design. After we finished developing our models, they were exported as high-quality STL files (3D models) and imported into the 3D Slicer program, Ultimaker Cura. Cura is a software that allows users to configure CAD models for 3D printing and customize infill and layer settings for their 3D printing environment. Additionally, Cura converts STL files to G-Code, a language used to control many automated machines, in preparation for the print. The G-Code file is then processed by the 3D printer, which converts it to x, y, and z coordinates and prints out the models layer by layer.

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PERSONAL EXPERIENCES AND HEALTH TOPICS: STARTING BRACHÏUM The idea was sparked when several members of our initiative volunteered with SMILE Canada to support Muslim youth with disabilities and their families. During this time, we had several first-hand experiences working with children requiring prostheses. SMILE Canada strives to ensure that all children are provided with the resources and support network for a happy, healthy lifestyle. While volunteering with this organization, we were involved with the mentorship program, where we developed meaningful relationships with our SMILE mentees and learned about their personal stories and experiences.

MANUFACTURING THE PROSTHESES Through research, we discovered that using manufacturing techniques, such as 3D printing and open-source electronics, could significantly reduce the cost of prosthetics.4,5 Our goal was to create custom Computer-Aided Design (CAD) models that would make both assembly and repairs straightforward. To calibrate the function of the arm to each user, we utilized open-source microcontrollers that convert analog electromyography (EMG) signals into digital pulse-width modulation signals used to control arm movement.

global perspective

INTRODUCTION With the average cost of commercially available prosthetics ranging from $4,000 to $75,000 CAD, these essential devices are inaccessible to physically disabled people.1 Production expenses of the various prosthesis types required for each individual’s functional needs will continue increasing in coming years. This is one of the many factors that contributes to health inequities affecting those with physical disabilities in the Canadian healthcare system. Prosthesis coverage across the country is highly variable; many individuals are forced to rely on personal resources, fundraising, or contributions from non-governmental organizations (NGOs) to meet this basic healthcare need. The Institute for Research on Public Policy and Statistics Canada reports that disabled individuals are more likely to be unemployed, have lower median incomes, and be less likely to graduate with a university degree than those without a disability, further contributing to this disparity.2,3 As a team, we address the cost barrier of prostheses by establishing Brachïum: a humanitarian initiative focused on creating an affordable, 3D printed, open-source transradial prosthesis prototype that could eventually be distributed to marginalized communities to improve their quality of life.

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Ku I, Lee GK, Park CY, Lee J, Jeong E. Clinical outcomes of a low-cost singlechannel myoelectric-interface threedimensional hand prosthesis. Arch Plast Surg. 2019;46(4):303–10. Available from: doi:10.5999/aps.2018.01375. IRPP. Poverty dynamics among vulnerable groups in Canada [Internet]. Available from: https://irpp.org/research-studies/povertydynamics-among-vulnerable-groups-incanada/ [cited 2021 Sep 17]. Government of Canada SC. The association between skills and low income [Internet]. 2016. Available from: https:// www150.statcan.gc.ca/n1/pub/75006-x/2016001/article/14322-eng.htm BBDCD241ABPQ/1?accountid=13631 [cited 2021 Sep 17]. Koprnicky J, Šafka J, Ackermann M. Using of 3D printing technology in low cost prosthetics. MSF. 2018;919:199-206. Available from: doi:/10.4028/www. scientific.net/MSF.919.199. Argueta-Diaz V, Spitzfaden CJ, Basso D, Ayers HL. Evaluation of a low cost prosthetic hand controlled by surface EMG sensors and vibrotactile feedback. Int J Serv Learn Eng. 2018;13(2):69-78. Available from: doi:10.24908/ijsle.v13i2.12816. Advancer Technologies. 3-lead muscle/electromyography sensor for microcontroller applications [Internet]. 2016. Available from: https://github. com/AdvancerTechnologies/MyoWare_ MuscleSensor/raw/master/Documents/AT04-001.pdf [cited 2021 Sep 17]. O’Neill C. An advanced, low cost prosthetic arm. IEEE Sensors. 2014;4948. Available from: doi:10.1109/ ICSENS.2014.6985043. Mercer JA, Bezodis N, DeLion D, Zachry T, Rubley MD. EMG sensor location: Does it influence the ability to detect differences in muscle contraction conditions? J Electromyogr Kinesiol. 2006;16(2):198– 204. Available from: doi:10.1016/j. jelekin.2005.07.002. Schweitzer W, Thali MJ, Egger D. Casestudy of a user-driven prosthetic arm design: Bionic hand versus customized body-powered technology in a highly demanding work environment. J NeuroEng Rehabil. 2018;15(1):1. Available from: doi:10.1186/s12984-017-0340-0. Salem FHA, Mohamed KS, Mohamed SBK, El Gehani AA. The development of bodypowered prosthetic hand controlled by EMG signals using DSP processor with virtual prosthesis implementation. Conf Papers Sci. 2013;2013. Available from: doi:10.1155/2013/598945.

Our completed prototype is capable of flexion, extension, abduction, adduction, and circumduction in multiple planes of movement at the metacarpophalangeal, interphalangeal, and radiocarpal joints. Additionally, our prosthesis benefits from low latency and a lightweight design, at a combined weight of under two lbs. The total production cost of the prosthesis device was approximately $83 CAD, including all costs associated with the 3D prototyping and manufacturing of the device. With this in mind, in comparison to the high costs of other prosthesis devices, Brachïum introduces an economical and open-source alternative to modern-day assistive devices. CONCLUSION AND FUTURE STEPS With the rate of amputees projected to double by 2050, our open-source prostheses aim to address a crucial gap in the local and global healthcare industry.7 In the first phase of Brachïum’s future plan, the prototype will be piloted with design and assembly instructions uploaded to an open-source website to provide access to users worldwide. Additionally, Brachïum plans on medically licensing our prosthesis as a type two medical device through Health Canada to commence the distribution of the arm. Eventually, we intend to reduce the cost of production and delivery of our prostheses via fundraising campaigns in an effort to improve the quality of life for those in need. Our end goal is to turn Brachïum into a licensed international NGO focused on lowering the disparity in the healthcare

FIGURE 1. Isometric view of transradial prosthesis prototype (full forearm and hand)

FIGURE 2. Exploded, dorsal view of transradial prosthesis prototype (hand)

system through custom engineered, lowcost medical devices. This plan was created with careful consideration of the manufacturing process. When planning out future steps, it is critical for us to ensure functionality of the product while limiting size, weight, material cost, and production time. With these constraints, it is crucial to continuously research and develop creative modifications in future iterations of the prosthesis, especially as the global healthcare industry continues to evolve. ACKNOWLEDGEMENTS First and foremost, we would like to thank Dr. Jessica Murphy and Dr. Sharon Grad for their continued support of our ideas. We would also like to thank SMILE Canada for allowing us to volunteer, share, and gain inspiration from their vision. Finally, without the guidance of our friends and family, this project would be impossible to complete. We truly appreciate all of their continued support. REVIEWED BY: DR. SHARON GRAD Dr. Sharon Grad is an associate clinical professor in the Faculty of Health Sciences at McMaster University. Dr. Grad is also a medical specialist in the field of physical medicine and rehabilitation. Dr. Grad has published several papers pertaining to amputation research.

FIGURE 3. Exploded, palmar view of transradial prosthesis prototype (full forearm and hand)

INTERVIEW SPOTLIGHT

AN INSIGHT INTO PALLIATIVE PEDIATRIC CARE DALRAJ DHILLON 1 , ERIC ZHANG 1 , JAMES WANG1 , & MATTHEW LYNN 2

Bachelor of Health Sciences, Class of 2024, McMaster University Bachelor of Health Sciences, Class of 2022, McMaster University

WHAT IS YOUR BACKGROUND AND HOW DID YOU COME TO BE INVOLVED IN PEDIATRIC PALLIATIVE CARE? I went to medical school at McMaster after undergrad at University of Toronto. I entered my pediatric residency at Queen’s, [where I] became interested in both pediatric oncology and pediatric palliative care. I pursued a fellowship at the Hospital for Sick Children in pediatric hematology oncology […] and joined McMaster Children’s Hospital as a pediatric palliative care physician and oncologist in 2015. In 2018, I transferred over to [...] full time palliative care.

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Palliative care has two connotations: one is the palliative care specialist resources, and the second is the approach to care that brings a focus on quality of life, [which] takes a holistic family-centered approach and recognizes when mortality is a risk or impending. [The time] when pediatric palliative care becomes involved is dependent on the family

WHEN DO YOU TYPICALLY SEE PEDIATRIC PALLIATIVE CARE BECOMING INVOLVED IN A PATIENT’S CARE?

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Pediatric palliative care is often an overlooked field of medicine. As terminally ill children make up a small proportion of patients in Canada, a less robust network of resources is available to deliver end-of-life care for these patients. To gain a better insight into this field, we sat down with Dr. David Lysecki, a pediatric palliative care physician at McMaster Children’s Hospital. He is also the founder and head of the Quality of Life & Advanced Care program at McMaster Children’s Hospital and the Division of Pediatric Palliative Medicine in the McMaster University Department of Pediatrics.

introduction

DR. DAVID LYSECKI

interview spotlight table of contents | DECEMBER 2021 M E D U CATO R

scenario [and the] comfort of the patient, but often we do our best work when we are involved at diagnosis. [We] support a family from the time of diagnosis with decision making and symptom management all the way through to a child’s end-of-life or transition into the adult world. Our program can happen as early as in utero, where we do prenatal consults for a fetus that’s been diagnosed with a life-threatening or life-limiting condition and support the family through that journey in utero and after birth, whether the child lives for moments or for decades.

“You know, I gave this medication —is there any chance that medication could have contributed to the end of life?”

WHAT DOES THIS CARE TYPICALLY LOOK LIKE FOR THE PATIENT AND THEIR FAMILY?

WHAT DOES THE PEDIATRIC PALLIATIVE CARE TEAM LOOK LIKE?

Our first priority and our role is about the quality of life of the child [which] can be divided into two aspects. [Firstly,] there are negative things that take away quality of life or cause suffering, [which] we try our best to eliminate, [whether] they be physical, spiritual, social, emotional, or psychological. We also try to find ways to increase [...] quality of life and opportunities for joy [by] helping families navigate the system and [problem solve] so that school, extracurricular activities, wish trips, special family moments and experiences can [be fostered]. Our program here is called “quality of life and advanced care”, or “quality care”, and [so] the second aspect of that care is around care planning, advanced care, and peace. So while we look at quality of life now, in the moment, we also look at quality of life in the future and challenges that may be ahead of the child, as anticipated [by] their medical teams and the literature. [We] ideally help families plan for [these challenges through] symptom management plans, advanced care plans if the child is critically unwell, technologies to support the child’s life, or to accept the limitations on the child’s life and ensure their comfort as they pass away.

A fully functioning palliative care team should be able to support the biological [and] biophysical needs of families. It’s important to recognize that grief isn’t something that happens only after someone dies. Grief is something that occurs every day throughout that journey. So when we talk about a pediatric palliative care team, I would say that all families should have the care around them to support [their] needs, [including] physician support, nursing support, social work, a care coordinator, and child life specialists, particularly for other siblings, but also for the child themselves. [Teams can also involve] a spiritual care advisor, and someone doing bereavement support, who [don’t] necessarily have to be health care professionals. [A support] network will probably look different for every child and family based on their unique circumstances, but ideally, a specialist pediatric palliative care team has all of those roles [to fill in] when there are gaps in their network. Our team at McMaster Children’s Hospital has three full time positions: one full time care coordinator, a 0.6 FTE nurse practitioner with a focus on perinatal palliative care, and [...] a child life specialist to support our families.

There is a need for experience and expertise to guide the family through those last moments, hours, [or] weeks, and support them with compassion, with forewarning about what to expect, treating symptoms as they arise, preparing for the end of life and discussing things like organ and tissue donation, funeral planning, or an autopsy. We also play a role in bereavement follow-up to support families ensuring that they end up with a nest of support around them which may come from professionals [or] community members. I think it’s a really important role that we play, because if there are unanswered questions or uncertainties that the family holds [as] they go off into the bereavement world outside of the acute health care system, they may never be able to get the answers that they’re looking for in the community. [Therefore,] we try to bridge that gap [through transitional bereavement support. The parents might ask:] “Remind me, what were the findings on the MRI again? Why did we make this decision?”

[These] questions come up, even sometimes when deep down a parent knows that [it] isn’t the case, [but] sometimes they really need to hear that to stop those thoughts from running through their head. We really focus on those things, trying to make each day the best day it can be, by being prepared for the next day and acknowledg[ing] that our journey with them may be days or decades.

WHAT ARE SOME COMMON CHALLENGES THAT YOU’VE ENCOUNTERED DURING YOUR TIME WORKING IN PEDIATRIC PALLIATIVE CARE? First off, we all acknowledge that this isn’t fair, and it shouldn’t be the case where children don’t have the opportunity to grow up [and] live long, where parents outlive their children. It is unfortunately the reality that we have to accept and focus on the things we can control. However, grief can act as a major barrier to a therapeutic relationship, as families may be reluctant to have advanced care conversations or to think about the future for their child, often [from] fear and anxiety. Sometimes the right way to approach this is to first address the grief, normalize them and accept them, and support the family as we guide them through the decisions in advance with clear minds rather than then deciding in a crisis. [Another challenge involves] apprehension about communicating with children about their condition. [The literature shows] that when

informed in a developmentally appropriate manner and [provided] with support, most children cope and do better with the information rather than them being left to wonder. Children are very intuitive [and] pick up on signs from their parents [and] their medical team. [Lastly] I would also just highlight that our medical system isn’t particularly designed for the unique needs of these families in particular; our system is typically very jurisdictional-based. We’ve got all of these borders and boundaries and these families are often dependent on a pediatric tertiary centre, but often live in these small communities. They bounce back and forth, [making it] challenging for [family members] to see their family doctor and look after their own health, particularly because they inevitably prioritize the needs of their children. Our families or parents continuously sacrifice their own health and well-being. We are always striving to not only support our patients better, but [also their] families.

WHAT ARE SOME OF THE WAYS YOU CAN SEE THE FIELD EVOLVING TO BETTER SUPPORT PATIENTS AND THEIR FAMILIES? There has been great evolution in the field over the past 25 years. I would say that the most important area is [...] the topic of equity. Let’s take Vancouver [for example, which] opened the first children’s hospice

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I think the most common misconception is that palliative care is end-of-life care and [is incompatible] with chemotherapy, surgery, and life-prolonging interventions [like] intubation, ventilation, and ICU admissions. [In reality] there really isn’t an either/ or, [since] palliative care is a focus on quality of life. There is no reason that a child or an adult shouldn’t have access to high quality physical symptom management, emotional support, psychological support, [and] spiritual support during their hardest times, when we can recognize these needs [in advance]. Study after study comes out showing that palliative care is actually cost-effective; [that] by providing families with the right support at the right times, we can often mitigate unnecessary hospital admissions [or] procedures, when families are fully counseled about the possible outcomes of that procedure within the context of their goals of care. [Ultimately], I feel that the cost of palliative care is a very valuable area to invest in, because you get better care, typically for less money.

CHECK OUT THE VIDEO INTERVIEW WITH DR. DAVID LYSECKI!

introduction interview spotlight

HAVE YOU NOTICED OR ENCOUNTERED ANY COMMON MISCONCEPTIONS WHEN IT COMES TO PALLIATIVE CARE, PARTICULARLY IN THE NEONATAL AND PEDIATRIC SETTING?

in North America in 1995, that offers amazing support to children and their families around them in life and death grievances. From prenatal issues to over 18, that model exists in Vancouver, [but] there are a lot of places in Canada where there are next to no supports. [...] The other related challenge is that [...] children represent about 1% of all people requiring palliative care. [Therefore], outside of major cities, you’re [typically] not going to have the need for full scale interdisciplinary pediatric palliative care teams in every small community. There needs to be partnerships between strong [and] robust teams at tertiary hospitals and community providers to support people across the vast map of Canada. Virtual technologies have really improved our ability to do that. But areas where there [aren’t] robust interdisciplinary pediatric palliative care teams don’t have that skeleton backbone upon which to build a network of support across their catchment.

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letter from STACEY RITZ RITZ STACEY My heartiest congratulations on reaching these milestones —the 20th Anniversary and 40th Issue of The Meducator! It’s so exciting to witness the ongoing success and evolution of this enterprise over the years, giving undergraduate students an outlet for communicating findings and ideas in the health sciences, and as a showcase for the impressive work of many folks in the BHSc community, the FHS, and the larger McMaster community who are committed to the university’s mission to advance human and societal health and well-being.

Science is often framed as an objective, empirical approach to building knowledge, but I think the role of story-telling in science is often underappreciated. The narrative line that connects the initial research question, to the design of the study, data acquisition, analysis and visualization, interpretation, and ultimate conclusions is not simply a descriptive process. It is an interpretive one, emerging not only from the material conditions of the research and the data themselves, but also from the purposes, commitments, and goals of researchers. Unlike scientific and scholarly journal publications that can be somewhat opaque for non-specialist readers, publications like The Meducator take up a valuable role in the knowledge ecosystem, not only disseminating knowledge, but deliberately doing so in ways that are engaging, accessible, and enjoyable for readers from a range of backgrounds. I want to commend the editorial teams from across the years who have done such an exemplary job of not only sustaining The Meducator, but continually advancing it, and mentoring incoming contributors to ensure its continuing viability. Student-led initiatives can often have a short lifespan if the leaders of the project don’t pay attention to succession planning and mentorship. The Meducator has managed to avoid this fate not only thanks to collaborative and forward-thinking leadership —the evolution of the journal over the years shows that not only do you “think outside the box,” you are always thinking about how you can grow and expand the box, and rethink the nature of the box itself! As an enterprise, The Meducator embodies and manifests some of the most important values of the BHSc (Hons) Program itself —collaboration, growth, critical thinking, community-mindedness, information literacy, and always, ALWAYS asking questions. Congratulations on your big 2-0!

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Issue 40

Articles inside

LETTER FROM STACEY

DR. DAVID LYSECKI

GLOBAL PERSPECTIVE

MACHINE LEARNING

NEUROABSTRACTS

SPINAL SURGERY

MEDBULLETINS

PATHOPROFILE

MEDUSTORY

MEDPULSE

INTRODUCTION

VIEWPOINTS