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MARCH 2020 | ISSUE 37

ANIMAL-ASSOCIATED EXPLORING ANOTHER PIECE ACTIVITIES OF THE PUZZLE

J U S T I F Y I N G A M E N TA L H E A LT H P R O G RA M AT C OC M E NI VTA E A LTA HC RC IHTAI LCA L EL NRGEEVSI EI W N CHILDREN M M OA RS TB EI DR M UN E RL SHI TY: W I T H A U T I S M S P E CT R U M D I S O R D E R

HOMEOPATHY PHYSICIAN-ASSISTED DYING A C O N T R OV E R S I A L TO P I C I N H E A LT H CA R E A N E W O P T I O N I N CA N A D I A N E N D O F L I F E CA R E

INTERVIEW WITH DR. SHINING LIGHT ON BIOMEDICINE: CAITLIN MULLARKEY I N T E RV I E W W I T H D R.B R U C E WA I N M A N, D I R E CT O R O F P ROODGE RA VT IHREUESDE US CAT I N TI O HN EM R NMWIONRALNDATO M Y

WWW.MEDUCATOR.ORG


table of CONTENTS

M E D U C ATO R

| MARCH 2020

table of contents

MARCH 2020

I

ISSUE 37

01 INTRODUCTION

CRITICAL REVIEW

02 MEDPULSE

12 ALZHEIMER’S

04 MEDBULLETINS

16 ANIMAL-ASSISTED ACTIVITIES

06 PATHOPROFILE

OPINION

08 IWCH ABSTRACTS

20 HOMEOPATHY

10 FORUMSPACE

22 INTERVIEW SPOTLIGHT 25 CONTRIBUTORS

COVER ARTIST WENDY ZHANG TOC ARTIST BEVERLY NG


dear reader,

INTRODUCTION ISSUE 37

Welcome to Issue 37 of The Meducator! From transnational research collaborations to coordinated responses to global crises, the field of health sciences has seen dramatic globalization in recent decades. Although this interconnectivity has brought about tremendous improvements to human health, it has also highlighted the cultural, ideological, and political divisions that hinder collaboration on this challenge that implicates us all. As conveyed by Wendy Zhang’s vibrant cover illustration, we ought to challenge our perceptions and biases toward others and appreciate our deep-rooted commonalities when tackling matters of health. At a time when the global community is gripped by threats of a pandemic, unity is crucial at both the level of policymakers and citizens to combat disease as well as social division. As you peruse the issue, we hope you are inspired to consider your own role in overcoming these barriers. Editors Aaron and Hargun start off Issue 37 by highlighting global health-related developments in Medpulse. Of special importance is the coronavirus outbreak in China, which has raised concern and elicited precautionary action on an international level. Dr. Caitlyn Mullarkey, an Assistant Professor at McMaster University whose research interests revolve around improving influenza vaccines, shares her opinion on the outbreak in this issue’s Interview Spotlight. Following MedPulse, editors Daniel and Shadi outline the genetics of valvular heart disease and explore novel treatments to influenza, hepatocellular carcinoma, and glaucoma. Editors Meera and Rohan then discuss the etiology, pathophysiology, and therapeutic advances pertaining to non-small cell lung cancers, a prevalent group of lung cancers that are relatively insensitive to chemotherapy.

introduction

In Issue 37, The Meducator continues its collaboration with the McMaster Health Forum as well as The International Women & Children’s Health Conference (IWCH). The ForumSpace article describes barriers and challenges in strengthening food security at McMaster, while the IWCH abstracts explore brain potential-facilitated speech comprehension, knowledge translation strategies in childhood disability, and maternal experiences of racialized women. We are excited to feature two Critical Reviews and an Opinion column. In his critical review on Alzheimer’s disease, Jake Colautti examines the pathophysiological roles of tau- and beta-amyloid and discusses treatment approaches that target these proteins. Terry Li and Leland Cheung part from basic science to evaluate the benefits and risks of implementing animal-assisted therapy for students at McMaster University. Finally, Hannah Silverman scrutinizes homeopathy’s place in modern medicine.

Sincerely,

JIM XIE

| MARCH 2020

EDWARD CUI

Bachelor of Health Sciences (Honours) Class of 2021

M E D U C ATO R

This issue was the product of close collaboration between all 46 members of our talented and hardworking staff. We cannot express enough appreciation for our hardworking team, the supportive McMaster community, and you, our engaged readers. We would like to give special thanks to our team leaders, Adrian, Annisa, Zahra, Daniel, Karishma, Kevin, Saba, and Suffia for their incredible student leadership. We would also like to give a warm welcome to the incoming Editors-in-Chief, Zahra Abdallah and Kevin Zhao. We are confident that they will continue to advance The Meducator as a platform for academic dissemination and dialogue in the health sciences.

Bachelor of Health Sciences (Honours) Class of 2020

1


MEDPULSE

WRITTEN BY: Aaron Wen & Hargun Kaur ARTIST: Michelle Chen

CRISPR Allows for Gene-Edited Food Products (January 2020, Canada)

The last major advance in genetically engineered food products occurred with the introduction of genetically modified organisms (GMO). Despite the World Health Organization declaring GMO foods to be safe for consumption, only 37% of Canadians believe that GMOs were safe to consume. Scientists are looking to introduce genetically edited products into the Canadian food system using CRISPR gene-editing technology. Unlike GMOs, however, gene-editing tools will disable genes rather than adding foreign genes to an existing genome. Although gene-edited foods face fewer regulatory hurdles from Health Canada and might alleviate public concern, critics argue that there should be close monitoring for health complications resulting from the consumption of these products. It will be interesting to see how Canadian regulatory organizations will manage the introduction of these products.

Microsoft launches AI for Health Initiative (January 2020, USA)

In January, Microsoft unveiled the AI for Health program, a five-year project to help healthcare organizations improve global health through leveraging the potential of artificial intelligence and machine learning. The $40 million program is an initiative that aims to support the efforts of select non-profits and healthcare innovators by providing them with AI tools and help from Microsoft’s leading data scientists to integrate these technologies into their work. Some of the initiative’s goals include working with organizations to improve the diagnosis of sudden infant death syndrome, tackling leprosy, increasing the usage of AI in diabetic retinopathy diagnostics, and improving cross-organizational data access.

References can be found at www.meducator.org

South Africa Stops Low-Cost Benefit Options for Healthcare (December 2019, South Africa)

The South African Council for Medical Schemes (CMS) plans to prohibit low-cost benefit options for healthcare, with the hope to ensure universal access to healthcare. The “low-cost benefit option” (LCBO) was initially created to provide healthcare options to the financially disadvantaged. However, the recent economic downturn in South Africa has made the LCBO seem unsustainable. Since then, the CMS has been working to create a new minimum benefits package as an alternative to the LCBO. No further details have been outlined about this new plan.


Concerns Over The Effects of Brexit on Healthcare (January 2020, United Kingdom)

With the United Kingdom (UK) formally leaving the European Union (EU) in 2020, there have been concerns about the emigration of foreign-born UK medical professionals and potential shortages in medical supplies. Tackling global outbreaks could also become harder if the UK loses access the EU’s early warning systems. As these outbreaks pose crossborder health threats, exiting the EU could affect global health.

Coronavirus Outbreak in China Surges Past 80,000 Cases Worldwide (February 2020, China) The 2019 coronavirus (COVID-19) has now reached over 80,000 cases worldwide, with Chinese health authorities having reported over 70,000 individuals in China alone. Multiple countries have suspended international transportation to heavily infected countries. The novel coronavirus shares 79.5% similarity to Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and enters through the same entry receptor: the ACE2 receptor. The National Institute of Health has begun to test an antiviral drug, remdesvir, as a possible treatment for COVID-19.

Surge in PTSD and Depression Symptoms Following Social Unrest in Hong Kong (February 2020, Hong Kong)

Studies have reported that almost one in three adults in Hong Kong (HK) have reported symptoms of post-traumatic stress disorder and one in ten experienced symptoms of depression. For many residents in HK, it is seen as shameful to have a mental illness. Costs of therapy in HK frequently exceed $300 USD per session. Therapy is often inaccessible even for those who actively seek it.

Arab Health 2020 Conference Promotes International Collaboration (January 2020, UAE)

Several Irish healthcare companies are preparing to showcase their world-class healthcare expertise and cutting edge solutions at Arab Health 2020, the largest healthcare exhibition and conference in the Middle East. The conference has also led to successful international commercial partnerships. The Irish digital health company, myPatientSpace, has partnered with the Neuro Spinal Hospital in Dubai to offer personalized digital health companions to patients. Integration of mobile applications into hospital care will reduce wait times and simplify appointment cancellations.

Researchers Predict Global Spread of Dengue (December 2019, Australia) Researchers have created a network model that predicts the monthly number of dengueinfected passengers at airports across the world. After tracking international air travel, the research team was able to calculate both the probability of passengers on any flight being infected with dengue and the probability of being infected with dengue at any travel destination. It is estimated that dengue causes around 50 to 100 million symptomatic infections per year, driven mostly by international air travel. However, under-reporting has led to a lack of awareness and diagnosis, making dengue an even more pressing issue to non-endemic countries.


MEDBULLETIN VALVULAR HEART DISEASE

medbulletin

UNDERSTANDING THE GENETIC COMPONENTS DA NIE L R AYNE R

D ANIEL R AYNER

Over the last couple of decades, only two classes of drugs have been approved for use in patients with influenza: M2 ionchannel inhibitors (e.g., rimantadine) and neuraminidase inhibitors (e.g., oseltamivir).1 However, resistance to these drugs has been increasing, with circulating influenza strains now predominantly resistant to M2 ion-channel inhibitors.2 Even resistance towards the current frontline for influenza treatment, neuraminidase inhibitors, is a health concern, as demonstrated by the oseltamivir-resistant influenza A(H1N1) pandemic during the 2008-2009 season.2,3

Occurring in approximately 2.5% of the general population, valvular heart disease (VHD) is a group of cardiovascular diseases involving the damage or defect of one of the four heart valves: pulmonary, aortic, tricuspid, and mitral.1,2 Despite its high frequency, therapeutic approaches for VHD are extremely limited, with surgery being the primary treatment for valve replacement or repair.3,4 Presently, only a small number of genes have been identified as monogenic causes of nonsyndromic VHD.5-7

Approved by the U.S. Food and Drug Administration (FDA) in October 2018, baloxavir marboxil (BM) is a novel anti-influenza drug that targets the RNA-dependent RNA polymerase (RdRp), the heterotrimeric enzyme responsible for transcription of viral mRNA.2,4 Specifically, BM inhibits the polymerase acidic (PA) protein, the subunit responsible for cleaving the 5’ end of host pre-mRNA, which is subsequently used as a primer for viral mRNA production.5 However, BM is not exempt from resistance mutations —I38T/M/F point mutations in the PA subunit were observed in 2.2% and 9.7% of BM recipients in phase II and phase III clinical trials, respectively.2 These substitutions were found to reduce the viral strains' susceptibility to BM by more than a factor of ten in those infected with influenza A(H1N1).2

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The presence of a new anti-influenza drug on the market may allow for the use of combination therapies for patients with complicated influenza infections.6 The combination of BM and oseltamivir was more effective than each monotherapy in treating influenza A in murine models, and human combination studies are currently underway.6,7

4

1.

Mushtaq A. Baloxavir: Game-changer or much ado about nothing? Lancet Respir Med. 2018;6(12):903-4. Available from: doi:10.1016/S2213-2600(18)30469-7.

2.

Hayden FG, Sugaya N, Hirotsu N, Lee N, de Jong MD, Hurt AC, et al. Baloxavir marboxil for uncomplicated influenza in adults and adolescents. N Engl J Med. 2018;379(10):913-23. Available from: doi:10.1056/NEJMoa1716197.

3.

Lee N, Hurt A. Neuraminidase inhibitor resistance in influenza: A clinical perspective. Curr Opin Infect Dis. 31(6):520-6. Available from: doi:10.1097/QCO.0000000000000498.

4.

Yoshino R, Yasuo N, Sekijima M. Molecular dynamics simulation reveals the mechanism by which the influenza cap-dependent endonuclease acquires resistance against baloxavir marboxil. Sci Rep. 2019;9(1):17464. Available from: doi:10.1038/ s41598-019-53945-1.

5.

O’Hanlon R, Shaw ML. Baloxavir marboxil: The new influenza drug on the market. Curr Opin Virol. 2019;35:14-8. Available from: doi:10.1016/j.coviro.2019.01.006.

6.

Fukao K, Noshi T, Yamamoto A, Kitano M, Ando Y, Noda T, et al. Combination treatment with the cap-dependent endonuclease inhibitor baloxavir marboxil and a neuraminidase inhibitor in a mouse model of influenza A virus infection. J Antimicrob Chemother. 2019;74(3):654-62. Available from: doi:10.1093/jac/dky462.

7.

Fujita J. Introducing the new anti-influenza drug, baloxavir marboxil. Respir Investig. 2020;58(1):1-3. Available from: doi:10.1016/j.resinv.2019.10.005.

Recently, research by Wünnemann and colleagues has led to the discovery of another monogenic VHD gene, ADAMTS19, which encodes an enzyme responsible for extracellular matrix modelling activity.8,9 Using whole-exome sequencing on two consanguineous families with prevalent early-onset VHD, researchers found that affected individuals had homozygous, loss-of-function alleles in ADAMTS19.8 Supplemented with an Adamts19 knockout murine model, Wünnemann and colleagues hypothesize that loss of Adamts19 interferes with shear stress signalling in the endothelial cells of the aortic valve, inducing upregulation of the transcription factor Klf2.8 Klf2 regulates Wnt9b, the ligand responsible for the remodeling of cardiac cushions into mature heart valves.10 This dysregulation of Klf2 leads to VHD through extracellular matrix disorganization, as well as increased cellularity and proteoglycan deposition in the valves.8 Improving our understanding of the genetic components, molecular pathways, and cellular mediators involved in the development of the disease may aid in treating VHD. Not only can it improve genetic screening for high-risk individuals, but it also opens up an avenue for potential VHD pharmacological therapies, which can delay or halt disease progression.11 1.

Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: A population-based study. Lancet. 2006;368(9540):1005-11. Available from: doi:10.1016/S0140-6736(06)69208-8. Zeng YI, Sun R, Li X, Liu M, Chen S, Zhang P. Pathophysiology of valvular heart disease. Exp Ther Med. 2016;11(4):1184-8. Available from: doi:10.3892/etm.2016.3048. 3. Itagaki S, Adams DH, Anyanwu AC. Triggers for surgical referral in degenerative mitral valve regurgitation. Circ J. 2013;77(1):2834. Available from: doi:10.1253/circj.cj-12-0972. 4. Maeda K, Kuratani T, Mizote I, Shimamura K, Takeda Y, Torikai K, et al. Early experiences of transcatheter aortic valve replacement in Japan. Circ J. 2013;77(2):359-62. Available from: doi:10.1253/circj.cj-12-0650. 5. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;437(7056):270-4. Available from: doi:10.1038/nature03940. 6. Ta-Shma A, Zhang K, Salimova E, Zernecke A, Sieiro-Mosti D, Stegner D, et al. Congenital valvular defects associated with deleterious mutations in the PLD1 gene. J Med Genet. 2017;54(4):278-86. Available from: doi:10.1136/jmedgenet-2016-104259. 7. Gould RA, Aziz H, Woods CE, Seman-Senderos MA, Sparks E, Preuss C, et al. ROBO4 variants predispose individuals to bicuspid aortic valve and thoracic aortic aneurysm. Nat Genet. 2019;51(1):42-50. Available from: doi:10.1038/s41588-018-0265-y. 8. Wünnemann F, Ta-Shma A, Preuss C, Leclerc S, van Vliet PP, Oneglia A, et al. Loss of ADAMTS19 causes progressive non-syndromic heart valve disease. Nat Genet. 2020;52(1):40-7. Available from: doi:10.1038/s41588-019-0536-2. 9. Brunet FG, Fraser FW, Binder MJ, Smith AD, Kintakas C, Dancevic CM, et al. The evolutionary conservation of the A disintegrin-like and metalloproteinase domain with thrombospondin-1 motif metzincins across vertebrate species and their expression in teleost zebrafish. BMC Evol Biol. 2015;15:22. Available from: doi:10.1186/s12862-015-0281-9. 10. Goddard LM, Duchemin AL, Ramalingan H, Wu B, Chen M, Bamezai S, et al. Hemodynamic forces sculpt developing heart valves through a KLF2-WNT9B paracrine signaling axis. Dev Cell. 2017;43(3):274-89.e5. Available from: doi:10.1016/j. devcel.2017.09.023. 11. Padang R, Bagnall RD, Semsarian C. Genetic basis of familial valvular heart disease. Circ Cardiovasc Genet. 2012;5(5):569-80. Available from: doi:10.1161/CIRCGENETICS.112.962894. 2.


SH AD I SADEGHI AN

The Farnesoid X Receptor (FXR) is a nuclear receptor expressed in the liver that is known to maintain bile acid homeostasis.1 Recently, FXR has also been implicated in hepatocellular carcinoma (HCC), acting as a tumour suppressor.1 This effect is dependent on the activation of the IL-6/Jak-2/STAT-3 inflammatory pathway —a molecular cascade that drives tumour formation in many types of cancer.1,2 It has also been established that the activation of STAT-3, a substrate in the inflammatory pathway, upregulates the expression of genes that further induce cell division and inhibit apoptosis.2,3 Recently, a growing body of evidence has suggested that FXR deficiency causes STAT-3 activation, resulting in cell proliferation.2

Glaucoma is the second leading cause of irreversible blindness worldwide.1 This condition involves the degeneration of retinal ganglion cells and is characterized by elevated intraocular pressure (IOP).1 The problems arising in glaucoma originate in the anterior chamber of the eye, where aqueous humour (AH) drainage via the trabecular meshwork (TM) is impeded.1 Since the damage to retinal ganglion cells in glaucoma is irreversible, the goal of treatment is to preserve remaining visual acuity by mitigating high IOP.2

Under FXR-deficient conditions (commonly observed in HCC) the STAT-3 pathway is activated by an increase in the expression of an inflammatory cytokine, IL-1β, which subsequently increases levels of IL-6. The reason for this upregulation is the increase in bile acid concentration resulting from FXR deficiency.4 This bile acid build-up induces cholestasis and hepatic inflammation, thus recruiting various inflammatory cytokines. As IL-6 binds to its receptor, the IL-6/Jak-2/STAT-3 pathway is activated. As a result, newly formed STAT-3 homodimers are able to activate downstream genes responsible for hepatic carcinogenesis.2 Various studies have demonstrated that FXR ligands cause an upregulation of FXR expression and reduce the cholestasis that initiates this carcinogenic cycle.3 Cell cycle analyses have shown that FXR ligation increases the number of HepG2 (HCC) cells at the cell cycle arrest phase, and decreases the cells in the synthesis phase.3,5 All of this demonstrates the ability of FXR to mitigate uncontrolled cell growth in the liver.3

It was first noticed in the 1990s that the pharmacological manipulation of the cytoskeleton of TM cells decreased aqueous humor outflow resistance, thus significantly reducing IOP.2 Rho kinase inhibitors play a key role in the rigidity of the cytoskeleton of TM cells and thus have been of particular pharmalogic importance, as they influence AH drainage efficiency.2,3 The GTPase Rho, when bound to guanosine triphosphate (GTP), is able to activate Rho kinase.3 Rho kinase is then able to undergo a series of biological reactions that change the properties of the cytoskeleton, which dictates the cell's morphology.4 By this mechanism, the protein increases the rigidity of the TM cells, affecting their mobility.3,4 At the same time, Rho kinase inhibitors are able to modulate other morphological issues in TM cells including changes in the extracellular matrix and mitigate irregular contractile forces.4 Overall, such changes allow for imparoved AH outflow, lowering IOP.4 A randomized, placebo-controlled study demonstrated that administration of 0.25% of a Rho-kinase inhibitor twice per day reduced IOP by 28%, or around 6.8 mmHg.5 Various other studies have had similar findings, demonstrating the promise of this practice. 1.

Weinreb R, Aung T, Medeiros F. The pathophysiology and treatment of glaucoma. JAMA. 2014;311(18):1901. Available from: doi:10.1001/jama.2014.3192.

2.

Attia Y, Tawfiq R, Ali A, Elmazar M. The FXR agonist, obeticholic acid, suppresses HCC proliferation & metastasis: Role of IL-6/ STAT3 signalling pathway. Sci Rep. 2017;(12502). Available from: doi:10.1038/s41598-017-12629-4.

2.

Inoue K. Managing adverse effects of glaucoma medications. Clin Ophthalmol. 2014:903. Available from: doi:10.2147/OPTH. S44708.

3.

Grohmann M, Wiede F, Dodd G, Gurzov E, Ooi G, Butt T, et al. Obesity drives STAT-1-dependent NASH and STAT-3-dependent HCC. Cell. 2018;175(5):1289-1306.e20. Available from: doi:10.1016/j.cell.2018.09.053.

3.

Tanna A, Johnson M. Rho kinase inhibitors as a novel treatment for glaucoma and ocular hypertension. Ophthalmology. 2018;125(11):1741-56. Available from: doi:10.1016/j.ophtha.2018.04.040

4.

Verbeke L, Mannaerts I, Schierwagen R, Govaere O, Klein S, Vander Elst I et al. FXR agonist obeticholic acid reduces hepatic inflammation and fibrosis in a rat model of toxic cirrhosis. Sci Rep. 2016;6:33453. Available from: doi:10.1038/srep33453

4.

5.

5. Staropoli J. Tumorigenesis and neurodegeneration: two sides of the same coin? BioEssays. 2008;30(8):719-727. Available from: doi:10.1002/bies.20784.

Moshirfar M, Parker L, Birdsong OC, Ronquillo YC, Hofstedt D, Shah TJ, et al. Use of rho kinase inhibitors in ophthalmology: A review of the literature. Med Hypothesis Discov Innov Ophthalmol. 2018;7(3):101–11. Available from: doi:https://www.ncbi. nlm.nih.gov/pubmed/30386798 [cited 2020 Feb 24].

5.

Williams RD, Novack GD, van Haarlem T, Kopczynski C, AR-12286 Phase 2A Study Group. Ocular hypotensive effect of the Rho kinase inhibitor AR-12286 in patients with glaucoma and ocular hypertension. Am J Ophthalmol. 2011;152(5):834-41.e1. Available from: doi:10.1016/j.ajo.2011.04.012.

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Bowlus C. Obeticholic acid for the treatment of primary biliary cholangitis in adult patients: Clinical utility and patient selection. Hepat Med. 2016;2016(8):89-95. Available from: doi:10.2147/HMER.S91709.

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S H A D I S A D E GHIAN

5


MUTATIONAL LANDSCAPE INFORMS THE TREATMENT OF

pathoprofile

Non-Small Cell Lung Cancer 1.

Duma N, Santana-Davila R, Molina J. Nonsmall cell lung cancer: Epidemiology, screening, diagnosis, and treatment. Mayo Clin Proc. 2019;94(8):1623-40. Available from: doi:10.1016/j.mayocp.2019.01.013.

2.

Molina J, Yang P, Cassivi S, Schild S, Adjei A. Non-small cell lung cancer: Epidemiology, risk factors, treatment, and survivorship. Mayo Clin Proc. 2008;83(5):584-94. Available from: doi:10.4065/83.5.584.

3.

Chen Z, Fillmore C, Hammerman P, Kim C, Wong K. Non-small-cell lung cancers: A heterogeneous set of diseases. Nat Rev Cancer. 2014;14(8):535-46.

4.

Santos G, Shepherd F, Tsao M. EGFR mutations and lung cancer. Annu Rev PatholMech. 2011;6(1):49-69. Available from: doi:10.1038/nrc3775.

5.

Ho C, Tong KM, Ramsden K, Ionescu DN, Laskin J. Histologic classification of nonsmall-cell lung cancer over time: Reducing the rates of not-otherwise-specified. Curr Oncol Rep. 2015 Jun;22(3):e164. Available from: doi:10.3747/co.22.2339.

6.

Provencio M, Isla D, Sรกnchez A, Cantos D. Inoperable stage III non-small cell lung cancer: Current treatment and role of vinorelbine. J Thorac Dis. 2011;3(3):197-204. Available from: doi:10.3978/j.issn.2072-1439.2011.01.02.

7.

Nangia V, Siddiqui F, Caenepeel S, Timonina D, Bilton S, Phan N, et al. Exploiting MCL1 dependency with combination MEK MCL1 inhibitors leads to induction of apoptosis and tumor regression in KRAS-mutant non-small cell lung cancer. Cancer Discov. 2018;8(12):1598613. Available from: doi:10.1158/21598290.CD-18-0277.

8.

Yoda S, Dagogo-Jack I, Hata A. Targeting oncogenic drivers in lung cancer: Recent progress, current challenges and future opportunities. Pharmacol Ther. 2019;193:2030. Available from: doi:10.1016/j. pharmthera.2018.08.007.

9.

Reck M, Heigener D, Mok T, Soria J, Rabe K. Management of non-small-cell lung cancer: Recent developments. Lancet. 2013;382(9893):709-19. Available from: doi:10.1016/S0140-6736(13)61502-0.

10. Ettinger D, Wood D, Aisner DL, Akerley W, Bauman J, Chirieac L, et al. Non-small cell lung cancer, version 5. 2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15(4):504-35. Available from: doi:10.6004/jnccn.2017.0050. 11. Liu X, Conner H, Kobayashi T, Kim H, Wen F, Abe S, et al. Cigarette smoke extract induces DNA damage but not apoptosis in human bronchial epithelial cells. Am J Resp Cell Mol. 2005;33(2):121-9. Available from: doi:10.1165/rcmb.2003-0341OC. 12. Do H, Wong N, Murone C, John T, Solomon B, Mitchell P, et al. A critical re-assessment of DNA repair gene promoter methylation in nonsmall cell lung carcinoma. Sci Rep. 2014;4(1). Available from: doi:10.1038/srep04186. 13. Agrelo R, Cheng W, Setien F, Ropero S, Espada J, Fraga M, et al. Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proc Natl Acad Sci USA. 2006;103(23):8822-7. Available from: doi:10.1073/pnas.0600645103. 14. Safar AM. Methylation profiling of archived non-small cell lung cancer: A promising prognostic system. Clin Cancer Res. 2005;11(12):4400-5. Available from: doi:10.1158/1078-0432.CCR-04-2378.

M A RC H 2020

15. Lee M, Tseng R, Hsu H, Chen J, Tzao C, Ho W, et al. Epigenetic inactivation of the chromosomal stability control genes BRCA1, BRCA2, and XRCC5 in non-small cell lung cancer. Clin Cancer Res. 2007;13(3):832-8. Available from: doi:10.1158/1078-0432.CCR-05-2694.

M E D U CATO R

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16. Johns Hopkins Medicine. Lung Cancer Types [Internet]. Available from: https://www.hopkinsmedicine.org/health/conditions-and-diseases/lung-cancer/lung-cancer-types [cited 2020 Feb 29].

6

17. Subramanian J, Govindan R. Lung cancer in never smokers: A review. J Clin Oncol. 2007;25(5):561-70. Available from: doi:10.1200/JCO.2006.06.8015. 18. Yale Medicine. Lung Cancer in Nonsmokers [Internet]. Available from: https://www.yalemedicine.org/conditions/lung-cancer-in-nonsmokers/ [cited 2020 Feb 29].

8

INTRODUCTION

Lung cancers are the leading cause of cancer deaths worldwide, with non-small cell lung cancers (NSCLC) accounting for approximately 85% of all lung cancers.1,2 Although they vary in clinical presentations, NSCLCs are best characterized as a group of cancers that share cellular and molecular origins.3 Importantly, NSCLCs differ histologically from small cell lung cancers (SCLCs) and are relatively insensitive to chemotherapy.4,5 Approximately 40% of patients with NSCLC present with advanced-stage cancer, for which the five-year survival rate is approximately 2%.6 Recent advances have begun to unravel the biology of NSCLCs. This has led to the development of novel targeted agents that exhibit greater efficacy, compared to chemotherapy alone, in patients with certain genetic mutations.2,3,7-9

ETIOLOGY AND CLASSIFICATION

Smoking is by far the leading risk factor for lung cancer, and accounts for more than 85% of all lung cancer related deaths.10 Cigarette smoke contains more than 6,000 components, many of which lead to DNA damage.11 Though most DNA damage is repairable, leftover unrepaired DNA due to epigenetic silencing of repair genes are hypothesized to lead to the development of NSCLC. To date, nine DNA repair genes have been found to be repressed by promoter hypermethylation, which has found to be increased in NSCLCs.12-15 The two predominant NSCLC histological phenotypes are adenocarcinoma (ADC; ~50%) and squamous cell carcinoma (SCC; ~40%). In general, ADCs develop in the distal airways, whereas SCCs develop in the proximal airway structures.3 ADC is the most common type of lung cancer in the United States and is the most frequently occurring type of lung cancer in nonsmokers.16-18 SCC is one of the few types of lung cancer more common in men than in women, and is more closely correlated with a history of tobacco use than other lung cancers.18,19 Regardless of histological phenotype, there are two genetic markers that are routinely profiled in NSCLC tumours to guide treatment decision making: mutations within the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) genes.20 EGFR and ALK mutations, which lead to the constitutive expression and overproduction of their encoded proteins, are mutually exclusive and are observed in about 15% and 7% of all NSCLC tumours, respectively. Despite these low frequencies, research suggests that these mutations are predictive of responses to targeted therapeutics.22

THERAPEUTIC ADVANCES

The discovery of EGFR and its ligand won the 1986 Nobel Prize in Medicine.22 Overexpression of EGFR and other receptor tyrosine kinases is associated with the development of tumours.4 Expressed in >60% of NSCLCs, EGFR is a gatekeeper to several downstream signalling molecules which play a crucial role in anti-apoptotic functions that promote cell survival.4,22,23 In 2004, two groups led by led by Lynch and Paez revolutionized the field of lung cancer research through reporting the discovery of important mutations in the tyrosine kinase (TK) domain of the EGFR gene in NSCLCs.4,24-27 They found that NSCLC cells harbouring select mutations on exons 18 and 21 of EGFR display constitutive receptor activation and dependency on the EGFR signalling pathway for survival.4,26,27 This discovery allowed scientists to postulate that antagonizing the receptor could reduce the rates of tumour progression.3,9,26 This hypothesis was confirmed after the administration of tyrosine kinase inhibitors (TKIs) was found to be effective in treating patients whose tumours had sensitizing mutations.9,28,29 Two TKIs, erlotinib and gefitinib, are currently approved for the treatment of NSCLC in Canada.30 With the development of these inhibitors, patients with these specific mutations can now live up to 3-4 years compared to 1 year for those without targetable mutations.31 The remarkable success of EGFR TKIs has highlighted the importance of identifying genotypespecific subsets of patients so that NSCLC treatment may be tailored to them.3,4,25,26 The recent identification of the fusion gene between echinoderm microtubule-associated protein-like 4


Pathoprofile doi:10.35493/medu.37.6

AUTHORS: Rohan Aananth & Meera Chopra ARTIST: Esra Rakab

(EML4) and ALK genes has expanded the list of targetable mutations in lung cancer.21,26,32 The EML4-ALK fusion gene is a result of a translocation mutation that occurs in a subset of ADCs which, similar to the EGFR mutation, causes constitutive activation of ALK kinase and aberrant downstream signalling.4,21,28 Though clinical trials are ongoing, two ALK inhibitors, ceritinib and crizotinib, have been approved for the treatment of ALK-positive NSCLC in Canada.33

FUTURE PERSPECTIVES

20. My Cancer Genome. Non-Small Cell Lung Carcinoma. [Internet]. Available from: https:// www.mycancergenome.org/content/disease/ non-small-cell-lung-carcinoma/ [cited 2020 Feb 29]. 21. Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561-6. Available from: doi:10.1038/nature05945. 22. Herbst R. Review of epidermal growth factor receptor biology. Int J Radiat. 2004;59(2):S21-6. Available from: doi:10.1016/j.ijrobp.2003.11.041. 23. Mccann A, Smyth P, Cogo F, Mcdaid WJ, Jiang L, Lin J, et al. USP17 is required for trafficking and oncogenic signaling of mutant EGFR in NSCLC cells. Cell Commun Signal. 2018;16(1). Available from: doi:10.1186/ s12964-018-0291-5. 24. Paez J. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-500. 25. Lynch T, Bell D, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan B, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of nonsmall-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-39. Available from: doi:10.1056/NEJMoa040938. 26. Kim C, Giaccone G. Precision oncology in non-small-cell lung cancer: Opportunities and challenges. Nat Rev Clin Oncol. 2018;15(6):348-9. Available from: doi:10.1038/s41571-018-0008-0. 27. Hata A, Niederst M, Archibald H, Gomez-Caraballo M, Siddiqui F, Mulvey H, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med. 2016;22(3):2629. Available from: doi:10.1038/nm.4040. 28. Medscape. Non-Small Cell Lung Cancer (NSCLC) [Internet]. Available from: https://emedicine.medscape.com/article/279960-overview [cited 2020 Feb 29].

pathoprofile

Although these discoveries have altered the public perception that little or no progress has been made in lung cancer research, many challenges lie ahead.4 One major challenge is the management of patients who acquire resistance to EGFR or ALK inhibitors after months or years of treatment.34,35 Epithelial-to-mesenchymal transition (EMT) is a process that commonly occurs in cancer whereby epithelial cells acquire stem cell-like properties.34,35 In NSCLCs, drugtolerant persister cells may undergo EMT, allowing them to develop greater resistance to TKIs and become more metastatic.27,34,36 The efficacy of combination drug therapies that also target the EMT is currently being investigated.34,36 Another challenge is the feasibility of testing the genetics of all patients with NSCLC for EGFR and ALK mutations to determine their course of treatment, especially given the low frequency of the alleles.9,28 Placing NSCLC patients on standard of care platinum-based chemotherapy without genetic testing is straightforward.9,29 However, facilitating broad, rapid, and high-quality diagnostic testing that is affordable for all patients with NSCLC is difficult without access to highly specialized cancer centres.4 Despite the new challenges, these landmark discoveries have given hope that more effective ways of managing NSCLCs are on the horizon.

19. Kenfield S, Wei E, Stampfer M, Rosner B, Colditz G. Comparison of aspects of smoking among the four histological types of lung cancer. Tob Control. 2008;17(3):198-204. Available from: doi:10.1136/tc.2007.022582.

29. Herbst R, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553(7689):446-54. Available from: doi:10.1038/nature25183. 30. Hirsh V, Melosky B, Goss G, Morris D, Morzycki W. A personalized approach to treatment: use of EGFR tyrosine kinase inhibitors for the treatment of non-small-cell lung cancer in Canada. Curr Oncol. 2012;19(2):78-90. Available from: doi:10.3747/co.19.1018. 31. Kris MG. How today’s developments in the treatment of non-small cell lung cancer will change tomorrow’s standards of care. Oncologist. 2005;10(2):23-9. Available from: doi:10.1634/theoncologist.10-90002-234. 32. Inamura K, Takeuchi K, Togashi Y, Hatano S, Ninomiya H, Motoi N, et al. EML4-ALK lung cancers are characterized by rare other mutations, a TTF-1 cell lineage, an acinar histology, and young onset. Mod Pathol. 2009;22(4):508-15. Available from: doi:10.1038/modpathol.2009.2.

34. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3’ kinase/AKT pathways. Oncogene. 2005;24(50):7443-54. Available from: doi:10.1038/sj.onc.1209091.

William Maich is pursuing a master’s degree in biochemistry at McMaster University. Supervised by Dr. Sheila Singh, his research surrounds immunotherapy for glioblastoma.

36. Raoof S, Ruddy D, Timonia D, Damon L, Engelman J, Hata A, et al. Targeting FGFR to overcome EMT-related resistance in EGFR-mutated non-small cell lung cancer. Oncogene. 2019;38(37):6399-6413. Available from: doi:10.1038/s41388-019-0887-2.

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REVIEWED BY: WILLIAM MAICH

35. Zhou P, Li B, Liu F, Zhang M, Wang Q, Liu Y, et al. The epithelial to mesenchymal transition (EMT) and cancer stem cells: implication for treatment resistance in pancreatic cancer. Mol Cancer. 2017;16(1). Available from: doi:10.1186/s12943-017-0624-9.

M E D U CATO R

33. Rothenstein J, Chooback N. ALK inhibitors, resistance development, clinical trials. Curr Oncol. 2018;25(1):59-67. Available from: doi:10.3747/co.25.3760.

EDITED BY: ALBERT STANESCU & JAMES YU

7


IWCH ABSTRACTS ASSESSMENT OF SPEECH COMPREHENSION IN NONVERBAL CHILDREN ON THE AUTISM SPECTRUM USING EVENT-RELATED BRAIN POTENTIALS Harpreet K. Jaswal1,2, Adianes Herrera-Diaz2,3, John F. Connolly2 Department of Psychology, Neuroscience, & Behaviour, McMaster University Centre for Advanced Research in Experimental & Applied Linguistics 3 Neuroscience Graduate Program, McMaster University

1

abstracts

2

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that can affect communication. Some individuals on the autism spectrum are labeled as nonverbal, showing no outward signs of comprehension or language use. However, research in brain injury and coma has shown that the absence of behavioural evidence for language comprehension does not equate to its inability. Based on these findings, this study explored whether some nonverbal children on the autism spectrum can still process the semantic features of language. Language processing was assessed using cognitive paradigms including the Subject Own Name (SON) paradigm, Peabody Picture Vocabulary Test (PPVT), and sentence comprehension. These paradigms can evoke event-related brain responses (ERPs) specific to language processing, which can then be recorded using electroencephalography (EEG). In this study, the ERPs related to language processing of nonverbal children on the autism spectrum (n = 26) were collected using EEG. Language processing in nonverbal children on the autism spectrum was compared to language processing of verbal autistic children (n = 23) and typically developed children (n = 12). All children were within the biological age range of 6-17, but were matched for intellectual

age for between-group comparisons. Intellectual age was measured using the Wechsler Intelligence Scale for Children, the Mullen Scales of Early Learning, and the Stanford-Binet Intelligence Scales. It is hypothesized that there will be individual differences in semantic processing in nonverbal children on the autism spectrum, where some individuals will produce ERPs indicative of language comprehension. Between-group comparisons will be conducted to determine language processing abilities of each group relative to one another. Within-group comparisons will be conducted to examine individual linguistic abilities of participants. If cognitivelinguistic function at some level can be demonstrated in any of these nonverbal children on the autism spectrum, it may provide compelling evidence that: (1) the diagnosis of nonverbal autism may in some cases be misleading and potentially detrimental to the person’s ability to receive appropriate treatment and resources; and (2) advanced measures, such as EEGs, must be used in conjunction with traditional behavioural measures to properly evaluate nonverbal autism. If our hypothesis is confirmed, the implications of our findings could be impactful not only at the service delivery level, but also for future policy reformation.

KNOWLEDGE TRANSLATION STRATEGIES TO SUPPORT SERVICE PROVIDERS’ IMPLEMENTATION OF THE ‘F-WORDS’ IN CHILDHOOD DISABILITY Alice Kelen Soper 1,2, Andrea Cross 1,3, Peter Rosenbaum 1,4, Jan Willem Gorter 1,4 CanChild Centre for Childhood Disability Research, McMaster University Faculty of Health Sciences, McMaster University School of Rehabilitation Science, McMaster University 4 Department of Pediatrics, McMaster University

1

2

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3

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Purpose: Service providers are adopting the ‘F-words’ in practice as a strengths-based approach to childhood disability. This study aimed to gain insight into service providers’ uses of the ‘F- words’, associated barriers, and knowledge translation strategies needed to support implementation. Methods: Service providers were invited to participate in an interview after completing an online survey on their clinical implementation of the ‘F-words’. Content analysis provided insight into the use of the ‘F-words’ and perceived barriers, as well as insight into identifying knowledge translation strategies to facilitate implementation. Results: 21 service providers from nine countries participated in interviews. Applications of the ‘F-words’ included their use as a conceptual framework, directly in practice, and in teaching/ training. Barriers included conflicting attitudes, insufficient

funding, language, and misalignment with organizational/ government priorities. To support the adoption of the ‘F-words’, participants recommended knowledge translation strategies including local opinion leaders, linkage and exchange, educational outreach and meetings, and distribution of educational materials. Conclusion: Understanding applications, barriers to use, and knowledge translation strategies will inform future directions to implement the ‘F-words’ in practice. A critical step in bridging this research-to-practice gap and encouraging greater widespread adoption requires collaboration with service providers to tailor knowledge translation strategies to fit the local context. Key words: Childhood disability, F-words, International Classification of Functioning, Disability and Health, service providers, implementation, knowledge translation strategies *F-words: Function, Family, Fitness, Fun, Friends, & Future


ARTIST Ruby Zheng

MENDING THE MATERNAL CARE GAP: UNDERSTANDING THE PRENATAL, CHILDBIRTH, AND POSTPARTUM EXPERIENCES OF RACIALIZED WOMEN Raisa Ladha, BPH1, & Elena Neiterman, PhD1

School of Public Health and Health Systems, Faculty of Applied Health Sciences, University of Waterloo

1

The majority of studies concluded negative experiences (16 of 25), with some featuring neutral experiences (8 of 25), and only 1 study detailing entirely positive experiences. Results were further categorized in 4 main categories to better understand the nature of experience: access, interaction, constraints, and attitudes. Conclusion: This review supports the growing need for providing culturally safe maternity care to more efficiently address the needs of racialized women. Potential conceptualizations of this form of care may include standardizing protocol across birthing facilities, utilizing medical interpreters, training healthcare professionals to provide positive and supportive experiences, and adopting shared decisionmaking to incorporate patient preferences into the safe delivery and care of a newborn child.

abstracts

Purpose: Although racialized women are among the poorest individuals in North America and face a higher risk for adverse pregnancy outcomes, little is known about their experiences in utilizing prenatal, childbirth, and postpartum healthcare services. The objectives of this scoping review were to inform future policy initiatives and healthcare practices that would enable racialized mothers to have access to compassionate and culturally safe care as they embark on their journey to motherhood. Methods: A scoping review of academic literature on racialized women in North America was conducted utilizing the Arksey & O’Malley framework. Results: In the reviewed literature, 25 of 53 studies sufficiently detailed the experiences of racialized women with their respective healthcare systems in obtaining prenatal, birthing or postpartum care.

M E D U C ATO R | MARCH 2020

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FORUMSPACE

Everyone at the table: Strengthening food security at McMaster University doi:10.35493/medu.37.10

ABEER AHMAD

Bachelor of Health Sciences (Honours Child Health) Class of 2020, McMaster University Correspondence: ahmada28@mcmaster.ca

CHRIS CHOI

Bachelors of Health Sciences Class of 2021, McMaster University

LYNAEA FILBEY

Bachelors of Arts & Science Class of 2020, McMaster University

M E D U CATO R

| M A RC H 2020

forumspace

CONTEXT

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Student food insecurity is an issue faced by many students at McMaster University. It is defined as the inability to access nutritious and safe food that meets an individual’s dietary, lifestyle, and cultural needs.1 In 2016, it is estimated that 40% of Canadian university students experienced moderate or severe food insecurity.2 Despite these numbers, food security is often overlooked due to perceptions that characterize experiences of student food insecurity as transitory. In reality, it is an urgent topic of discussion in campus settings given the detrimental impacts it can have on a student’s mental and physical health.3 Discerning the problem and identifying potential solutions for this issue is crucial in optimizing the social, physical, and psychological wellbeing of McMaster students. Given the lack of data on food insecurity in postsecondary settings, extensive consultations with campus stakeholders have provided the McMaster Health Forum with a valuable opportunity to better understand the nuanced context surrounding this issue. Student food insecurity is a complex, intersectional issue that is greatly influenced by individual-level factors, campus dynamics, and government decisions. High prevalence of student food insecurity combined with macro-level developments may put even more students at risk. The rising cost of tuition, changes to the Ontario Student Assistance Program (OSAP), and the increased cost of housing point to the importance of strengthening food security for McMaster students.

most students hold a variety of financial responsibilities such as rent and tuition, which can interfere with a student’s ability to afford adequate food. For students of low-income backgrounds –particularly those who rely on government loans or grants as their primary form of income– it can be difficult to allocate enough money to food, potentially rendering them food insecure.2 Notably, while costs like rent and tuition are paid monthly and biannually, respectively, food is a far more flexible financial pressure as it rarely calls for upfront payments. Consequently, it is more practical for many students to sacrifice food when funds have already been allocated to more fixed aspects of student living. It becomes clear, then, that there is a strong link between student financial instability and food security; however, it is important to acknowledge that this link is magnified for students of marginalized identities. Students that identify as Indigenous, black, LGBTQ+, and/or disabled are more likely to encounter barriers such as having a low socioeconomic status, in achieving food security.4,5,6 Thus, it is paramount that the problem of student food insecurity is not separated from larger sociocultural structures that financially marginalize some students more than others.

Another major challenge to achieving student food security is ensuring that diverse student expectations and needs are aligned with the various pressures placed on campus food services. Students today have a wider variety of dietary expectations than previous generations, partly due to an increasingly diverse student body and a rise in society-wide health conscientiousness surrounding food. University food services are accommodating this trend, but it has been harder PROBLEM for them to keep up with rapidly changing individual needs. Understanding and addressing an issue as complex as student This challenge may contribute to a sense of food insecurity food security at McMaster University poses numerous for students who use campus food services as their primary challenges at both a macro and micro level. source of food. One of the most salient barriers university students face to achieving food security is student financial uncertainty as Many students perceive that the role of campus food services a result of high student costs.2 In order to attend university, is to provide subsidized meals in order to support students who are already burdened by other finances. However, food


ARTIST Ruby Zheng

Lastly, while a number of services exist on campus to help alleviate student food insecurity, several individual-level factors influence the success of these interventions. Evidence suggests that while the majority of students recognize the financial and health costs of purchasing food on campus, many students continue to use campus food services as a primary source of meals.2,8 In managing multiple obligations, such as extracurricular activities, academic commitments, and employment, many students may not be able to commute to affordable grocery stores to purchase healthy foods and may additionally be unable to prepare their own meals at REVIEWED BY: DR. KAELEN MOAT

Many students also report a lack of knowledge of preparing and budgeting for healthier meals.2,8 While several initiatives on campus provide opportunities for students to develop food literacy skills, many students are unaware of such services.8,9 Lack of culturally diverse programming may serve as a barrier for students in learning how to cook culturally-relevant foods. Students’ motivations to access appropriate services and support may additionally be aggravated by a lack of awareness about the issue of food insecurity, as well as a student culture which normalizes experiences of food inadequacy.8

NEXT STEPS

A key aspect to strengthening food security at McMaster University is compiling relevant stakeholder insights that are critical in facilitating intersectional dialogues and informing policy decisions. To support this process, the McMaster Health Forum hosted a student panel on strengthening efforts to support food security on March 6, 2020. The student panel program, which invites 14-16 students to the McMaster Health Forum for high-level deliberation, is an innovative approach to gaining insights about student values, views, and experiences related to high-priority topics on campus. The panel aims to incite change by sparking an ongoing dialogue between student leaders, senior university administration, and other stakeholders.

1. 2. 3. 4. 5. 6. 7. 8.

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FAO, IFAD, UNICEF, WFP, WHO. The state of food security and nutrition in the world 2019. Safeguarding against economic slowdowns and downturns. Rome: FAO; 2019. Report No.: ISBN 978-92-5-131570-5. Silverthorn D. Hungry for knowledge: Assessing the prevalence of student food insecurity on five Canadian campuses. Toronto(ON): Meal Exchange; 2016. Available from: http://cpcml.ca/publications2016/161027-Hungry_for_Knowledge.pdf. [cited 2020 Mar 2]. Jessiman-Perreault G., McIntyre L. Household food insecurity narrows the sex gap in five adverse mental health outcomes among Canadian adults. Int J Environ Res Public Health. 2019;16(3):319. Available from: doi:10.3390/ijerph16030319. Dietitians of Canada. Prevalence, severity and impact of household food insecurity: A serious public health issue. Dietitians of Canada; 2016. Silverthorn D, Abraham A, Baldwin M, Bosse A, Fraser J, Izard D, et al. Hungry for knowledge: Assessing the prevalence of student food insecurity on five Canadian campuses. Meal Exchange; 2016. Tishcoff R. Affordability: Results from the 2017 Ontario Post-Secondary Student Survey. Ontario Undergraduate Student Alliance; 2019. McMaster University. Annual financial report: 2018-2019. McMaster University; 2019. Maynard M. Experiences of food insecurity among undergraduate students at the University of Waterloo: Barriers, coping strategies, and perceived health and academic outcomes. UWSpace. 2019. Available from: http://hdl.handle.net/10012/10669. Maynard M. Experiences of food insecurity among undergraduate students: “You can’t starve yourself through school”. Canadian Journal of Higher Education. 2018;48(2):130-148. Available from: https://eric. ed.gov/?id=EJ1189978

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Dr. Kaelan A. Moat is Managing Director at the McMaster Health Forum, an Assistant Professor (part-time) in McMaster’s Department of Health Research Methods, Evidence, and Impact, and a member of Centre for Health Economics and Policy Analysis (CHEPA). His research focuses on evidence in health policymaking.

home.8 Time constraints may serve as a barrier to students in accessing campus food security initiatives that have limited hours of operation.

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services experience various pressures that reduce their ability to adjust the price of foods according to student demands. Due to decreases in public funding to universities, food services have become an increasingly important contributor to the university operating budget.7 McMaster food services’ commitment to sustainability through local procurement also limits their ability to adjust food prices as revealed through our extensive consultations with key campus stakeholders. Furthermore, campus food services must provide competitive wages and benefits to unionized staff. Meanwhile, communication between university food services and students has been limited. For example, there are no university-wide systems that gather data on food security indicators and invite student insights in food-related decision making. Thus, broader culture trends around food and campus bureaucracy affect students’ experiences with food security.

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A RT I S T KIEN NAGALES

CRITICAL REVIEW

Tau and beta-amyloid in Alzheimer’s disease: Theories, treatments strategies, and future directions


doi:10.35493/medu.37.12

JAKE COLAUTTI

Bachelor of Health Sciences (Honours), Class of 2023, McMaster University Correspondence: colauttj@mcmaster.ca

ABSTRACT Alzheimer’s disease is a severe neurodegenerative disease characterized by the deposition of neuritic plaques on neuronal membranes and the formation of neurofibrillary tangles within neurons. Several proteins, such as amyloid beta and tau, play major roles in the pathophysiology and progression of Alzheimer’s disease and are important factors to consider when developing novel therapeutics. The following review outlines the current understanding of the role these peptides play in Alzheimer’s and the state of therapeutics that target them. Contrary to previous theories, it is now understood that soluble amyloid beta and tau proteins are more neurotoxic than the insoluble aggregates they form. Treatments that target the individual biosynthetic pathways of these neurotoxic proteins have been ineffective. Thus, new therapies must overcome challenges associated with pharmacokinetics and clinical research design.

Several mechanisms have been proposed to explain the neurotoxicity of Aβ. While it was once thought that plaques were the primary toxic species in AD, it has recently been demonstrated that soluble Aβ40 and Aβ42 oligomers are in fact more responsible for cell death than their aggregated counterparts.20,21 These soluble Aβ species exhibit a secondary structure consisting of either two hydrophobic β-pleated sheet regions or the formation of a β-barrel, which cause cell death by inserting into neuronal membranes and destabilizing them.22,23 Additionally, it has been proposed that Aβ oxidatively damages membrane lipids, prematurely triggers neuronal apoptotic mechanisms, and opens calcium channels in neuronal membranes leading to electrical imbalances and subsequently cell death.24-26 Ultimately, fewer neurons result in fewer synapses and decreased cognitive function. In summary, Aβ is a class of proteins produced by proteolytic cleavage of the transmembrane APP by β- and γ-secretases. Through the formation of fibrils, plaques, and soluble oligomers, Aβ plays a major role in neuronal cell death and is one of several proteins implicated in AD.

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TAU PROTEINS In addition to Aβ, tau proteins have been significantly studied and play a more important role in AD. Tau describes a family of six protein isoforms that result from alternative splicing of the MAPT gene located on human chromosome 17.27,28 These isoforms may vary, with an additional 29- or 54-amino acid sequence found at the N-terminus of certain isoforms implicated in AD.27

M E D U CATO R

AMYLOID PROTEINS Amyloid beta (Aβ) peptides are among the most studied proteins implicated in the pathophysiology of AD. They form the basis of one of the most popular hypotheses regarding AD pathology, the amyloid cascade hypothesis, which suggests that Aβ proteins aggregate into plaques on neuronal membranes, leading to a series of pathological changes that ultimately result in the clinical symptoms of AD.7 These proteins are produced through a series of biosynthetic secretory pathways beginning with the proteolytic cleavage of the amyloid precursor protein (APP), encoded by a highly conserved gene located on chromosome 21.9,10 APP is an integral protein with a single transmembrane domain that is normally cleaved by α-secretase, an enzyme that releases the soluble extracellular domain of APP.11 This pathway is non-amyloidogenic, as APP is cleaved at a residue contained within the Aβ primary sequence.12 In AD, however, APP is instead cleaved extracellularly by β-secretase and in the transmembrane region by γ-secretase, an oligomeric enzyme complex composed primarily of presenilin proteins.13,14 These presenilin proteins and the transmembrane APP cleavage for which they are responsible are essential in the

Soluble Aβ oligomers form fibrils and plaques through a well-described process known as nucleation-dependent polymerization (Figure 1). Initially, individual monomers interact with each other through hydrogen bonding and Van der Waals forces, gradually forming larger polymers. Since this nucleation phase is thermodynamically unfavourable, it is the rate-limiting step in the polymerization process. After a nucleus of adequate size has formed, monomers can interact at several sites allowing a complete fibril to form rapidly.17 The rate-limiting step can be overcome by adding alreadyformed nuclei, known as seeds, to a solution of Aβ monomers, thus significantly accelerating fibril polymerization.18,19 These polymers grow continuously, eventually adhering to neuronal membranes in large, complex structures known as neuritic plaques.

critical review

INTRODUCTION Alzheimer’s disease (AD) is a neurodegenerative condition resulting in ~3.5% of all human deaths — a statistic projected to triple by 2050 as a result of aging populations.1-3 While it is typically characterized by severe memory loss, AD also results in linguistic, visuospatial, and cognitive deficits, primarily due to damage of the hippocampus.4 AD commonly affects those greater than 65 years old.5 Therapies have focused on inhibiting the accumulation of amyloid and tau proteins, but these treatments have been ineffective.6-8 The objective of this review is to discuss the current understanding of the roles and mechanisms of key proteins and oligomers in the pathophysiology of AD, address the shortcomings of current treatment strategies, and offer insight into future research and therapeutic directions.

development of AD.15 The reason for this remains elusive. This abnormal pathway is generally understood to be the mechanism by which Aβ proteins are derived from APP.4 Aβ exists in several forms, the most toxic of which contain 40 and 42 amino acids, known as Aβ40 and Aβ42, respectively. These forms are present in both human blood and cerebrospinal fluid (CSF).16

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Mahanani WR (2016). Global health estimates 2016: deaths by cause, age, sex, by country and by Region, 20002016. World Health Organization. Dataset, Excel Sheet. Available from: https://www.who.int/healthinfo/global_burden_disease/GHE2016_Deaths_WBInc_2000_2016.xl [accessed 2019 Dec 23] Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–2050) estimated using the 2010 census. Neurology. 2013 May 7;80(19):1778. Available from: doi:10.1212/WNL.0b013e31828726f5. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer’s disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88(9):1337–42. Available from: doi:10.2105/ AJPH.88.9.1337. Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. Harrison’s principles of internal medicine. 20th ed. New York, NY: McGraw-Hill Education; 2018. 4048. Kawas C, Gray S, Brookmeyer R, Fozard J, Zonderman A. Age-specific incidence rates of Alzheimer’s disease. Neurology. 2000;54(11):2072. Available from: doi:10.1212/ WNL.54.11.2072. Ballatore C, Lee VM-Y, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci. 2007;8(9):663. Available from: doi:doi. org/10.1038/nrn2194. Hardy JA, Higgins GA. Alzheimer’s disease: the amyloid cascade hypothesis. Science. 1992;256(5054):184–6. Available from: https://go.galegroup.com/ps/anonymous?id=GALE%7CA12207965&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=00368075&p=HRCA&sw=w [cited 2019 Dec 23]. Haas C. Strategies, development, and pitfalls of therapeutic options for Alzheimer’s disease. J Alzheimers Dis. 2012;28(2):241–81. Available from: doi.org/ 10.3233/ JAD-2011-110986. Kang J, Lemaire H-G, Unterbeck A, Salbaum JM, Masters CL, Grzeschik K-H, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987;325(6106):733–6. 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J Pharmacol Exp Ther. 2018;365(3):507. Available from: doi.org/10.1124/ jpet.117.244699. Herreman A, Serneels L, Annaert W, Collen D, Schoonjans L, De Strooper B. Total inactivation of γ–secretase activity in presenilin-deficient embryonic stem cells. Nat. Cell Biol. 2000;2(7):461–2. Available from: doi. org/10.1038/35017105. Zhang Z, Nadeau P, Song W, Donoviel D, Yuan M, Bernstein A, et al. Presenilins are required for γ-secretase cleavage of β-APP and transmembrane cleavage of Notch-1. Nature Cell Biology. 2000;2(7):463–5. Available from: doi. org/10.1038/35017108. Seubert P, Vigo-Pelfrey C, Esch F, Lee M, Dovey H, Davis D, et al. Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature. 1992;359(6393):325–7. Available from: doi.org/10.1038/359325a0. Chothia C, Janin J. Principles of protein–protein recognition. Nature. 1975;256(5520):705–8. Available from: doi. org/10.1038/256705a0. Jarrett JT, Berger EP, Lansbury PT. The carboxy terminus of the beta-amyloid protein is critical for the seeding of amyloid formation: implications for the pathogenesis of Alzheimer’s disease. Biochemistry. 1993;32(18):4693–7. Available from: doi.org/10.1021/bi00069a001. Niewold TA, Hol P, Lutz E, Gruys E. Enhancement of amyloid induction by amyloid fibril fragments in hamster. Lab Invest. 1987;56(5):544–9. Available from: https://europepmc. org/article/med/3553738. [cited 2019 Dec 22]. Larson ME, Lesné SE. Soluble Aβ oligomer production and toxicity. J Neurochem. 2012;120(s1):125–39. Available from: doi.org/10.1111/j.1471-4159.2011.07478.x. Viola KL, Klein WL. Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis. Acta Neuropathol. 2015;129(2):183–206. Available from: doi. org/10.1007/s00401-015-1386-3. Ahmed RT, Akcan M, Khondker A, Rheinstadter M, Bozelli Jr J, Epand RM, et al. Atomic resolution map of the soluble amyloid beta assembly toxic surfaces. Chem Sci. 2019;10:6072-82. Available from: doi.org/10.1039/ C9SC01331H. Ngo ST, Nguyen PH, Derreumaux P. Impact of A2T and D23N Mutations on Tetrameric Aβ42 Barrel within a dipalmitoylphosphatidylcholine lipid bilayer membrane by replica exchange molecular dynamics. J Phys Chem B. 2020;124(7):1175-82. Available from: doi:10.1021/acs. jpcb.9b11881. Koppaka V, Axelsen PH. Accelerated accumulation of amyloid β proteins on oxidatively damaged lipid membranes. Biochemistry. 2000;39(32):10011–6. Available from: doi. org/10.1021/bi000619d. Demeester N, Baier G, Enzinger C, Goethals M, Vandekerckhove J, Rosseneu M, et al. Apoptosis induced in neuronal cells by C-terminal amyloid ß-fragments is correlated with their aggregation properties in phospholipid membranes. Mol. 2000;17(4):219–28. Available from: doi. org/10.1080/09687680010015838. Kawahara M, Kuroda Y, Arispe N, Rojas E. Alzheimer’s β-amyloid, human islet amylin, and prion protein fragment evoke intracellular free calcium elevations by a common mechanism in a hypothalamic GnRH neuronal cell line. J Biol Chem. 2000;275(19):14077–83. Available from: doi. org/10.1074/jbc.275.19.1407. Himmler A. Structure of the bovine tau gene: alternatively spliced transcripts generate a protein family. Mol Cell Biol. 1989;9(4):1389. Available from: doi.org/10.1128/ MCB.9.4.1389. Neve RL, Harris P, Kosik KS, Kurnit DM, Donlon TA. Identification of cDNA clones for the human microtubule-associated protein tau and chromosomal localization of the genes for tau and microtubule-associated protein 2. Mol Brain Res. 1986;1(3):271–80. Available from: doi. org/10.1016/0169-328X(86)90033-1. Schweers O, Schönbrunn-Hanebeck E, Marx A, Mandelkow E. Structural studies of tau protein and Alzheimer paired helical filaments show no evidence for beta-structure. J Biol Chem. 1994;269(39):24290–7. Available from: http:// www.jbc.org/content/269/39/24290.short. Mukrasch MD, Bibow S, Korukottu J, Jeganathan S, Biernat J, Griesinger C, et al. Structural polymorphism of 441-residue tau at single residue resolution. PLoS Biol. 2009;7(2):e1000034. Available from: doi.org/10.1371/ journal.pbio.1000034. Weingarten MD, Lockwood AH, Hwo SY, Kirschner MW. A protein factor essential for microtubule assembly. Proc Natl Acad Sci USA. 1975;72(5):1858. Available from: doi. org/10.1073/pnas.72.5.1858. Hu X, Viesselmann C, Nam S, Merriam E, Dent EW. Activity-dependent dynamic microtubule invasion of dendritic spines. J Neurosci Res. 2008;28(49):13094. Available from: doi.org/10.1523/JNEUROSCI.3074-08.2008. Margolis RL, Wilson L. Opposite end assembly and disassembly of microtubules at steady state in vitro. Cell. 1978;13(1):1–8. Available from: doi.org/10.1016/00928674(78)90132-0. Cleveland DW, Hwo S-Y, Kirschner MW. Purification of tau, a microtubule-associated protein that induces assembly of microtubules from purified tubulin. J Mol Biol. 1977;116(2):207–25. Available from: doi. org/10.1016/0022-2836(77)90213-3. Drechsel DN, Hyman AA, Cobb MH, Kirschner MW. Modulation of the dynamic instability of tubulin assembly by the microtubule-associated protein tau. Mol Biol Cell. 1992;3(10):1141–54. Available from: doi.org/10.1091/ mbc.3.10.1141.

Due to its mostly hydrophilic nature, tau does not exhibit a compact secondary structure similar to many other proteins and is naturally unfolded.29,30 These physical properties make tau unique among proteins and are important to consider when developing a biochemical understanding of AD. Unlike Aβ, the role of tau proteins in healthy physiology is well understood. These proteins are essential for the stabilization of microtubules in neurons, which facilitate intracellular transport and neurotransmission.31,32 Microtubules are polymers of the dimeric protein tubulin, and are regulated through two distinct phases: a shrinking phase known as catastrophe, whereby tubulin subunits are removed from one end, and a growth phase known as rescue, whereby tubulin subunits are added to the opposite end.33 Tau slows the rate of catastrophe and accelerates rescue by binding to individual tubulin dimers and inducing conformational changes that strengthen interactions between the various tubulin units.34-36 This allows microtubules to grow to considerable lengths, which is particularly important in neurons, where microtubules must facilitate the transport of vesicles over great distances down the axon. The role of tau in AD has been widely studied and involves several different signalling pathways. Under normal conditions, tau and other microtubule-associated proteins are phosphorylated to decrease their affinity for tubulin, thereby detaching them from microtubules. This is advantageous in certain circumstances since microtubuleassociated proteins often serve as obstacles

for motor proteins as they transport cargo over microtubules.37 Tau in AD is hyperphosphorylated at several sites, which excessively decreases its affinity for tubulin and limits its ability to stabilize microtubules.38-40 The shift of this balance towards the hyperphosphorylated state has been observed in vivo, suggesting that this process in AD may be the result of an imbalance between phosphatases and kinases.41,42 Tau in AD is also subject to cleavage by several proteases which releases protein fragments that may further decrease the ability of tau to stabilize microtubules, resulting in neuronal death.43,44 Both hyperphosphorylation and proteolytic cleavage of tau cause it to be detached from microtubules and increase its propensity to aggregate into insoluble structures known as neurofibrillary tangles (NFTs).45 NFT formation is similar to Aβ aggregation in several ways: it follows a nucleationdependent mechanism that can be accelerated through the addition of seeds, and it is likely that these large aggregates are less neurotoxic than the soluble oligomers and monomers from which they are formed.46-49 Tau, like Aβ, is an important protein implicated in the pathophysiology of AD due to its ability to form aggregates via hyperphosphorylation. However, there are significant differences between NFT and Aβ processes, such as the fact that NFTs are cytosolic while Aβ aggregates are extracellular.50 The exact mechanisms of tau toxicity are unclear, although it is likely that hyperphosphorylated and aggregated tau causes neuronal death by failing to support microtubules.51

FIGURE 1. A simple nucleation-dependent polymerization mechanism.

NUCLEUS

kg Kn LAG TIME

kg

Kg

SEEDED GROWTH

Monomers (depicted as violet spheres) are in equilibrium with small oligomers in the thermodynamically unfavourable nucleation phase shown on the left (Kn<<1). When a nucleus of adequate size forms, monomers can interact at various sites and the process becomes favourable (Kg>>1), leading to a period of rapid growth, shown on the right.17 The rate limiting step can be skipped entirely by adding exogenous nuclei to a solution of monomers.18,19 Adapted from: Harper JD, Lansbury PT Jr. Models of amyloid seeding in Alzheimer’s disease and scrapie: Mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem. 1997;66(1):385-407. Available from: doi:10.1146/annurev.biochem.66.1.385.


Tau, however, has not been a therapeutic target in AD, likely because research focused on Aβ for several decades without considering the possibility that tau may be a key driver. The development and testing of novel treatments for AD currently face many challenges. Firstly, any drug that aims to treat AD must cross the blood-brain barrier (BBB), a tight membrane of epithelial cells that cover much of the brain and spinal cord.65 A great deal of research is focused on bypassing the BBB, employing strategies such as encapsulating drugs in modified red blood cells or creating openings with ultrasound.66,67 Additionally, given that current AD diagnosis is based primarily on cognitive tests and that AD progresses slowly over an extended period, designing effective clinical trials is difficult.68 Challenges associated with drug delivery, AD diagnosis, and clinical research design combined with the complexity of AD pathophysiology make drug discovery challenging.

Some drugs adopt the opposite approach; rather than inhibit β- and γ-secretases, they stimulate α-secretase. As described above, APP can be cleaved through an amyloidogenic pathway that involves β- and γ-secretase or a non-amyloidogenic pathway that involves α-secretase.12,13 By activating protein kinase C, drugs such as bryostatin and semagacestat enhance α-secretase activity, leading to decreased Aβ production in vitro.62,63 Early clinical trials demonstrate significant cognitive improvement and no adverse side effects, but also report potential bioaccumulation at higher doses.64 Therefore, α-secretase stimulation is a promising avenue of research and warrants further exploration.

CONCLUSION Tau, Aβ, APP, and the various secretases, proteases, and kinases that regulate their synthetic pathways have all been investigated as potential drug targets in AD, with limited success. The chemical processes of this disease, such as the nucleation-dependent polymerization of both tau and Aβ proteins, the destabilizing effects these processes have on neuronal membrane, and their related neurotoxicity, are crucial concepts in understanding AD. Novel therapeutics will need to address the relationships between these complex pathways, as well as overcome difficulties associated with drug delivery, clinical research, and the inherent complexity of AD pathophysiology.

36.

37. 38.

39.

40.

41.

42.

43.

44.

45. 46.

47.

48. 49.

50.

51. 52. 53. 54.

55.

56. 57.

58.

59.

TABLE 1. Summary of AD therapies targeting protein pathways Treatment

Mechanism

Trial Stage

60.

Reference 61.

Phase I: Safety and efficacy

May 201554

Verubecestat

β-secretase inhibitor Phase I: Safety and efficacy

Egan 201956

Lanabecestat

β-secretase inhibitor Phase I: Safety and efficacy

Wessels 201957

Semagacestat

γ-secretase inhibitor Phase III: Superiority

Doody 2013

LY450139

γ-secretase inhibitor Phase II: Tolerance

Fleischer 2008

LY450139

γ-secretase inhibitor Phase II: Tolerance

Siemers 200661

62.

64.

60

PEER REVIEWED BY: DR. JOHN PAUL OLIVERIA Dr. Oliveria is an Assistant Clinical Professor at McMaster University and a postdoctoral scholar at Stanford University, as well as a member of the McMaster Institute for Research on Aging. He studies the molecular mechanisms of Alzheimer’s disease and the immunology underlying allergies. EDITED BY: JERRY DU & ADRIAN WONG

63.

59

65. 66.

67.

68.

| M A RC H 2020

BACE1 inhibitor

M E D U CATO R

LY2886721

Panda D, Goode BL, Feinstein SC, Wilson L. Kinetic stabilization of microtubule dynamics at steady state by tau and microtubule-binding domains of tau. Biochemistry. 1995;34(35):11117–27. Available from: https://pubs.acs. org/doi/pdf/10.1021/bi00035a017. Mandelkow E-M, Thies E, Trinczek B, Biernat J, Mandelkow E. MARK/PAR1 kinase is a regulator of microtubule-dependent transport in axons. J Cell Biol. 2004;167(1):99–110. Available from: doi.org/10.1083/jcb.200401085. Köpke E, Tung Y-C, Shaikh S, Alonso A del C, Iqbal K, Grundke-Iqbal I. Microtubule-associated protein tau. Abnormal phosphorylation of a non-paired helical filament pool in Alzheimer disease. J Biol Chem. 1993;268(32):24374– 84. Available from: http://www.jbc.org/content/268/32/24374.short. Brandt R, Lee G, Teplow DB, Shalloway D, Abdel-Ghany M. Differential effect of phosphorylation and substrate modulation on tau’s ability to promote microtubule growth and nucleation. J Biol Chem. 1994;269(16):11776–82. Available from: http://www.jbc.org/content/269/16/11776.short. [cited 2019 Dec 11]. Illenberger S, Zheng-Fischhöfer Q, Preuss U, Stamer K, Baumann K, Trinczek B, et al. The endogenous and cell cycle-dependent phosphorylation of tau protein in living cells: implications for Alzheimer’s disease. Mol Biol Cell. 1998;9(6):1495–512. Available from: doi.org/10.1091/ mbc.9.6.1495. Härtig W, Stieler J, Boerema AS, Wolf J, Schmidt U, Weißfuß J, et al. Hibernation model of tau phosphorylation in hamsters: selective vulnerability of cholinergic basal forebrain neurons – implications for Alzheimer’s disease. Eur J Neurosci. 2007;25(1):69–80. Available from: doi.org/10.1111/ j.1460-9568.2006.05250.x. Planel E, Richter KEG, Nolan CE, Finley JE, Liu L, Wen Y, et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci Res. 2007;27(12):3090. Available from: doi.org/10.1523/ JNEUROSCI.4854-06.2007. Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, Weintraub ST, et al. Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer’s disease. J Neurosci Res. 2004;24(36):7895. Available from: doi.org/10.1523/JNEUROSCI.1988-04.2004. Guo T, Dakkak D, Rodriguez-Martin T, Noble W, Hanger DP. A pathogenic tau fragment compromises microtubules, disrupts insulin signaling and induces the unfolded protein response. Acta Neuropathol Commun. 2019;7(1):2. Available from: doi.org/10.1186/s40478-018-0651-9. Mandelkow E-M, Mandelkow E. Biochemistry and cell biology of tau protein in neurofibrillary degeneration. Cold Spring Harb Perspect Med. 2012;2(7):a006247. Available from: doi.org/10.1101/cshperspect.a006247. Congdon EE, Kim S, Bonchak J, Songrug T, Matzavinos A, Kuret J. Nucleation-dependent tau filament formation the importance of dimerization and an estimation of elementary rate constants. J Biol Chem. 2008;283(20):13806–16. Available from: doi.org/10.1074/jbc.M800247200. von Bergen M, Friedhoff P, Biernat J, Heberle J, Mandelkow E-M, Mandelkow E. Assembly of τ protein into Alzheimer paired helical filaments depends on a local sequence motif (306VQIVYK311) forming β structure. Pc Natl Acad Sci US. 2000;97(10):5129. Available from: doi.org/10.1073/ pnas.97.10.5129. Cowan C, Mudher A. Are tau aggregates toxic or protective in tauopathies? Front Neurol. 2013;4:114. Available from: doi. org/10.3389/fneur.2013.00114. Lasagna-Reeves CA, Castillo-Carranza DL, Sengupta U, Sarmiento J, Troncoso J, Jackson GR, et al. Identification of oligomers at early stages of tau aggregation in Alzheimer’s disease. FASEB J. 2012;26(5):1946–59. Available from: doi.org/10.1096/fj.11-199851. Bancher C, Brunner C, Lassmann H, Budka H, Jellinger K, Wiche G, et al. Accumulation of abnormally phosphorylated τ precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res. 1989;477(1):90–9. Available from: doi.org/10.1016/0006-8993(89)91396-6. Lei P, Ayton S, Moon S, Zhang Q, Volitakis I, Finkelstein DI, et al. Motor and cognitive deficits in aged tau knockout mice in two background strains. Mol Neurodegener. 2014;9(1):29. Available from: doi.org/10.1186/1750-1326-9-29. Hu X, Hicks CW, He W, Wong P, Macklin WB, Trapp BD, et al. Bace1 modulates myelination in the central and peripheral nervous system. Nat Neurosci. 2006;9(12):1520–5. Available from: doi.org/10.1038/nn1797. Willem M, Garratt AN, Novak B, Citron M, Kaufmann S, Rittger A, et al. Control of peripheral nerve myelination by the ß-Secretase BACE1. Science. 2006;314(5799):664. Available from: doi.org/10.1126/science.1132341. May PC, Willis BA, Lowe SL, Dean RA, Monk SA, Cocke PJ, et al. The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans. J Neurosci Res. 2015;35(3):1199. Available from: doi.org/10.1523/JNEUROSCI.4129-14.2015. May PC, Dean RA, Lowe SL, Martenyi F, Sheehan SM, Boggs LN, et al. Robust central reduction of amyloid-β in humans with an orally available, non-peptidic β-Secretase inhibitor. J Neurosci Res. 2011;31(46):16507. Available from: doi. org/10.1523/JNEUROSCI.3647-11.2011. Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, et al. Randomized trial of verubecestat for prodromal Alzheimer’s disease. N Engl J Med. 2019;380(15):1408–20. Available from: doi.org/10.1056/NEJMoa1812840. Wessels AM, Tariot PN, Zimmer JA, Selzler KJ, Bragg SM, Andersen SW, et al. Efficacy and safety of lanabecestat for treatment of early and mild Alzheimer disease: the AMARANTH and DAYBREAK-ALZ randomized clinical trials. JAMA Neurol. 2019; Available from: https://doi. org/10.1001/jamaneurol.2019.3988. Elvang AB, Volbracht C, Pedersen LØ, Jensen KG, Karlsson J, Larsen SA, et al. Differential effects of γ-secretase and BACE1 inhibition on brain Aβ levels in vitro and in vivo. J Neurochem. 2009;110(5):1377–87. Available from: doi. org/10.1111/j.1471-4159.2009.06215.x. Doody RS, Raman R, Farlow M, Iwatsubo T, Vellas B, Joffe S, et al. A phase 3 trial of Semagacestat for treatment of Alzheimer’s disease. N Engl J Med. 2013;369(4):341–50. Available from: doi.org/10.1056/NEJMoa1210951. Fleisher AS, Raman R, Siemers ER, Becerra L, Clark CM, Dean RA, et al. Phase 2 safety trial targeting amyloid β production with a γ-secretase inhibitor in Alzheimer disease. Arch Neurol. 2008;65(8):1031–8. Available from: doi. org/10.1001/archneur.65.8.1031. Siemers ER, Quinn JF, Kaye J, Farlow MR, Porsteinsson A, Tariot P, et al. Effects of a γ-secretase inhibitor in a randomized study of patients with Alzheimer disease. Neurology. 2006;66(4):602. Available from: doi.org/10.1212/01. WNL.0000198762.41312.E1. Ibarreta D, Duchén M, Ma D, Qiao L, Kozikowski AP, Etcheberrigaray R. Benzolactam (BL) enhances sAPP secretion in fibroblasts and in PC12 cells. NeuroReport. 1999;10(5). Available from: https://journals.lww.com/neuroreport/Fulltext/1999/04060/Benzolactam__BL__enhances_sAPP_ secretion_in.26.aspx [cited 2019 Dec 23]. Garrido JL, GODOY JA, Alvarez A, Bronfman M, Inestrosa NC. Protein kinase C inhibits amyloid β peptide neurotoxicity by acting on members of the Wnt pathway. FASEB J. 2002;16(14):1982–4. Available from: doi.org/10.1096/ fj.02-0327fje. Nelson TJ, Sun M-K, Lim C, Sen A, Khan T, Chirila FV, et al. Bryostatin effects on cognitive function and PKC in Alzheimer’s disease phase IIa and expanded access trials. J Alzheimers Dis. 2017;58(2):521–35. Available from: doi:10.3233/JAD-170161. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman’s: the pharmacological basis of therapeutics. 13th edition. New York, NY: McGraw-Hill Education; 2017. 1808. Himbert S, Blacker MJ, Kihm A, Pauli Q, Khondker A, Yang K, et al. Hybrid erythrocyte liposomes: functionalized red blood cell membranes for molecule encapsulation. Adv. Biosyst. 2020;1900185. 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critical review

TREATMENT APPROACHES Several therapies have been developed that attempt to disrupt the protein pathways involved in AD (Table 1). The amyloidogenic pathway is frequently the target of such therapies, many of which inhibit β- and γ-secretase. Initial studies on AD in β-secretase knockout mice models showed significantly reduced blood and CSF Aβ concentrations. However, neuronal myelination in these mice was significantly impaired, suggesting that β-secretase plays a role in healthy physiology.52,53 In spite of this, pharmacological β-secretase inhibitors have been developed, which have proven promising in vitro but do not translate to clinical benefits.54-57 Similarly, γ-secretase inhibitors have demonstrated significant in vitro reduction of Aβ, but have shown no clinical benefit despite decreasing plasma Aβ concentration.58-61 This points to a more complex role of Aβ in AD that is not yet fully understood.

15 21


A RT I S T JEFF ZHANG

CRITICAL REVIEW Animal-assisted activities: Justifying a mental health program at McMaster University


doi:10.35493/medu.37.16

TERRY LI

Bachelor of Health Sciences (Honours) Class of 2020, McMaster University lit60@mcmaster.ca

LELAND CHEUNG

Bachelor of Science in Nursing Class of 2020, McMaster University cheunl6@mcmaster.ca

M E D U CATO R | M A RC H 2020

CONTEXTUALIZING MENTAL HEALTH AT MCMASTER Mental health issues often act as barriers in the lives of postsecondary students in Ontario. The Council of Ontario Universities reported that 65% of students experienced overwhelming anxiety in 2016, presenting a 7% increase from 2013.1 Within this period, the Council also reported a 6% increase in depression, from 40% to 46%.1 These increasing trends have spurred Ontario universities to prioritize addressing mental health issues and invest in a collection of initiatives to support student mental well-being. McMaster University has launched a number of programs to improve student mental health, including programs which use animals within a therapeutic context: Pups Advising within Social Sciences (PAWSS) and Dogs at Mac.2,3 Both organizations utilize certified therapy dogs at informal, drop-in sessions around campus during which students can freely interact with the dogs.2,3 These events are scheduled during exam season and other stressful periods of the school year, and aim to improve student mental health outcomes.2,3 Attempts to define interventions that incorporate animals have been ongoing since the 1980s, with widely used definitions including animal-assisted therapy (AAT) and animal-assisted activities (AAA).4 AAT utilizes animals to deliver individualized therapies led by a licensed

EVALUATING THE EFFECTIVENESS OF AAAS Research studies evaluating AAA-associated mental health benefits have produced mixed results. Brooks et al. conducted a systematic review of published and grey literature up until March 2017 and found 17 quantitative studies exploring the effects of human-animal interactions on mental health.5 Some of the studies correlated animal companion interactions with reduced feelings of loneliness, depression, and anxiety.5 Through actions such as petting and sharing close contact with animals, participants experienced improvements in depression and mood.5 In contrast, other studies reported neutral effects; for example, depression was found to be as common in pet owners as in non-pet owners.5 These mixed research findings may be due to several factors, as reported by Serpell et al.6 Most studies that evaluated animal-assisted interventions had methodological flaws, including small sample sizes, poorly defined research questions, a lack of standardized measures, and non-randomized assignment of participants to interventions.6 These methodological issues make it challenging to accurately evaluate the effectiveness of AAAs. While the findings were mixed, none of the studies included in the systematic review by Brooks et al. found positive humananimal interactions, such as petting, playing, and hugging, to be detrimental to mental health.5 This paucity indicates there is minimal risk associated with using animals in a therapeutic setting.5 However, it is important to acknowledge that the review evaluated the benefits of human-animal interactions in the context of animal ownership, and the weaker emotional bonds between students and animals would therefore likely result in diminished health benefits.5 Nonetheless, the human-animal interactions during play at the McMaster AAA sessions should be similar to those between an animal and its owner, meaning that the minimal risk associated with using animals in Brook et al.’s therapeutic setting should also apply to these sessions.5 Therefore, while findings made by Brooks et al. do not fully represent McMaster’s AAA services, they are promising in terms of support for the initiative.5

critical review

ABSTRACT For many students at McMaster University, adequate mental health is an elusive luxury. This mental health crisis has called for the inception of multiple programs to ensure the wellbeing of the student body. Animal-assisted activities (AAA), such as “PAWSS” or “Dogs at Mac,” are such types of programs that aim to relieve student stress through wholesome interaction with animals. Given that McMaster University has finite resources dedicated to improving student mental health, it is important to evaluate whether these programs are truly beneficial. This review has found literature to support McMaster’s use of AAA. The sessions offer the potential for mental health benefits at an extremely low cost. Additionally, positive university student perceptions toward animal-assisted interventions indicate a clear public interest in AAA events. The schedule of the animals used in AAA also upholds their welfare, which helps mitigate any ethical concerns regarding animal-assisted interventions. While the true efficacy of AAA has not yet been determined due to mixed research literature around the topic, no studies have identified detrimental effects resulting from positive humananimal interactions. This paucity suggests that there is very little risk associated with using animals in a therapeutic setting when one accounts for its potential benefit.

professional, while AAAs are interventions involving animals that are often not individualized for a specific client.3,4 Based on these definitions, the services offered by PAWSS and Dogs at Mac fall under the AAA classification. The purpose of this paper is to determine whether AAAs are an effective use of university resources for improving student mental health. To provide a holistic evaluation of AAA services, several factors will be examined: the mental health benefits associated with AAAs, perceptions towards animals in therapeutic settings, ethical considerations, and cost-effectiveness. Overall, it can be hypothesized that AAA use at the university is justifiable.

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Council of Ontario Universities. Mental Health [Internet]. Ontario’s Universities. 2019 . Available from: https://ontariosuniversities.ca/issues-priorities/student-supports [cited 2019 Dec 9]. McMaster University. PAWSS [Internet]. McMaster Faculty of Social Sciences. 2019 . Available from: https://socialsciences.mcmaster.ca/pawss [cited 2019 Dec 9]. McMaster University. Dogs at MAC. 2019. Available from: https://dogsatmac. mcmaster.ca [cited 2019 Dec 9]. Jones M, Rice S, Cotton S. Incorporating animal-assisted therapy in mental health treatments for adolescents: A systematic review of canine assisted psychotherapy. PLOS ONE. 2019;14(1):e0210761. Available from: doi:10.1371/journal. pone.0210761. Brooks H, Rushton K, Lovell K, Bee P, Walker L, Grant L et al. The power of support from companion animals for people living with mental health problems: A systematic review and narrative synthesis of the evidence. BMC Psychiatry. 2018;18(1). Available from: doi:10.1186/s12888018-1613-2. Serpell J, McCune S, Gee N, Griffin J. Current challenges to research on animal-assisted interventions. Appl Dev Sci. 2017;21(3):223-233. Available from: do i:10.1080/10888691.2016.1262775. Irvine L. Sociology and anthrozoology: Symbolic interactionist contributions. Anthrozoös. 2012;25(Supplement 1):123-137. Available from: doi: https://doi.org/10.2752/17530371 2X13353430377174. Fine AH, Mokhatab S. Handbook on animal-assisted therapy: Foundations and guidelines for animal-assisted interventions. 4th ed. Cambridge: Academic Press; 2015. 21-40 p. Beetz A, Uvnäs-Moberg K, Julius H, Kotrschal K. Psychosocial and psychophysiological effects of human-animal interactions: The possible role of oxytocin. Front Psychol. 2012;3. Available from: doi:10.3389/fpsyg.2012.00234. Guéguen N, Ciccotti S. Domestic dogs as facilitators in social interaction: An evaluation of helping and courtship behaviors. Anthrozoös. 2008;21(4):339-349. Available from: doi:10.2752/175303708X371564. Koller D, Goldman R. Distraction techniques for children undergoing procedures: A critical review of pediatric research. J Pediatr Nurs. 2012;27(6):652-681. Available from: doi:10.1016/j.pedn.2011.08.001. Pritchard, PA. “Take a paws” with therapy dogs and make it a howling success. In: Sittler RJ, Rogerson TJ. (eds.) The Library Outreach Casebook. Chicago: Association of College and Research Libraries; 2018. p.119-128. Zents C, Fisk A, Lauback C. Paws for intervention: Perceptions about the use of dogs in schools. J Ment Health. 2016;12(1):82-98. Available from: doi: 10.1080/15401383.2016.1189371. Schoenfeld-Tacher R, Hellyer P, Cheung L, Kogan L. Public perceptions of service dogs, emotional support dogs, and therapy dogs. Int J Environ Res Public Health. 2017;14(6):642. Available from: doi:10.3390/ijerph14060642. Glenk L. Current perspectives on therapy dog welfare in animal-assisted interventions. Animals. 2017;7(12):7. Available from: doi:10.3390/ani7020007.

THEORETICAL BENEFITS OF AAA Despite the uncertainties surround-ing AAA effectiveness, several theories have attempted to explain why human-animal interactions may benefit mental health. Numerous theories focus on how this interaction operates, including those which examine the relationship through a symbolic interactionist perspective or through the perspective of therapy animals.7,8 However, this paper examines biopsychosocial theories that focus more on the mental health benefits associated with AAA. One theory is the “social catalyst effect,” where the presence of animals may indirectly stimulate positive social interactions and relationships with other humans.6,9 Experiments by Guéguen and Ciccotti demonstrated that dogs may help facilitate social interactions as people tended to act more friendly to those who had dogs compared to those who did not (p < 0.005).10 In the case of the AAA sessions at McMaster, the therapy animals may help facilitate positive social interactions between students attending the event. A second theory takes a more biological approach, as Beetz et al. have tried to explain the psychophysiological benefits of AAA by outlining how human-animal interactions release oxytocin.9 This hormone is able to reduce epinephrine and norepinephrine levels while also decreasing depressive mood.9 A third theory claims that animals can act as a distraction from negative mental states.8 Koller et al. found that distracting images, sounds, and activities can be used to reduce anxiety and other forms of emotional distress.11 Several preliminary studies have also suggested that animals may be intrinsically effective at attracting and holding human attention.8 Most notably, human infants have been found to have a significant preference for images of animals compared to images of motor vehicles, toys, or other objects.8,11 While all three theories provide reasonable explanations to justify the benefits of AAA for mental health, they have yet to be validated in clinical research studies. JUSTIFICATIONS FOR AAA USE AT MCMASTER UNIVERSITY As no definitive conclusions can currently be drawn about the effectiveness of

AAA, and no strongly substantiated theories support the mental health benefits of AAA, it may be difficult to justify utilizing these services at McMaster University. However, the AAA sessions offered by organizations such as PAWSS and Dogs at Mac have a high potential for benefit and are extremely costeffective. A paper by Pritchard described a “Take a Paws” therapy dog event that was introduced at a University of Guelph library to relieve exam stress.12 The library partnered with the St. John Ambulance Therapy Dog program which limited costs of executing the event to those of parking, bottled water, and a package of puppy pads.12 Health and safety services were provided by unpaid student volunteers from the University of Guelph’s First Response team.12 The therapy animal sessions run by McMaster University closely mirror the events hosted at the University of Guelph. For example, partnerships with local organizations such as the Hamilton-Burlington Society for the Prevention of Cruelty to Animals (SPCA) allow for inexpensive access to therapy dogs. Furthermore, McMaster’s Emergency First Response Team (EFRT) is comprised of volunteers who are on campus to ensure the health and safety of students during AAA sessions. Therefore, the cost-efficient nature of running events by PAWSS and Dogs at Mac would counteract the uncertainty concerning the benefits and effectiveness of AAA. There is also evidence that students generally accept the use of animals to improve mental health in an academic setting. A study by Zents et al. evaluated the efficacy of therapy animals in improving mental wellbeing within a school setting.13 The study collected data regarding the perceptions of 196 students and 105 faculty members to determine attitudes towards four therapy dogs.13 It was found that students strongly supported the use of therapy animals in schools.13 However, the majority of the study participants were in the sixth to eighth and eleventh to twelfth grades. This major limitation prevents study conclusions about student perceptions from being completely applicable to McMaster’s demographic. A study by Schoenfeld-Tacher et al. used online surveys to collect data regarding perceptions of assistance animals held by individuals ranging from ages 18 to 45.14 This demographic more closely simulates


the population at McMaster University. The study concluded that 56.3% of respondents agreed that therapy animals should be used if they had the potential to be helpful.14 In the absence of research literature evaluating university student perceptions of AAA, the papers by Zents et al. and Schoenfeld-Tacher et al. provide insight into the positive perceptions of students and adults towards animal usage within therapeutic settings. It is not unreasonable to assume that these perceptions will be reflected in the university student population.

EDITED BY: ALBERT STANCESCU AND JAMES YU

M E D U CATO R | M A RC H 2020

CONCLUSION Several considerations help justify AAA use at McMaster University. AAA sessions are extremely cost-effective as they offer the potential for mental health benefits at a very low cost. Additionally, the positive university student perceptions toward animal-assisted interventions suggest a clear demand for AAA events. By following a schedule which upholds the welfare of animals used in AAA, the use of these interventions can be deemed ethical and therefore morally acceptable. Finally, no studies have identified detrimental effects resulting from positive human-animal interactions, suggesting that there is very little risk associated with using animals in a therapeutic setting. While the factors outlined above support the use of AAA at McMaster, the true efficacy of AAA has not yet been determined, as demonstrated by mixed findings in the existing literature. To attain a more definitive conclusion on whether McMaster’s AAA sessions are justified, additional studies utilizing stronger research methodologies are needed. Until then, these wonderful animals will continue to ease the stress of McMaster students.

Dr. Mark Norman is a postdoctoral fellow in the Department of Health, Aging & Society at McMaster University. He completed his PhD in the Faculty of Kinesiology and Physical Education at the University of Toronto. His dissertation examined sport and physical culture in Canadian federal prisons. His research considers the social significance of sport, physical culture, and recreation in carceral settings, touching on questions of social control, agency, and resistance in and through physical activity. He also studies the significance of alternative prison activities, such as yoga and animal-assisted interventions.

critical review

ETHICAL CONSIDERATIONS The final consideration for AAA use is whether McMaster University’s current use of animals in AAA sessions can be ethically justified. A paper by Glenk reviewed current literature that followed therapy animals’ welfare during animal-assisted interventions.15 The review concluded that implementing animals into therapeutic environments was considered not particularly stressful for participating animals.15 However, some isolated cases of teasing and mistreatment of visiting therapy animals were reported.15 To avoid situations that would cause work-related strain and decrease animals’ quality of life, guidelines for animal use in therapeutic settings should be followed.15 Current recommendations include monitoring for signs of fatigue, giving animals ample opportunities to rest, limiting the duration of therapy sessions to 60 minutes, and limiting the number of visits to 3 sessions per week.15 It appears that the services offered by PAWSS and Dogs at Mac follow these guidelines as AAA sessions tend to be less than 60 minutes and only run a handful of times during the school year. Therefore, the welfare of the animals used in AAA is being upheld.

REVIEWED BY: DR. MARK NORMAN

19


OPINION

ARTIST

WENHUI (WENDY) YU

Homeopathy Pseudo-Science or Effective Treatment?

doi:10.35493/medu.37.20

HA NNA H S ILV E R MA N

Bachelor of Health Sciences (Honours) Class of 2020, McMaster University Correspondance: silvermh@mcmaster.ca

opinion

ABSTRACT One of the most controversial topics in healthcare is whether complementary and alternative medicine (CAM) can replace modern medicine. Homeopathy has become a popular form of CAM, and while it is generally regarded as safe, it has not been proven effective. Most scientific professionals mistrust homeopathy due to the lack of scientific rigour and credibility in studies that seek to analyze homeopathic practices; many argue that any positive outcomes may be attributed to the placebo effect. While homeopathy cannot replace conventional medicine, the therapeutic effects of homeopathic consultation addresses the impersonal nature of traditional medicine.

PART 1: HOMEOPATHY LACKS SCIENTIFIC BASIS AND SHOULD NOT REPLACE CONVENTIONAL MEDICINE

M E D U CATO R

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INTRODUCTION

20

Developed over 200 years ago by German physician Samuel Christian Hahnemann, homeopathy is a form of alternative medicine practice based on belief in “The Law of Similars” —the idea that a natural substance that causes symptoms in a healthy person can be used to cure the same symptoms in a sick person.¹ Several types of homeopathic treatments exist, ranging from auto-isopathy, whereby treatments for ailments stem from the patient’s own body, to classical homeopathy, in which individualized natural remedies are given.2 Physicians are wary of recommending homeopathy and other forms of complementary and alternative medicine (CAM) due to a lack of proven efficacy and long-term risk assessments.³ As the trend towards distrust in the healthcare system and medicine increases, it is important that patients are aware of the risks of pursuing homeopathy in place of traditional pharmacological interventions.⁴

THE DILUTION EFFECT

There are several principles of homeopathy that contradict scientific ideology. One such principle is the dilution effect, wherein remedies that are more dilute have more potent effects. These remedies are prepared by diluting a mixture several times, shaking vigorously between each dilution.⁵

Almost none of the original remedy remains at the end as the dilutions often fall below 1 mol/L, the scientifically determined limit for dilutions.⁶ As such, any effects from these treatments would be implausible.⁷ Hahnemann explained the discrepancy by stating that water is able to change structures to capture the “essence” of the diluted molecule.⁸ Several studies have attempted to corroborate this claim using techniques such as magnetic imaging and thermoluminescence, but strong conclusions have not been reached.9,10 Since this principle conflicts with scientific knowledge, it is hard for the medical community to consider such an effect to be possible, let alone effective. For this reason, homeopathy is often dismissed as “the ultimate fake,” and “concentrated nonsense.”11,12 Unless convincing research emerges, there is no plausible reason that such heavy dilution would cause any effect whatsoever.

EFFECTIVENESS

Few studies have been able to demonstrate the positive effects of homeopathic remedies. One clinical trial review concluded that limitations on study quality and conflicting evidence demonstrate the overall lack of scientific credibility of homeopathic remedies.13 A large area of interest for the potential usage of homeopathic remedies is in cancer pain relief. In a European survey, 35.9% of cancer patients reported using homeopathy or other forms of CAM.14 However, a review on homeopathy showed that using this form of treatment in conjunction with chemotherapy did not


yield enough evidence of any clinical effect.15 Overall, due to the lack of conclusive studies, there is insufficient evidence that there are any benefits of using homeopathic remedies.

therapeutic effects, better evidence can emerge if high quality and large-scale randomized controlled trials are performed.29

RISK ASSESSMENT

A high degree of scientific rigour is needed to determine whether homeopathic remedies are anything more than a placebo. Regardless, the popularity of homeopathy and its therapeutic effects suggest that physicians should try to appeal to the individualized needs of each patient. Although it would be unethical to recommend homeopathy if the physician does not believe in its effectiveness, conventional healthcare practitioners should be more open-minded towards integrating the holistic framework of homeopathic treatments to help patients feel a greater personal degree of care.

While homeopathic treatment is generally regarded as safe, temporary negative effects, referred to by homeopaths as “aggravations,” are sometimes seen in patients. These effects are justified by the notion that symptoms must first worsen in order to improve.16,17 Although aggravations, which can depend on the treatment, are generally tolerable, adverse effects can emerge, including swelling, bleeding, abdominal pain, and rashes, with rare cases involving hospitalization.18,19,20 These effects could stem from toxicity or allergic reactions to common homeopathic remedies, including low dilutions of heavy metals (e.g. arsenic, mercury).18 The lack of regulations surrounding remedies also raises concern as the Food & Drug Administration regulates that any ingredient can be considered “homeopathic” and have remedial use.21 When potential allergens, toxins, or heavy metals are involved in the preparation, the risk of adverse effects outweighs any possibility of benefits.

CONCLUSION

REVIEWED BY: DR. JAMES DOUKETIS Dr. James Douketis is a professor in the Department of Medicine at McMaster University. He is the associate director of the clinical teaching unit at St. Joseph’s Hospital and works as a staff physician at St. Joseph’s Hospital for clinical thromboembolism and general internal medicine services. His research interests center on thromboembolism and antithrombotic therapy.

PART 2: CONVENTIONAL MEDICINE CAN LEARN FROM HOMEOPATHY HOLISTIC ASPECT OF HOMEOPATHY

INTEGRATING A PERSONALIZED APPROACH TO CONVENTIONAL MEDICINE

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ing adverse events in routine homeopathic practice. Homeopathy. 2004;93(4): 203-9. Available from: doi:10.1016/j. homp.2004.07.007. Stub T, Salamonsen A, Alraek T. Is it possible to distinguish homeopathic aggravation from adverse effects? A qualitative study. Forsch Komplementarmed. 2012;19(1):13-9. Available from:doi:10.1159/000335827. Posadzki P, Alotaibi A, Ernst E. Adverse effects of homeopathy: A systematic review of published case reports and case series. Int J Clin Pract. 2012;66(12):1178-88. Available from: doi:10.1111/ijcp.12026. Farrell J, Campbell E, Walshe JJ. Renal failure associated with alternative medical therapies. Ren Fail. 1995;17(6):759-64. Available from: doi:10.3109/08860229509037644. Kerr HD, Yarborough GW. Pancreatitis following ingestion of a homeopathic preparation. N Engl J Med. 1986;314(25):1642-3. Available from: doi:10.1056/NEJM198606193142512. Federal Register. Homeopathic Product Regulation: Evaluating the Food and Drug Administration’s Regulatory Framework After a Quarter-Century; Public Hearing [Internet]. Federal Register. 2015. Available from: https://www.federalregister.gov/ documents/2015/03/27/2015-07018/ home opathic-pro duct-re gulation-evaluating-the-food-and-drug-administrations-regulatory-framework [cited 2019 Nov 26]. Jain A. Does homeopathy reduce the cost of conventional drug prescribing?: A study of comparative prescribing costs in general practice. Homeopathy. 2003;92(2):71-6. Available from: doi:10.1016/S1475-4916(03)000043. Tai-Seale M, McGuire TG, Zhang W. Time allocation in primary care office visits. Health Serv Res. 2007;42(5):1871-94. Available from: doi:10.1111/j.1475-6773.2006.00689.x. Shang A, Huwiler-Müntener K, Nartey L, Jüni P, Dörig S, Sterne JA, et al. Are the clinical effects of homoeopathy placebo effects? Comparative study of placebo-controlled trials of homoeopathy and allopathy. Lancet. 2005;366(9487):726-32. Available from: doi:10.1016/S0140-6736(05)67177-2. Ernst E. Is homeopathy a clinically valuable approach? Trends Pharmacol Sci. 2005;26(11):547-8. Available from: doi:10.1016/j.tips.2005.09.003. Brien S, Lachance L, Prescott P, McDermott C, Lewith G. Homeopathy has clinical benefits in rheumatoid arthritis patients that are attributable to the consultation process but not the homeopathic remedy: A randomized controlled clinical trial. Rheumatol Oxf Engl. 2011;50(6):1070-82. Available from: doi:10.1093/rheumatology/keq234. Prousky JE. Repositioning individualized homeopathy as a psychotherapeutic technique with resolvable ethical dilemmas. J Evid-Based Integr Med. 2018;23. Available from: doi:10.1177/2515690X18794379. Swiss Medical Weekly. Beliefs, endorsement and application of homeopathy disclosed: A survey among ambulatory care physicians [Internet]. Available from: https://smw.ch/article/ doi/smw.2017.14505 [cited 2019 Nov 26]. Ernst E. Homeopathy: What does the “best” evidence tell us? Med J Aust. 2010;192(8):458-60. Available from: doi:5694/j.1326-5377.2010.tb03585.x.

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Homeopathy Center. What is Homeopathy? [Internet]. 2017. Available from: https://www. homeopathycenter.org/what-is-homeopathy [cited 2019 Nov 26]. Mathie RT, Ramparsad N, Legg LA, Clausen J, Moss S, Davidson JRT, et al. Randomised, double-blind, placebo-controlled trials of non-individualised homeopathic treatment: Systematic review and meta-analysis. Syst Rev. 2017;6(1):63. Available from: doi:10.1186/ s13643-017-0445-3. Bellavite P. Homeopathy and integrative medicine: Keeping an open mind. J Med Person. 2015;13(1):1–6. Available from: doi:10.1007/s12682-014-0198-x. Armstrong K, Rose A, Peters N, Long JA, McMurphy S, Shea JA. Distrust of the health care system and self-reported health in the United States. J Gen Intern Med. 2006;21(4):292. Available from: doi:10.1111/j.15251497.2006.00396.x. Jonas WB, Kaptchuk TJ, Linde K. A critical overview of homeopathy. Ann Intern Med. 2003;138(5):393-–9. Available from: doi:10.7326/0003-4819138-5-200303040-00009. Homeowatch. Homeopathy’s “Law of Infinitesimals” [Internet]. 2002 Mar 20. Available from: https://www.homeowatch.org/basic/infinitesimals.html [cited 2019 Dec 1]. Grimes, D.R. Proposed mechanisms for homeopathy are physically impossible. Focus Altern Complement Ther. 2012;17(3):149– 55. Available from: doi:10.1111/j.20427166.2012.01162.x. Sagar SM. Homeopathy: Does a teaspoon of honey help the medicine go down? Curr Oncol. 2007 Aug;14(4):126–7. aAvailable from: doi:10.3747/co.2007.150. van Wijk R, Bosman S, van Wijk E. Thermoluminescence in ultra-high dilution research. J Altern Complement Med. 2006;12(5):43743. Available from: doi:10.1089/ acm.2006.12.437. Aabel S, Fossheim S, Rise F. Nuclear magnetic resonance (NMR) studies of homeopathic solutions. Br Homeopath J. 2001;90(1):1420. Available from: doi:10.1054/ homp.1999.0458. Quackwatch. Homeopathy: The Ultimate Fake [Internet]. 2016 Aug 25. Available from: ht t p s : / / w w w. q u a c k watc h . o rg / 0 1 Q u a c keryRelatedTopics/homeo.html [cited 2019 Nov 26]. Office for Science and Society - McGill University. Homeopathic Dilutions Amount to Concentrated Nonsense [Internet]. 2018 Apr 19. Available from: https://www.mcgill.ca/oss/article/ quackery/homeopathic-dilutions-amount-concentrated-nonsense [cited 2019 Nov 26]. Mathie RT. Controlled clinical studies of homeopathy. Homeopathy. 2015;104(4):32832. Available from: doi:10.1016/j. homp.2015.05.003. Molassiotis A, Fernández-Ortega P, Pud D, Ozden G, Scott JA, Panteli V, et al. Use of complementary and alternative medicine in cancer patients: A European survey. Ann Oncol. 2005;16(4):655–63. Available from: doi:10.1093/annonc/mdi110. Milazzo S, Russell N, Ernst E. Efficacy of homeopathic therapy in cancer treatment. Eur J Cancer. 2006;42(3):282-9. Available from: doi:10.1016/j.ejca.2005.09.025. Thompson E, Barron S, Spence D. A preliminary audit investigating remedy reactions includ-

M E D U CATO R

Despite the lack of credible scientific evidence, many patients still report benefits from homeopathy. A 2005 study published in The Lancet reviewed placebo-controlled studies on homeopathy, finding that in the vast majority of these studies, there was no significant difference between effects from homeopathic remedies and placebos.24,25 Interestingly, another study found that upon homeopathic consultation, rheumatoid arthritis patients derived more clinical benefits compared to the standard of care.26 As such, the healing effects that homeopathic patients experience stem mainly from the consultation. Potentially, if physicians integrated a personalized approach to their practice similar to the individualized care offered by homeopathy, the therapeutic outcomes attributed to homeopathy could be replicated.27 A 2017 study which surveyed physicians in Zurich showed that half of those who prescribed homeopathic remedies did so not because they believed in homeopathy, but because they wanted to achieve other therapeutic effects. These effects include the placebo effect of the remedies and the healing effect of the consultation.28 However, an ethical problem is posed when physicians deceive their patients by prescribing remedies that they do not believe provide any clinical effect. Although many reviews that favour homeopathy are selectively biased and do not prove effectiveness beyond non-specific

1.

opinion

Despite the lack of scientific validity, homeopathy offers its patients something on which conventional medicine often falls short: personalized care. Patients who seek homeopathic treatment are attracted to the ‘holistic’ aspect. In contrast to the average of 15.7 minutes spent with primary care physicians, homeopathic patients receive longer individualized treatment, with the average length of an initial consultation being around an hour.22,23 This type of personalized care, combined with overall distrust in pharmaceuticals, contributes to the rise in CAM usage worldwide.

EDITED BY: NURI SONG & NICK TELLER

21


IN T E R V IE W SPOTLIGHT

DR. C A I T L IN MUL L A R K E Y VIRUSES IN THE MODERN WORLD MICHAL MOSHKOVICH2 & SOPHIE ZARB1

1

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

2

This year, we had the pleasure of sitting down with Dr. Caitlin Mullarkey to hear her thoughts on topics ranging from the COVID-19 outbreak to advice for undergraduate students in STEM. Dr. Mullarkey is an Assistant Professor in the Faculty of Health Sciences who specializes in the fields of virology and immunology. A Rhodes Scholar, Dr. Mullarkey had the incredible opportunity of working on a novel influenza vaccination strategy as her PhD during her time at Oxford. As the COVID-19 outbreak is still rapidly developing, some of the statistics quoted in the interview are no longer accurate. This interview was conducted on February 5th, 2020.

AS AN UNDERGRADUATE STUDENT AT SWARTHMORE COLLEGE, YOU WERE AWARDED THE PRESTIGIOUS RHODES SCHOLARSHIP TO STUDY AT OXFORD UNIVERSITY. WHAT WAS THAT EXPERIENCE LIKE AND HOW DID IT IMPACT YOUR RESEARCH INTERESTS? Swarthmore College is a small liberal arts institution and I’m not going to say liberal arts institutions don’t necessarily exist in Canada, but they are certainly rare. I had a broad biology education as an undergraduate and so I didn’t have all these specialized courses that you have at Mac. I took cell biology, organismal and population biology, microbiology, and plant biology. So, I really had a firm understanding in diverse biological disciplines and I was very interested in the little bit of immunology and virology that I learned about in a microbiology course that I took. But I didn’t feel like I had the knowledge to pursue it at a higher level. So that’s what I started to study when I went to Oxford, and I really got into immunology and virology as a graduate student. I initially did a master’s degree in immunology, and as a part of that master’s, a short research project in a lab that worked on influenza virus vaccines, which became the focus of my career. So my experience at Oxford, as a Rhodes Scholar, really started my trajectory in virology and immunology, something that I did a master’s in, a PhD, and then a postdoc, and now it’s something that I love to teach to undergrads.


There have been three coronavirus outbreaks in the 21st century. The first would have been SARS (2003) which is very familiar to the Canadian population, MERS in 2012, and now this new coronavirus. There are certain features of this virus that are good, and there are certain features of this virus that are bad. And remember this is an outbreak that’s unfolding so our information is still evolving. People are publishing papers every single day with new data and information that help shape our response and our view of this outbreak. So what are some good things about this virus? If we compare it to its cousin SARS at the sequence level, it shares about 80% nucleotide homology. SARS had a mortality rate of about 10%. This new virus seems to be quite a bit lower at about 2%. So from a mortality standpoint, maybe less of a concern than SARS. However, there is higher morbidity with this virus, meaning more people are infected. SARS infected around 8,000 people. This virus has around 25,000 confirmed cases, which could be an underestimate. Some people say that over 100,000 people are affected. I’ll point out that the vast majority of deaths, 80% of the mortalities are in individuals over 65. So the virus seems to disproportionately affect older people that might have other comorbidities. There is definitely evidence that it is transmitting human to human and that there is community- acquired viral transmission. In SARS, there were a lot of what we call “nosocomial infections,” meaning infections happening in hospitals with healthcare workers and other people that were in the hospitals. But we didn’t see a lot of community-acquired SARS. This virus looks different in that way. And in fact, even when we talk about community-acquired viruses, they resemble a little more of influenza viruses, which are spread within the community. This presents some challenges from a quarantine perspective, as it’s very difficult to stem the spread and isolate infected individuals. I would say, globally, WHO (World Health Organization) is approaching it correctly. I think health agencies around the world are, for the most part, giving it a healthy amount of concern. I don’t think we need to panic here at McMaster or in Canada —we only have four confirmed cases.

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HOW DOES THE EMERGING CORONAVIRUS PANDEMIC COMPARE WITH OTHER RECENT VIRUS OUTBREAKS, INCLUDING THE SARS CRISIS OF 2003? Most people that were infected with SARS experienced severe disease and were symptomatic, which means they got the virus, felt very terrible, and a lot of them showed up in hospital. Because that virus manifested with more severe disease, it allowed us to isolate individuals that presented symptoms, and what was responsible for stopping the outbreak was good isolation and quarantine measures. One of the differences with this new coronavirus is that not all people infected are experiencing severe symptoms so they are not turning up at the hospital or they might not even be staying home from work or school. This presents a problem for the current outbreak and is at least one reason why we are seeing this sustained, humanhuman transmission. If you don’t know you are sick, and you don’t know that you have been

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ONE OF THE BIGGEST NEWS STORIES THIS WINTER HAS BEEN THE GLOBAL THREAT OF THE CORONAVIRUS. PANIC AND FEAR HAVE SPREAD EVEN FASTER THAN THE VIRUS ITSELF AND INCREASED DEMAND FOR MASKS AND HAND SANITIZER HAVE DEPLETED STOCK EVERYWHERE. IN YOUR OPINION, IS THIS FEAR JUSTIFIED, BASED ON THE INFORMATION AVAILABLE TODAY, AND WHY OR WHY NOT? Is this something we should be worried about as a global scientific community? I think that there’s definitely evidence that we should have a health concern about this virus and how it’s spreading, as well as what that means for public health. Because we live in an age of global travel, this presents some challenges when we have new pathogens that arise and are transmitting in certain areas of the world. So I think as a global scientific community, should we be concerned about it? Yes. Do we need to be worried about it here at McMaster and Canada? Not yet. Coronavirus is a very large family of RNA viruses. They are responsible for 10-30% of the colds we experience over the winter. They are a pathogen that is very common to humans —

most of us will have already been infected with coronaviruses.

interview spotlight

AS YOU HAVE TAUGHT US IN OUR BIOCHEMISTRY AND CELL BIOLOGY COURSES THIS YEAR, VACCINATION IS THE MOST EFFECTIVE WAY TO PREVENT VIRAL INFECTION. CAN YOU TELL US ABOUT THE PROCESS INVOLVED IN DEVELOPING A NEW VACCINE? The process of developing a new vaccine can be very protracted; taking decades for the vaccine to reach the clinic if it even does. There are many hurdles that prophylactic vaccines need to overcome. First, you have to have in vitro, animal model, or serological evidence in humans that what you want to target on the virus or in the viral life cycle will in some way inhibit that virus from replicating. We call this proof of principle. Once you have this evidence, you need to choose how you are going to deliver your vaccine. You would do some testing again in cell culture and in vitro models first. If that looked good you would move on to animal models, assuming that there is an animal model for your particular disease pathogen. If everything looked good after testing on animal models and the vaccine was still eliciting a protective response, you would then move into human clinical trials. If you get there, there is usually another hurdle I should mention in this process; besides just having good data you also have to have money. Bringing a vaccine to the clinic takes an estimated billion dollars, and at any point, drug companies or whoever is developing, can say, “well, we’re not going to fund this anymore because it’s just too much money, and there’s not enough evidence that this is going to work or that it is going to be profitable.” We continue to monitor the safety of the vaccine and the adverse effects even after its license. In this age of vaccine hesitancy, where people may have some questions about vaccines or are reluctant to receive vaccines because they doubt their safety, we take that into consideration both before and after the vaccine is licensed. We monitor these things and if any data suggests that there are some cluster of adverse effects, this is immediately monitored by government agencies. So, the process is very rigorous and the vast majority of candidates will not make it to the clinic. The vaccines that we have are certainly safe and have gone through very rigorous testing.

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in contact with somebody that has potentially been sick, it is very difficult to put into place quarantine, isolation, and contact-tracing measures. And, again, the good thing about this new virus is that it doesn’t really cause, in most people, very severe disease. The bad thing is as a result, this makes it harder for us to trace and control it through traditional means.

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table of contents interview spotlight

Coronaviruses infect a very wide range of species, so their virus is familiar to humans because of the common cold that affects many individuals over cold and flu season. Coronavirus also infects many different mammals like bats, camels, and civet cats. What we know from the SARS outbreak in the early 2000s is that the virus originally came from a bat, and the bat virus infected civet cats, most likely in China’s live animal markets where we bring together a whole bunch of species that are not usually used to coming into contact with each other in the wild. Civet cats are a delicacy in China that are consumed by humans, and that is how we think we got SARS from bats.

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The evidence suggests that this virus looks a lot like a bat virus —it’s about 96% identical. We are not exactly sure though if there’s any intermediate species at play here, whether or not this virus has jumped directly from bats into humans or maybe has gone through another species along the way. WITH SO MUCH ATTENTION BEING FOCUSED ON THE WUHAN CORONAVIRUS OUTBREAK, LESS ATTENTION IS BEING PAID TO ANOTHER, PERHAPS MORE DEADLY VIRUS THAT HAS ALREADY KILLED THOUSANDS OF PEOPLE AND HAS INFECTED MANY MORE —THE FLU. DESPITE THE FACT THAT A FLU VACCINE IS WIDELY AVAILABLE AND ACCESSIBLE EVERY WINTER, MANY PEOPLE CHOOSE NOT TO BECOME VACCINATED. HOW WOULD YOU ACCOUNT FOR THIS UNFORTUNATE REALITY? The flu vaccine is unique from any other vaccine in that every year we have to reformulate it. The vast majority of vaccines you get as a child protect you for life, whereas flu vaccines we have to get a new one every year. It is a vaccine that is partially effective, and its effectiveness depends on how well the strains of the vaccines are matched to the strains that are circulating in humans. So I think part of the reason why people have been reluctant to take up the vaccine may be due to its efficacy in certain years that we have not gotten it right. It is not very efficacious and so people do not see a benefit in getting the vaccine. I think there are a lot of myths surrounding the flu vaccine that also explain why people are hesitant. People say, you know, “Oh, you can get the flu from the flu vaccine.” That’s not true. “I’m healthy, I don’t need it.” Okay. It’s not just about you. It’s about stemming the spread of flu within the community. It’s unfortunate because if we are going to compare the flu to the ongoing coronavirus in terms of morbidity, its mortality far surpasses the outbreak of the coronavirus that’s happening globally. As far as I know, there are no licensed antivirals for coronaviruses. There are some that are experimental, papers that say “XYZ” antivirals can work against coronaviruses and they’re massively scrambling to try to mobilize some of those for this particular outbreak.

IN YOUR OPINION, CAN WE LEARN ANYTHING FROM THE SUCCESS OF SCHOOL-BASED VACCINATION STRATEGIES, SUCH AS THE HPV VACCINE PROGRAM IN ONTARIO? HAS THIS APPROACH BEEN EXPLORED FOR THE FLU VACCINE? Nationally, there are not mandatory immunizations for school attendance. Only Ontario and New Brunswick have this policy. There are certain states that have piloted influenza vaccines in schools and are looking at the cost-benefit analysis. This is not completely applicable to Canada because the flu vaccine is paid for by OHIP. Thus, in the US, that cost benefit analysis is shaped a little bit differently in terms of who is paying for the vaccine. I think if it increases uptake, it’s definitely a good idea. I think that there are some logistical challenges because, like I said, flu vaccines have to be administered every year and they change every year. Rolling this out in a school system is no small feat, but if it increases uptake, and there is definitely evidence from these US studies that it does increase uptake, I’m all for it. ON A DIFFERENT NOTE, WE UNDERSTAND THAT YOU TEACH AN ONLINE COURSE ENTITLED DNA DECODED. CAN YOU TELL US WHAT PROMPTED THE CREATION OF THIS COURSE? WHAT DIFFERENCES DO YOU SEE BETWEEN IN CLASS AND ONLINE LEARNING? HOW DO YOU THINK THE ONLINE FORMAT LENDS ITSELF TO EDUCATION, AND SPECIFICALLY TO THE SCIENCES? Online learning has experienced a huge boom in the last decade. I think people are very excited about these educational platforms in terms of changing the scope of what’s accessible in higher education. I don’t know if they’ve quite lived up to the hype, but there is certainly really rich online content now on a variety of disciplines. It’s free and is taught by experts. One of the sites that hosts a lot of these massive open online courses or MOOCs as they’re called is Coursera, and you can go on Coursera and take an online course and learn how to program, or learn quantum physics, and so forth. So, I think that’s certainly very exciting. Who is actually accessing that information? What demographics are using these platforms? You might be surprised to learn that the vast majority of people that access these platforms already have undergraduate degrees or some level of higher education. So, is it reaching the demographics we thought it would? To some extent, but still our ability to make these online courses and reach large audiences is very beneficial. It was an exciting project to take on. So far that course has somewhere around 6000 learners that have accessed it in some capacity, so it feels good that we’ve been able to reach people on different continents across different age ranges and different educational levels, but it’s certainly a different experience than having face time with the students.


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