Issue 35

APRIL 2019 | ISSUE 35

PACRITINIB EXPLORING ANOTHER PIECE A N OV E L T R E AT M E N T F O R M Y E LO F I B R O S I S OF THE PUZZLE CLEARING C O M O R B I D M E N TATHE L H E A LTSMOKE H C H A L L E N G EON S IN CHILDREN 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 CANNABIS A N I N T E RV I E W W I T H D R. J A M E S M A C K I L LO P, CPHYSICIAN-ASSISTED O - D I R E CTO R O F T H E M I C H A E L G. D E GDYING R O OT E N EI DN I CA I A N NE AN BDI SO FR EL SI FEEA CA CA ENNETWR EO FP OT IROM C I NNAALD CA R C RH E

SHINING LIGHT ON BIOMEDICINE: THE HIDDEN CURRICULUM WW WACTI NOMNA NN,UDRISRI ENCT I TNST EURV N DI E RA P PI TRHE CDI R.B AT ERDU ICME PA G OR OF E D UI O CAT ET DH UE CAT N I O N P R O G RA M I N A N ATO M Y

WWW.MEDUCATOR.ORG

table of

CONTENTS

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I

ISSUE 35

TOC ARTIST

KARISHMA MEHTA

02 INTRODUCTION 03 MEDPULSE 05 MEDBULLETIN 07 PATHOPROFILE 09 ABSTRACTS 11 FORUMSPACE OPINION 13 Youth tobacco use: A pressing global health and human rights challenge CRITICAL REVIEW 15 Pacritinib: A novel chemotherapeutic agent for treating myelofibrosis 19 Understanding regulatory B Cell development with single cell analyses 23 INTERVIEW SPOTLIGHT UNDERGRADUATE NURSING JOURNAL 26 The medicalization of childbirth: A necessary practice for safety or a lack of evidence-based practice? 28 “Be the Bridge” collaboration: Our journey 31 What is the hidden curriculum, and how does it affect nursing students? 3 4 CONTRIBUTORS

COVER ARTIST WENDY ZHANG

M E D U CATO R | DAT E M E D U CATO R | A P R I L 2019

table of of contents table contents

APRIL 2019

ISSUE 35 INTRODUCTION INTRODUCTION

dear reader, Welcome to Issue 35 of The Meducator! The field of health sciences is under trial. Whether it is the deep-rooted skepticism surrounding vaccinations or the increasing tide of patients turning towards alternative therapies, healthcare debates can have serious implications for the health of individuals and populations. We are future professionals, researchers, policymakers and citizens; as captured by Wendy Zhang’s cover design, it is our responsibility to turn this tide by being stewards of good science. Just as how the physician is depicted to be scrutinizing the minute details of their patient’s retina, Wendy reminds us to appraise the news and literature in sciencewith a finer comb. This starts by looking within. After all, translating scientific knowledge is a process: one that starts with the personal awareness to acknowledge the privileges afforded to us by our education. In Issue 35 of The Meducator, we look outwards. An opinion piece written by Michael Lee and Puru Panchal focuses on the prevalent youth tobacco use in Indonesia and the public health issues that it presents. This issue also features abstracts from the International Women and Children’s Health Conference that explore the topics of endometriosis, reproductive health needs in Uganda, and mental health issues within immigrant and refugee families.

In this Issue, we continue to highlight recent developments in the basic sciences, especially relating to immune pathologies. Editors Milena Cioana and Sarah Asbury examine the disease mechanisms and the clinical presentation of Hodgkin’s lymphoma in this issue’s Pathoprofile. In his critical review, Kashyap Patel highlights the therapeutic potential of pacritinib in treating myelofibrosis, a rare bone marrow disorder. This is followed by Samantha Visva’s critical review of the use of computer modeling to uncover the complex mechanisms underlying regulatory B cell development.

introduction

In Issue 35 of The Meducator, we also look within. In this issue’s ForumSpace, Fellows Chloe Gao, Kartik Sharma, and Peter Belesiotis discuss their planned use of student panels to promote a culture of sexual consent within McMaster University. Dr. James MacKillop, Co-Director of the Michael G. DeGroote Centre for Medicinal Cannabis Research, kindly provides us with timely insights on the future of medicinal cannabis in Canada.

We are excited to continue our newfound collaboration with McMaster students from our School of Nursing. Issue 35’s Nursing Section features an opinion piece by Lauren Filbey that addresses the over-medicalization of childbirth; a global perspective detailing a pilot project to improve health literacy in a lowincome Hamilton community; and a critical review by Simon Farquharson on the underappreciated role of hidden curricula on nursing education.

Sincerely,

M E D U CATO R

We are incredibly thankful to the many talented individuals who have lent their unique strengths to this issue of The Meducator. Kevin, Sheila, Matilda, Bob, Adrian, Edward, Parnika, and Daniel, thank you so much for being incredible student leaders. We would also like to thank the McMaster community for supporting us and engaging with our content. As you read our issue, please remember: science needs you. Exercise your eyes, ears, and voice. Turn the tide: one individual, one family, and one community at a time.

| A P R I L 2019

EVA LIU

Bachelor of Health Sciences (Honours) Class of 2020

OWEN DAN LUO

Bachelor of Health Sciences (Honours) Class of 2019

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AUTHOR: DANIEL DIATLOV & JESSICA CHEE

MEDP

Measles outbreaks continue in US cities January 2019 // US Over the last several months, over 200 cases of measles have been reported on the east and west coasts of the US. Cases have been reported in the states of Washington and New York, and have been attributed to the anti-vaccination movement. Most states allow for exemption from vaccination based on religious beliefs, but 18 states (including Washington), also allow parents to opt out of vaccinating their children based on personal beliefs. The measles virus is highly contagious and kills 1 in every 1000 children, with people between the ages of 5 and 20 at greatest risk.1

A new mobile app to combat mosquitoborne diseases February 2018 // Atlanta, US The Epi Info Vector Surveillance application is a mobile app developed by the Centers for Disease Control and Prevention (CDC) that allows users to track and enter mosquito surveillance data. The data is uploaded to a dashboard that provides users with local trends related to mosquito-borne diseases. The app is currently optimized for surveillance of mosquitoes in the Aedes and Culex genera, with Anopheles surveillance under development. The creators of this app hope to improve the quality of mosquito data and identify popular breeding sites of diseasecarrying mosquitoes in real-time.2

Marburg virus found in bats in Sierra Leone December 2018 // Sierra Leone The deadly Marburg virus has been found for the first time in bats in West Africa. Marburg virus causes similar symptoms to the Ebola virus, and is often fatal. Although no cases of human infection have been reported in the area, people living near the bats may be at risk. The bats transmit the virus through their saliva, feces, and urine as they feed on fruit. Contaminated fruit and bat bites may then pass the virus on to humans or other animals.3

Blood marker to monitor Alzheimer’s disease January 2019 // Bonn, Germany Blood tests present a promising diagnostic method for Alzheimer’s disease (AD) due to their relatively low cost and ease of access. A group from the German Center for Neurodegenerative Diseases has recently found a potential biomarker for AD, the neurofilament light chain (NfL) protein. The researchers found that elevated NfL levels in the cerebrospinal fluid correlated with high serum NfL levels prior to the onset of AD symptoms. However, NfL levels are only indicative of familial AD, which represents approximately 5% of AD cases.4

PULSE

ARTIST: ESRA RAKAB

Cloning monkeys for disease research in China January 2019 // China Primates are the ideal animal model for studying higher brain function and brain disorders. However, a high sample number of monkeys is needed to determine whether or not results are due to genetic variation. Recently, scientists in China have successfully genetically modified and cloned macaques to produce five primates with almost identical genes. As this process becomes more refined, it will hopefully provide a more eďŹƒcient animal model to study neurological diseases free from influences due to genetic variations.8

Immigration to US alters gut microbiome November 2018 // Southeast Asia US immigrant populations were shown to be more susceptible to metabolic diseases post-immigration. This may be due to rapid changes in the gut microbiome. Researchers examined the gut microbiomes of US immigrants from Southeast Asia. They recruited new immigrants from the Hmong and Karen tribes, ethnic minorities originally from China and Myanmar. There was a significant loss of diversity in their gut microbiomes soon after immigration. In addition, overall microbiome diversity continued to decrease the longer participants remained in the US.7

Shigella resistance to azithromycin and ciprofloxacin January 2019 // Victoria, Australia Shigellosis is a highly infectious disease caused by Shigella bacteria. Infected individuals typically experience diarrhea, stomach cramps, and fever. To test for antimicrobial resistance, Shigella isolates were taken from infected patients in Victoria, Australia, between January 2016 and March 2018. Antibiotic resistance rates towards ciprofloxacin and azithromycin were high, at 17.6% and 50.6%, respectively. This is of particular concern because ciprofloxacin is currently the first-line oral treatment for Shigella, with azithromycin being the second-line treatment.5

Drones deliver vaccines to the remote islands of Vanuatu December 2018 // Vanuatu One of the greatest challenges of living in a remote location is accessibility to modern medicine. Vanuatu, a chain of islands in the South Pacific, is a perfect example: its hot climate, mountainous landscape, and frequent rain make it diďŹƒcult to deliver vaccines between islands. The use of drones has proven to be an excellent solution. The drones fly from island to island with vaccines kept cool in temperature-monitored styrofoam boxes. This technology provides an important global health solution that can easily be applied in other remote nations.6

REFERENCES CAN BE FOUND ON MEDUCATOR.ORG

MEDBULLETIN SUSTAINED PAIN

M E D U CATO R

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medbulletin

CHANGING OUTCOME MEASURES FOR TARGETED PAIN THERAPY

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OSTEOPOROSIS GENE REPAIR A NEW MOLECULAR RECEPTOR LINKING β-THALASSEMIA: EXERCISE AND A NEW ROAD TO A BONE CURE DEVELOPMENT

TA K HL I Q A MIR

TAK HLI Q AMIR

Chronic pain affects almost one-fifth of Canadians, representing around 6 million people. 1 Normally, the reaction to painful stimuli involves two distinct responses. The first-line response is a reflexive withdrawal to prevent or limit injury, while the second-line response involves coping behavioural reactions, such as pressing on an injury to alleviate sustained pain. 2,3 Despite being considered important evolutionary responses, the mechanism by which these signals travel between the body and the brain remains unknown.

Osteoporosis is a disorder characterized by the age-related weakening of bone, and is commonly associated with the decrease in estrogen production in women over time. 1 It is estimated that over 2 million Canadians suffer from osteoporosis. 2 The decrease in bone mineral density occurs when the rate of bone resorption exceeds formation, a process largely mediated by osteocytes, the most abundant regulatory cells found in bones. 3 Since osteocytes decrease in number over time, they play a key role in the pathogenesis of age-related osteoporosis.

A recent study published by Huang et al. presents an answer to this, demonstrating that separate neural pathways govern the reflexive and coping responses following an injury. 4 The researchers suggest that TAC1 neurons, located in the dorsal horn of the spinal cord, mediate the sustained pain nerve-signalling pathway. By assessing pain response in TAC1-intact mice in comparison to mice with chemically-inactivated TAC1 neurons, the researchers showed that TAC1-disabled mice exhibited loss of pain-coping behaviours (e.g. paw licking), with no effect on normal withdrawal reflexes. 4 In contrast, TAC1-intact mice exhibited normal prolonged paw licking following injury. It was further concluded that TRPV1 neurons, which are known to mediate the sensation of prolonged pain, connect to TAC1 neurons in the dorsal horn to relay pain signals to the brain. 4 These findings are of great significance because of their clinical “bench-to-bedside” implications. Current methodologies to assess the efficacy of pain-relieving compounds often measure the initial reflexive response for chronic pain assessment, rather than the sustained pain response due to tissue damage. 5,6 The researchers suggest that measuring the wrong outcome could have discounted some drug therapies as ineffective when they may have successfully ameliorated sustained pain. With the costly societal impacts of chronic pain and the ongoing opioid epidemic, the research by Huang et al. presents a new opportunity to develop treatments prioritizing the deep, sustained pain response over reflexive withdrawal behaviours.

Irisin is a hormone released by muscles during exercise that was discovered in 2012. 4 Despite its demonstrated beneficial effects in exercise, the underlying role of irisin in the molecular mechanisms of exercise and bone development has been unclear. A team of researchers from the Dana-Farber Cancer Institute recently discovered new irisin receptors, which may represent the link between exercise and bone development. 5 The newly discovered irisin receptors belong to the αV class of integrins, and enable irisin to bind to and activate osteocytes. 6 Using a mouse model, the group demonstrated that injection of irisin elevated sclerostin levels, which is characteristic of bone resorption. 6 Additionally, in mice that had undergone ovariectomies to simulate osteoporosis, the genetic ablation of irisin hindered osteocytic osteolysis, thereby protecting against bone loss. 6 The discovery of irisin receptors has the potential to influence future therapies for osteoporosis. Despite its role in bone resorption, some patients have shown improvements in bone density following intermittent irisin treatment. 7 Future steps include investigating isoforms of irisin and its receptors as well as irisin inhibitors. Researchers are also interested in further exploring irisin’s potentially differential effects in other areas where it is highly expressed, including skeletal muscle, the heart, and the brain. 6

1.

Schopflocher D, Taenzer P, Jovey R. The prevalence of chronic pain in Canada. Pain Res Manag. 2011;16(6):445-50. Available from: doi:10.1155/2011/876306.

1.

Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: Now and the future. Lancet. 2011;377(9773):1276-87. Available from: doi:10.1016/S0140-6736(10)62349-5.

2.

Pesheva E. Nerve-signaling pathway that drives sustained pain found [Internet]. 2018 Dec 13. Available from: https://news. harvard.edu/gazette/story/2018/12/researchers-identify-pathway-that-drives-sustained-pain-following-injury/ [cited 2019 Feb 15].

2.

Osteoporosis Canada. Impact Report 2018. Canada: Osteoporosis Canada; 2018. 6 p.

3.

3.

Price DD, Dubner R. Mechanisms of first and second pain in the peripheral and central nervous systems. J Invest Dermatol. 1977;69(1):167-71. Available from: doi:10.1111/1523-1747.ep12497942.

Rochefort GY. The osteocyte as a therapeutic target in the treatment of osteoporosis. Ther Adv Musculoskelet Dis. 2014;6(3):7991. Available from: doi:10.1177/1759720X14523500.

4.

4.

Huang T, Lin SH, Malewicz NM, Zhang Y, Zhang Y, Goulding M, et al. Identifying the pathways required for coping behaviours associated with sustained pain. Nature. 2019;565(7737):86. Available from: doi:10.1038/s41586-018-0793-8.

Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463. Available from: doi:10.1038/nature10777.

5.

5.

J Cobos E, Portillo-Salido E. “Bedside-to-bench” behavioral outcomes in animal models of pain: Beyond the evaluation of reflexes. Curr Neuropharmacol. 2013;11(6):560-91. Available from: doi:10.2174/1570159X113119990041.

Saltus R. ‘Exercise hormone’ found to target key bone cells [Internet]. The Harvard Gazette. 2018 Dec 14. Available from: https://news.harvard.edu/gazette/story/2018/12/exercise-related-hormone-irisin-found-to-target-key-bone-cells/ [cited 2019 Feb 14].

6.

Smith ES. Advances in understanding nociception and neuropathic pain. J Neurol. 2018;265(2):231-8. Available from: doi:10.1007/s00415-017-8641-6.

6.

Kim H, Wrann CD, Jedrychowski M, Vidoni S, Kitase Y, Nagano K, et al. Irisin mediates effects on bone and fat via αV integrin receptors. Cell. 2018;175(7):1756-68. Available from: doi:10.1016/j.cell.2018.10.025.

7.

Colaianni G, Mongelli T, Cuscito C, Pignataro P, Lippo L, Spiro G, et al. Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Sci Rep. 2017;7(1):2811. Available from: doi:10.1038/s41598-017-02557-8.

BRAIN CANCER

ALZHEIMER’S

AN OPPORTUNITY FOR CAR T CELL BASED THERAPY

SCRAMBLED GENE IN TANGLED BRAINS J AMES YU Emerging evidence indicates that neurons in the brain can display somatic mosaicism, which means that they are genomically different from one another. 1 These genomic differences between neurons are the result of mutations during aging, and may contribute to the development of neurodegenerative diseases including Alzheimer ’s disease (AD). 1,2 Patients who develop AD have more copies of the amyloid precursor protein (APP) gene in their neurons than healthy individuals. 1

However, a recent study conducted by Samaha et al. could circumvent this challenge. Samaha et al. noted that cancer endothelial cells overexpress a protein called activated leukocyte cell adhesion molecule (ALCAM). 2,3 Binding of the T cell CD6 ligand to ALCAM allows T cells to migrate out of the blood vessel and infiltrate the brain. 3,4 With this in mind, the researchers generated a highlyspecific synthetic CD6 analogue with multiple binding domains for ALCAM, named homing-system CD6 (HS-CD6). 3,4 This new ligand was inserted into a CAR T cell that recognizes tumour-associated antigens commonly found in glioblastoma cells. 2 The CAR T cells were then tested in a mice model with surgically-implanted glioblastomas.

In a groundbreaking study, Lee et al. suggest a mechanism by which abnormal forms of the APP gene can be incorporated into the neurons of patients with AD. 3 Normally, neurons transcribe mRNA copies of the APP gene, which can be translated into proteins for common brain functions such as learning and memory. However, in some cases, the reverse transcriptase enzyme can turn the RNA back into DNA, creating copies of the APP gene that can be added back into the neuron’s genome in the form of genomic cDNAs (gencDNA). 3 Because reverse transcriptase is prone to making errors when converting RNA into DNA, the copies of the APP gene integrated back into the genome are often mutated variants. The cleavage of these mutated APP variants can result in the creation of toxic beta-amyloid plaques that interfere with brain function and cause sporadic AD. 1,3

The researchers found that mice injected with the HS-CD6 CAR T cells experienced complete remission of cancer. 3 While this finding is promising, further research is required to see if this CAR T cell therapy can also persist in an immunosuppressive microenvironment and cause minimal toxicity. 1,4 Ultimately, the findings by Samaha et al. will likely contribute to a novel strategy to target solid brain tumours using CAR T cells. Editor ’s note: “A homing system targets therapeutic T cells to brain cancer ” by Samaha et al. 3 has been retracted in Nature as of 20 February, 2019 due to issues with figure presentation and underlying data.

medbulletin

JA ME S YU Chimeric antigen receptor (CAR) T cells are genetically-engineered T cells that bind to specific tumour markers via their CAR receptors. This leads to CAR T cell proliferation and elimination of their target cancer cells. 1 However, creating CAR T cells that target solid tumours is difficult because tumour tissues frequently downregulate ligands recognized by T cells. 1 Furthermore, brain cancers, including glioblastoma, are protected by the blood-brain barrier, which prevents CAR T cells from accessing these targets.

In accordance with age being one of the strongest risk factors for AD, Lee et al. found that APP gencDNA increased with age in murine models. 3,4 Furthermore, when reverse transcriptase inhibitors were introduced, the formation of APP gencDNA greatly decreased. Consequently, the researchers suggested that drugs blocking reverse transcriptase may affect AD onset. These findings may prompt novel investigations in AD pathophysiology, a field that has long been stagnant. M E D U CATO R

2. 3. 4.

1.

Platten M. T cells engineered to home in on brain cancer. Nature. 2018;561(7723):319–20. Available from: doi:10.1038/ d41586-018-05883-7.

Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR, Rehen SK, et al. Genomic mosaicism with increased amyloid precursor protein (APP) gene copy number in single neurons from sporadic Alzheimer’s disease brains. Elife. 2015;4:e05116. Available from: doi:10.7554/eLife.05116.

2.

Samaha H, Pignata A, Fousek K, Ren J, Lam FW, Stossi F, et al. A homing system targets therapeutic T cells to brain cancer. Nature. 2018;561(7723):331–7. Available from: doi:10.1038/s41586-018-0499-y.

Lodato MA, Rodin RE, Bohrson CL, Coulter ME, Barton AR, Kwon M, et al. Aging and neurodegeneration are associated with increased mutations in single human neurons. Science. 2018;359(6375):555–9. Available from: doi:10.1126/science.aao4426.

3.

Brown MH, Dustin ML. Steering CAR T cells into solid tumors. N Engl J Med. 2019;380(3):289–91. Available from: doi:10.1056/NEJMcibr1811991.

Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, et al. Somatic APP gene recombination in Alzheimer’s disease and normal neurons. Nature. 2018;563(7733):639–45. Available from: doi:10.1038/s41586-018-0718-6.

4.

Verheijen BM, Vermulst M, van Leeuwen FW. Somatic mutations in neurons during aging and neurodegeneration. Acta Neuropathol. 2018;135(6):811–26. Available from: doi:10.1007/s00401-018-1850-y.

A P R I L 2019

D’Aloia MM, Zizzari IG, Sacchetti B, Pierelli L, Alimandi M. CAR-T cells: The long and winding road to solid tumors. Cell Death Dis. 2018;9(3):282. Available from: doi:10.1038/s41419-018-0278-6.

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HODGKIN’S LYMPHOMA Pathoprofile

AUTHORS: Milena Cioana & Sarah Asbury ARTIST: Suffia Malik EDITED BY: Kevin Chen & Sheila Yu

INTRODUCTION Hodgkin’s lymphoma (HL) is a type of cancer that affects the lymphatic system. It is one of the most common lymphomas in the Western world, with an annual incidence of about 3 cases per 100,000 persons.1 In 2017, 990 Canadians were diagnosed with HL, of which 140 died.2 The age groups most affected by HL are individuals 20-40 years old and those 55 or older. In general, cancerous tumours are the result of transformed cells that proliferate uncontrollably and invade healthy tissues.3 While HL usually starts in peripheral lymph nodes, it can also affect organs such as the liver, lung, and the bone marrow.2 The tumour cells causing the malignancy can take on different phenotypes, and as a result the disease is divided into two major types: classical HL and nodular lymphocyte-predominant HL. This Pathoprofile will focus specifically on the classical form of HL, which accounts for 95% of HL cases.1

CELLS IN CLASSICAL HL HL is diagnosed by the presence of transformed B cells known as Hodgkin and ReedSternberg (HRS) cells, which drive tumourigenesis.4 Although HRS cells are critical to HL pathogenesis, they only comprise 1 – 10% of the tumour tissue, which is otherwise dominated y normal fi ro lasts, endothelial cells and infiltratin immune cells.5

Chromosomal Translocation

Pro-B Cell

Lymph node

B CELL DEVELOPMENT

Double-stranded DNA break NFκB or

B cells are an integral component of the adaptive JAK/STAT immune system responsible for the production of antibodies that related gene Immunoglobulin Promoter recognize foreign or self molecules known as antigens.6 Antibodies contain a variable region which can bind the antigen, and a constant region which can activate the immune response. The immune system must recognize a diverse repertoire of antigens to protect the host from the extensive number of pathogens encountered during their lifetime. This diversity is generated by genetic recombination which involves the introduction of double-stranded breaks in the DNA. This produces B cells that express a unique B cell receptor. After a naïve cell encounters its correspon in anti en for the first time, it will un er o a itional recom ination e ents terme somatic hypermutation as well as class switching before becoming a mature B cell.6

TRANSFORMATION INTO HRS HRS cells, the tumour cells responsible for HL, originate from clonally related mature B cells as evidenced by their identical gene recombinations at the antibody locus.7 The properties of cancerous cells are acquired, in part, from mutations affecting protooncogenes, which are typically genes that promote proliferation and cell survival. Proto-oncogenes can become cancer-causing oncogenes if mutated or upregulated.8 HRS cells acquire transforming mutations from chromosomal translocations that result from inappropriate resolution of double-stranded DNA breaks elicited by antibody gene recombination.4 Typically, proto-oncogene expression is tightly regulated to prevent unwanted cellular proliferation and survival. The translocation of the proto-oncogene downstream of the antibody transcription promoter results in constitutive expression, thus causing continuous unregulated oncogene activation.9,10 Typically, B cells with deleterious B cell receptors undergo apoptosis; however, HRS cells escape apoptosis and do not mature further.11 HRS cells resemble pre-apoptotic germinal centre B cells that have undergone somatic hypermutation.10

CELL SIGNALING PATHWAYS IN HL

7

NF-kB and JAK-STAT cell signalling pathways are commonly affected by oncogenes expressed in HRS cells.7,9,12–15 While both of these pathways are normally activated in B cells and other immune cells, they are not constitutively active as in the malignant cells of classical HL.16 NF-kB is a transcription factor important for lymphocyte proliferation and survival, thereby endowing

it with oncogenic potential.17 Deregulated activation of the NF-kB pathway due to constitutively expressed NF-kB-related oncogenes can contribute to a cancerous phenotype in HRS cells. This is achieved by inducing unregulated proliferation, increasing the likelihood of cell survival and tissue invasion, and producing cytokines that contribute to the tumour microenvironment.18 The JAK-STAT pathway, normally activated by cytokines, regulates cell proliferation, differentiation, and survival, thereby also endowing it with oncogenic potential.15 JAK-STAT pathway mutations in HL can lead to constitutive activation of STAT transcription factors regardless of cytokine binding, resulting in uncontrolled cell proliferation and survival.9 Dysregulation of both the JAK-STAT and NF-kB pathways is mechanistically diverse and can be caused by oncogenes affecting proteins at any step that either increase pathway activation or decrease activity of pathway inhibitors.15

TUMOUR MICROENVIRONMENT n HL, only a small proportion of the tumour tissue is compose of the mali nant H cells.9 mmune cells inclu in an cells, eosinophils, neutrophils, plasma cells, an mast cells infiltrate the lymphoma an su stantially contri ute to tumour mass. espite immune infiltration, the tumour is not estroye ecause of a hi hly immunosuppressi e en ironment.19 HRS cells can produce anti in ammatory cyto ine β and induce T regulatory cell differentiation, which can prevent T cell activation.19 There are also intrinsic changes to HRS cells that aid in immune evasion. They often carry a mutated β2-microglobulin, a component of MHC class , resultin in re uce anti en presentation to cytoto ic cells.4 n some cases, the patient s H cells will irectly inhi it cell activation by upregulating programmed death-ligand 1 (PD-L1).4 Activated T cells express the PD-1 receptor and binding of H cell P L to cell P inhi its the cell response. P L is often upre ulate followin copy num er amplification, which is a common translocation affecting the JAK-STAT pathway in HRS cells.4,20 Blocking PD-1 mediated T cell suppression, termed “checkpoint inhibition”, is a novel therapeutic target Proliferating for treating HL.20 Preliminary clinical data suggests PD-1 checkpoint inhibition may transformed B Cells e especially efficacious in HL patients with high copy numbers of JAK2.20

CLINICAL PRESENTATION

Hodgkin’s and Reed-Sternberg Cells

Patients with HL present with enlarged lymph nodes at the site of disease resulting from tumour tissue composed of H cells an tumour infiltratin immune cells. f the enlar ement of me iastinal no es is si nificant, the mass effect can produce chest pain and shortness of breath. Around 40% of patients will present with a series of symptoms known as “B symptoms,” which include unexplained profound weight loss, high fevers, and drenching night sweats. These symptoms are generally more common in severe forms of the disease.1 n a ition, each su type of HL has istinct clinical features. efiniti e ia nosis for HL is achie e throu h iopsy from a lymph no e or suspecte or an, and the histology will determine the type of HL that the patient has. From this, the appropriate treatment can be decided.

PEER REVIEWER: Dr. Jonathan Bramson Dr. Jonathan Bramson is a Professor in the Department of Pathology and Molecular Medicine and the Vice Dean of Research in the Faculty of Health Sciences. He holds a Tier I Canada Research Chair in Translational Cancer Immunology and the John Bienenstock Chair in Molecular Medicine. The Bramson lab is focused on developing methods to direct cancer patients’ immune systems to attack their tumours. Currently, the lab is using synthetic biology methods to direct T cells against discrete tumour targets. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

Kuppers R, Engert A, Hansmann M. Hodgkin lymphoma. J Clin Invest. 2012;122(10):3439-47. Available from: doi: 10.1172/JCI61245. Canadian Cancer Society’s Advisory Committee on Cancer Statistics. Canadian Cancer Statistics 2017. Toronto, ON: Canadian Cancer Society; 2017. 142 p. Report No.: ISSN 0835-2976. Cooper GM. The Cell: A Molecular Approach. 2nd ed. Sunderland, MA: Sinauer Associates; 2000. 725-66 p. Zain J, Kwak LW. Management of Lymphomas: A Case-Based Approach. Cham, Switzerland: Springer International Publishing; 2017. 1-249 p. Report No.: ISBN 978-3-319-26825-5. Küppers R. The biology of Hodgkin’s Lymphoma. Nat Rev Cancer. 2009;9(1):15–27. Available from: doi:10.1038/nrc2542. Murphy K. Janeway’s Immunobiology. 8th ed. New York (NY): Garland Science; 2012. 157-426 p. Mathas S, Hartmann S, Kuppers R. Hodgkin Lymphoma: Pathology and biology. Semin Hematol. 2016;53(3):139–47. Available from: doi:10.1053/j.seminhematol.2016.05.007. Chial H. Proto-oncogenes to oncogenes to cancer [Internet]. Nature Education. 2008. Available from: https://www.nature.com/scitable/topicpage/proto-oncogenes-to-oncogenes-to-cancer-883 [cited 2019 Feb 3]. Vainchenker W, Constantinescu SN. JAK/STAT signaling in hematological malignancies. Oncogene. 2013;32(21):2601–13. Available from: doi:10.1038/onc.2012.347. Hosono M., Chatal JF. Resistance to Targeted Anti-Cancer Therapeutics. Vol 18. Cham, Switzerland: Springer; 2018. 9-31 p. Küppers R. Mechanisms of B-cell lymphoma pathogenesis. Nat Rev Cancer. 2005;5(4):251–62. Available from: doi:10.1038/nrc1589. Tiacci E, Ladewig E, Schiavoni G, Penson A, Fortini E, Pettirossi V, et al. Pervasive mutations of JAK-STAT pathway genes in Classical Hodgkin Lymphoma. Blood. 2018;131(22):2454–65. Available from: doi:10.1182/blood-2017-11-814913. Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trumper L, Kapp U, et al. Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin Lymphoma. Blood. 2002;99(2):618–26. Available from: doi:10.1182/blood.V99.2.618.

14. 15. 16. 17. 18. 19. 20.

21. 22. 23. 24.

Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K, et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene. 2006;25(18):2679–84. Available from: doi:10.1038/sj.onc.1209151. Heppler LN, Frank DA. Rare mutations provide unique insight into oncogenic potential of STAT transcription factors. J Clin Invest. 2018;128(1):113–15. Available from: doi:10.1172/JCI98619. Kuppers R, Engert A, Hansmann M. Hodgkin lymphoma. J Clin Invest. 2012;122(10):3439-47. Available from: doi:10.1172/JCI61245. Silva PB, Real JM, Baiocchi OC, Esteves GH, Junior JG, Brito FN, et al. Gene Networks and canonical pathways analysis in classical hodgkin lymphoma patients. Blood. 2016;128:5298. Available from: http:// www.bloodjournal.org/content/128/22/5298 [cited 2019 Feb 3]. Karin M. NF-κB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol. 2009;1(5):a000141. Available from: doi:10.1101/cshperspect.a000141. Aldinucci D, Celegato M, Casagrande N. Microenvironmental interactions in classical Hodgkin lymphoma and their role in promoting tumor growth, immune escape and drug resistance. Cancer Lett. 2016;380(1):243–52. Available from: doi:10.1016/j.canlet.2015.10.007. Roemer MG, Ligon AH, Engert A, Younes A, Santoro A, Zinzani PL, et al. Chromosome 9p24.1/PD-L1/PDL2 alterations and PD-L1 expression and treatment outcomes in patients with classical Hodgkin lymphoma treated with nivolumab (PD-1 blockade). Blood. 2016;128(22):2923. Available from: http://www. bloodjournal.org/content/128/22/2923 [cited 2019 Feb 3]. Shannon-Lowe C, Rickinson AB, Bell AI. Epstein–Barr virus-associated lymphomas. Philos Trans R Soc Lond B Biol Sci. 2017;372(1732):20160271. Available from: doi:10.1098/rstb.2016.0271. Massini G, Siemer D, Hohaus S. EBV in Hodgkin lymphoma. Mediterr J Hemtol Infect Dis. 2009;1(2): e3009013. Available from: doi: 10.4084/MJHID.2009.013. Grufferman S. Epidemiology and Hereditary Aspects of Hodgkin and Non-Hodgkin lymphomas. 1st ed. New York: Springer Publishing; 2018. 772 p. Jacobson CA, Abramson JS. HIVA-associated Hodgkin’s lymphoma: Prognosis and therapy in the era of cART. Adv Hemtol. 2012;2012:507257. Available from: doi: 10.1155/2012/507257.

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ABSTRACTS 2018 International Women and Children's Health Conference IDENTIFYING NOVEL THERAPIES FOR ENDOMETRIOSIS: THE EFFECT OF MELATONIN ON ENDOMETRIAL EPITHELIAL CELL PROLIFERATION

abstracts

CHRISTIE (CHUNYI) TAN, JACQUELINE LIM, WARREN G. FOSTER Department of Obstetrics and Gynecology, McMaster University

Endometriosis is a debilitating disease affecting 10-15% of women of reproductive age and is characterized by the growth of endometrial epithelium and stromal cells outside the uterine cavity. The condition is believed to be estrogen-dependent: the growth of lesions depends on the proliferation of endometrial cells due to increased synthesis of estrogen. Melatonin, a hormone involved in the maintenance of circadian rhythms, may be therapeutically effective. Previous research discovered the expression of melatonin receptors (MR1 and MR2) in endometrial epithelial cells and also suggested that melatonin has the ability to reduce lesion size by suppressing cell proliferation. This investigation studied the effects of melatonin on human endometrium epithelial carcinoma cell (RL95-2) proliferation in vitro. Cells were treated with varying concentrations of melatonin (10-10, 10-9, 10-8, 10-7, and 10-6 M). As a positive control, cells were treated with 10-9 M estradiol to emulate endometriotic conditions on the cellular level. The cultures were

either incubated for 24 or 48 hours. Cell viability was measured using a colorimetric assay (MTT). Results indicated that estradiol had little effect on cell viability after 24 hours. The effect of melatonin treatment alone was also negligible at this time point. However, at hours, estra iol treatment si nificantly in uce cell proliferation. While melatonin alone had no effect, cell proliferation was attenuated after co-incubation with melatonin and estradiol. These preliminary analyses suggested that melatonin shows promise as a prospective therapy for endometriosis due to its ability to attenuate estrogen-induced proliferation. However, the exact mechanisms of melatonin action have yet to be elucidated. Future avenues of research include studying the effects of these treatments using other endometrial epithelial cell lines and examining the effects of melatonin on estrogen receptor expression. c nowle ements esearch supporte

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WHAT WOMEN WANT: A QUALITATIVE ASSESSMENT OF REPRODUCTIVE HEALTH IN UGANDA

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SARAH PETERS Michael G. DeGroote School of Medicine, McMaster University

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Women living in Uganda face barriers to accessing consistent, highquality reproductive healthcare services. The infant and maternal mortality rates in Uganda are among the top 20 and 40 worldwide, respectively. Two-thirds of married Ugandan women do not utilize contraceptives, and more than half of pregnancies are unintended.

delivery, including more empathetic care, health education, and informed consent. Furthermore, 19% of women felt that their experiences would be improved by receiving more care, support, and cooperation from their male partners during pregnancy, family planning, and family care. Wakiso District is a Ugandan region encircling the capital city, nter iewees ha thematically similar su estions on how access to ampala. o assess specific arriers limitin access to appropriate and delivery of local reproductive and gynecological healthcare could reproductive healthcare in this region, 41 women between the ages be improved. Further investigations should focus on understanding of 14 and 80 were interviewed about their experiences utilizing the complex intersection of healthcare funding, family structure, local healthcare services. With the aid of a translator, responses were and cultural context in order to provide a framework for tangible coded and sorted into three categories: resources, male involvement, improvement. and healthcare delivery. Acknowledgements: Research supported by Enoch Magala, Centre The results showed that 51% of respondents reported a need for for outh ri en e elopment nitiati es, a a a a e, an a. more resources at health centres, specifically asic supplies e. . water, beds, and plumbing) and medical supplies (e.g. sutures, gloves, and medications). 32% reported a need for improved healthcare

CHALLENGES IN MENTAL HEALTH CARE SERVICES: INTERGENERATIONAL CONFLICTS IN IMMIGRANT AND REFUGEE FAMILIES AASTHA GULATI1,2, HUNSTER YANG7, RAMZAN RANA1, LLOY WYLIE3-6 Department of Psychology, Western University Department of Medical Sciences, Western University 3 Department of Psychiatry, Western University 4 Department of Pathology, Western University

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Department of Anthropology, Western University Schulich School of Medicine and Dentistry, Western University 7 Department of Global Health, McMaster University 5

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y mental health care pro i ers in Lon on, ntario. he fin in s revealed key elements that contribute to intergenerational con icts re ar in mental health within immi rant an refu ee families. n particular, the e periences of cultural con ict, lac of communication between family members, and stigma surrounding mental health in uence the inter enerational challen es that newcomer families face. The results suggested that mental health issues arisin from inter enerational con icts must e a resse through alternate methods, such as a family-based approach. The study merits further investigation into the development of practiceand policy-level strategies to better support the mental health of immigrant and refugee families in Canada.

abstracts

Various challenges have emerged for mental health care workers with the increasing number of immigrant and refugee populations settling in Canada. Newcomers of all ages arrive with complex mental health histories, traumas, and strenuous migration journeys. Therefore, the resettlement process comes with a multitude of challenges regarding adequate access to mental health care services. Research has shown that these barriers distinctly impact the mental health and wellness of children and families. This study consi ere the factors that in uence inter enerational challen es among immigrant and refugee populations, and explored how these issues could be addressed by mental health care service providers and routine practices. The study was part of a larger research project on immigrant and refugee health led by Dr. Lloy Wylie. This investigation involved 21 semi-structured interviews and two focus groups conducted

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Conroy S, Cotter A. Self-reported sexual assault in Canada. Canada: Statistics Canada; 2017. 34 p. Report No.:85-002-X. Ontario Government. Law Document English View [Internet]. 2016 Mar 8. Available from: https://www.ontario.ca/laws/statute/S16002 [cited 2019 Feb 12]. McMaster University. Preventing and responding to sexual violence [Internet]. 2019. Available from: https://www.mcmaster.ca/vpacademic/ Preventing_and_Responding_to_Sexual_Violence.html [cited 2019 Feb 12].

Student panel: Creating a culture of consent at McMaster University CHLOE GAO1 , KARTIK SHARMA 2 , PETER BELESIOTIS1 Bachelor of Health Sciences (Honours) Program, Class of 2020, McMaster University 2 Bachelor of Arts & Science (Honours) Class of 2020, McMaster University Correspondence: gaoc11@mcmaster.ca 1

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THE CONTEXT

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OUR PROCESS The McMaster Health Forum has helped to demonstrate the value of informing policymakers about priority issues with the best-available research evidence, systematically elicited citizens’ values, and stakeholder insights by convening over 50 citizen panels. As this year’s Forum Fellows, we aimed to adapt the Forum’s Citizen Panels program to identify strategies for creating a culture of consent at McMaster University through student/staff engagement. To realize our vision, we developed and piloted a new Fellowdriven program —Student Panels— that took into account lessons learned to date in conducting citizen panels.

Sexual violence is a significant societal problem that has a pronounced impact on university campuses.1 Currently, several policies and programs are in place to deal with sexual violence at the provincial level in Ontario, as well as on university campuses across the province. For example, the Ontario government instituted the Sexual Violence and Harassment Action Plan Act We outline below the five key stages involved in in 2016, which outlines the legal obligations for our process of convening the first student panel. In all Ontario universities to support survivors and addition, an overview of the student brief that was handle reports of sexual violence.2 At McMaster, developed to inform the panel and key features of the Sexual Violence Policy was introduced in the student panels are provided in Table 1. 2016. This policy outlines the roles of various stakeholders in responding to complaints of sexual First, we established a diverse and experienced violence involving members of the university steering committee, consisting of people involved community, the process through which complaints with current efforts to create a culture of consent are adjudicated, and the sanctions that may result.3 on campus. Through in-person meetings, our Such policies reflect both the importance of steering committee provided input that shaped all dealing with sexual violence and decision-makers’ facets of the project, including the student brief that will be sent to participants prior to the panel, desire to address the problem at many levels. key informants to interview before preparing the At McMaster University, recent social movements student brief, the recruitment strategy, and postregarding sexual violence (e.g. the #MeToo panel dissemination strategies. movement) have prompted discourse and planning of various approaches to build a culture Second, we developed a draft outline of the student of consent, rather than focus only on after-the- brief, hereafter referred to as terms of reference fact interventions in response to cases of sexual (TOR), which outlined the problem, options for violence. However, achieving such goals in a way addressing it, and implementation considerations that reflects the best-available research evidence to be included. The TOR was developed iteratively and integrates systematically elicited insights from and informed by data and research evidence, as key stakeholders on campus (including students well as the views and experiences of steering who have lived experience with sexual violence) is committee members and key informants. an ongoing challenge. The 2018/2019 McMaster Third, during the process of developing the TOR, Health Forum Fellows sought to build on a we identified key informants in collaboration citizen-engagement process already established with our steering committee. We conducted brief at the Forum to develop a unique approach that interviews with six of them to solicit feedback to could help address this gap. further shape and refine the TOR.

In the fourth stage, we drafted the student brief with input from NEXT STEPS Health Forum staff and our steering committee. This brief will be pre-circulated to all panelists prior to the panel. The brief is meant We are currently recruiting students to participate in the student to support informed deliberations by presenting the best-available panel. Following the panel, we will compile key themes that data and evidence about the problem, options for addressing it, emerge from the discussion into a panel summary that will be broadly disseminated to inform and support any future campusand implementation considerations. level initiatives taken at McMaster or elsewhere to drive action Lastly, we are currently in the process of recruiting a diverse group towards creating a culture of consent. of 14-16 students to participate in the panel, which will convene As with other McMaster Health Forum programs, we will on March 26, 2019. conduct formative and summative evaluations of all components of the Student Panels program through surveying panellists to PRELIMINARY FINDINGS ensure that the program can effectively spark action on campuslevel issues. This evaluation will allow us to reflect on what In the student brief, we identified three driving forces that make worked and what can be improved upon in future Student Panels sexual violence a pressing challenge and that highlight the need that address other high-priority, student-centered issues. to foster a culture of consent. These include the following:

2) cultural norms and socializations can prevent people from exercising bodily autonomy; and 3) current efforts focus on responding to cases of sexual violence, and little attention is devoted to proactively preventing new cases. In collaboration with our steering committee, the potential elements of the solution were formulated by surveying the problem, looking at what has been implemented on other campuses and in other organizations, incorporating feedback from key informants, and analyzing research evidence. The three elements of a potential solution in the brief include: 1) establishing coordination structures that clarify leadership, integrate objectives, and strengthen collaboration across the university administration and campus groups; 2) complementing after-the-fact interventions with costeffective primary prevention (public health) efforts; and

Table 1: Overview of key features of student briefs and panels compared to citizen panels

Key Features of Student Briefs • Describe what is known (and not known) about a high-priority issue currently being faced by students at McMaster University. • Provide descriptions of the policy context at the campus and the provincial level. • Write in plain-language. • Use the best-available research evidence (with priority given to systematic reviews instead of single studies whenever possible) to provide credible information to support the panel deliberations.

3) addressing the cultural basis of sexual and gender-based violence.

• Address a high-priority issue currently being faced by students at McMaster University that: ◊ Can, at least in part, be addressed by leaders at the university; ◊ Is driven by McMaster University student priorities, rather than the priorities of policymakers, stakeholders, and researchers; ◊ Is informed by a pre-circulated plain-language student brief; ◊ Convenes 14-16 students involved in or affected by the issues or by future decisions related to the issue; ◊ Ensures fair representation that reflects the diversity of students involved in or affected by the issue; ◊ Engages the Forum Fellows and Forum staff to assist with the deliberation; ◊ Allows for frank, off-the-record deliberations by following the Chatham House rule; and ◊ Aims to find common ground and identify the values underlying different positions.

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 how to support the use of research evidence in health system policymaking. Dr. Michael Wilson is the Assistant Director of the McMaster Health Forum, an Associate Professor in the Department of Health Research Methods, Evidence, and Impact, and a member of CHEPA. His research focuses on supporting the use of research evidence by health system decision-makers, including policymakers and stakeholders such as community-based organizations. EDITED BY SABA MANZOOR & PARNIKA GODKHINDI

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One challenge we faced was identifying systematic reviews relevant to these elements. The limited research available about these possible elements of a solution underscores the need to elicit student perspectives through the Student Panels program.

Key Features of Student Panels

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1) sexual violence is a widespread problem in society, particularly on university campuses;

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Youth Tobacco Use:

A Pressing Global Health and Human Rights Challenge MICHAEL YO-HAN LEE1 & PURU PANCHAL 2 Bachelor of Health Sciences (Honours) Biomedical Sciences Specialization, Class of 2019, McMaster University 2 Bachelor of Health Sciences (Honours) Global Health Specialization, Class of 2019, McMaster University Correspondence: leem10@mcmaster.ca1; panchalp@mcmaster.ca2 1

ABSTRACT

Youth smoking is prevalent in Indonesia. 90% of Indonesian children have smoked a cigarette by age 13 and many remain as smokers into adulthood. As a result of this addiction, many households have cigarettes as their second highest expenditure. Smoking is a considerable financial burden on families and the Indonesian health system. Previous international and domestic attempts to reduce Indonesian smoking rates from economic, political, and health systems fronts have not succeeded due to lobbying from tobacco corporations. A stronger stance must be considered —one of childhood development and a right to freedom from addiction. Advocating for physician-patient education, age limits, and childhood education to key stakeholders in the federal government may help leverage strategic foreign policies to internationally address this human rights issue.

Tobacco use is the most preventable cause of mortality worldwide, yet it kills over seven million people annually.1 It remains widespread, especially in low and middle income nations. Indonesia has a particularly high prevalence of smokers, most notably among its youth. Over 90% of all Indonesian children have smoked a cigarette by age thirteen. Moreover, 76% of Indonesian males older than 15 smoke frequently.2 In comparison, only 7.6% of high school students are smokers in the US.3 Annually, smoking-related diseases kill 250,000 people and hospitalize over 600,000 people in Indonesia. It costs $45.9 billion USD to treat tobacco-related diseases.4,5 Some individuals prioritise cigarettes over basic necessities such as food and education. In fact, tobacco is the second highest household expenditure in Indonesia after rice.5 Indonesia lacks comprehensive tobacco control policies compared to other Southeast Asian countries, which have stricter anti-tobacco measures. Without action, youth smoking will perpetuate high rates of adult smoking, increasing mortality rates and healthcare costs. Thus, proactively preventing individuals from starting to smoke is key to ensuring the health of Indonesian youth.

POLITICAL, ECONOMIC, AND CULTURAL BARRIERS TO CHANGE

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IDENTIFYING THE PROBLEM

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The World Health Organization Framework Convention on Tobacco Control (WHO FCTC) was developed by 168 nations in response to the global tobacco epidemic. It provides demand and supply reduction strategies to limit the spread of tobacco.6 Although this non-binding agreement has been legally ratified by 181 nations, Indonesia has not signed, instead electing to

continue its relationship with tobacco companies. In addition, the Tobacco Advertising, Promotion, and Sponsorship (TAPS) criteria under the Association of Southeast Asian Nations (ASEAN) aims to regulate cigarette advertisement.5 Similarly, this non-binding agreement provides little incentive for Indonesian adoption. Economically, Indonesia cites financial losses in sales and exports as the main factor for not increasing cigarette taxation. The neighbouring state, Malaysia, imposes a 49% mark-up sales tax on the retail price compared to Indonesia’s 31%; however, both are below the WHO FCTC recommended tax of 70%.7 In comparison, the average Ontarian pays 170% (including HST) mark-up on tobacco duty.8 The Indonesian government’s reluctance to raise tariffs is largely based on speculation that higher tax rates will damage tobacco tax revenue, which forms 10% of the Indonesian domestic revenue.9 However, studies by both the World Health Organisation and the Million Death Study indicate that this is a misconception: in other countries like India, higher cigarette taxes yielded an increase in government tax revenue despite a decrease in cigarette consumption.10 Culturally, tobacco use has been associated with masculinity. Historically, male smoking is an expression of individual identity.11,12 Anecdotal evidence in Inside Indonesia depicts that teenage boys are given cigarettes following their circumcision, since cigarettes are believed to accelerate the healing process and signal the transition into manhood. Those who do not smoke are considered feminine or abnormal.13 Since their establishment, tobacco companies have leveraged this cultural association using targeted advertisements to young consumers, strengthening the bond to masculinity, which resulted in increased cigarette purchases.14 Native Indonesians in a youth focus group identified four cultural themes on tobacco addiction: (1) smoking as a culturally internalized habit, (2) striving to become a man, (3) the way we smoke is not dangerous and (4) the struggle against dependency— all of which are exacerbated by tobacco advertisements. The combination of factors, ranging from economic interests to cultural perpetuation, all pose barriers for youth on the road to liberation from tobacco.13

RECOGNITION OF YOUTH NICOTINE ADDICTION AS AN INFRINGEMENT ON HUMAN RIGHTS & STRATEGIES Strategies that address youth smoking through international treaties, domestic taxation, and advertisement regulation have not succeeded. Thus, perhaps it is time to explore the issue from the perspective of human rights. The United Nations Convention on the Rights of the Child, co-signed by Indonesia, maintains that children have the right to develop in a healthy manner free from addiction.15 As such, it is important

for diplomats and government officials to also recognize nicotine addiction as an infringement of these rights. This declaration is echoed by the Office of the United Nations High Commissioner for Human Rights, who issued a statement that all people —regardless of race, religion, political belief, economic or social condition— are entitled to the highest standard of health.16 Documentation of the chain-smoking, two-year-old named Aldi Suganda provides anecdotal evidence of how tobacco can violate children’s rights.17 This story, along with many others, provides an avenue for dialogue with the Indonesian government so that it may enact stricter anti-smoking laws and improve protections for children.18,19,20 Hence, the Indonesian government’s inaction in addressing the smoking addiction epidemic is a serious infraction of the human rights code.

PHYSICIAN EDUCATION AND POLICY PERSPECTIVE

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Unfortunately, optimism among medical ranks has failed to translate into policies aimed at addressing youth smoking addiction. Mandating physician education for smoking cessation dialogue, implementing a cigarette purchasing age limit, and childhood health education on tobacco addiction are three potential policies that may improve the youth tobacco landscape. The Indonesian government refuses to take measures to prevent youth smoking, which infringes on children’s right to health. As Canadians, we stand by our belief in universal human rights. Hence, reaching out to stakeholders like the Director General of the Office of International Affairs for the Health Portfolio, has the potential to facilitate strategic bilateral partnerships with Indonesia that reflect Canadian interests in preserving children’s rights.

R E V I E W E D B Y D R . G O D E F R O Y G U I N D O N & S O P H I YA G A R A S I A Dr. Godefroy Emmanuel Guindon is an Assistant Professor in the McMaster Department of Health Research Methods, Evidence, and Impact. He is also an Associate Member of the McMaster Department of Economics. His research interests include various topics in health economics. Sophiya Garasia is a PhD candidate in Health Economics at McMaster University. Her primary area of focus is health policy, but her other interests include health economics and healthcare.

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World Health Organization. WHO global report on trends in prevalence of tobacco smoking 2015 [Internet]. 2015. Available from: https://www.who.int/tobacco/global_report/2015/en/ [cited 2019 Jan 15]. World Health Organization. WHO report on the global tobacco epidemic, 2017 Country profile Indonesia WHO Framework Convention on Tobacco Control (WHO FCTC) Status Socioeconomic context [Internet]. 2017 Available from: https://www.who.int/tobacco/ surveillance/policy/country_profile/idn.pdf [cited 2019 Jan 15]. Wang TW, Gentzke A, Sharapova S, Cullen KA, Ambrose BK, Jamal A. Tobacco product use among middle and high school students — United States, 2011–2017. MMWR Morb Mortal Wkly Rep. 2018;67(22):629–33. Available from: http://www.cdc.gov/mmwr/volumes/67/wr/mm6722a3.htm?s_cid=mm6722a3_w [cited 2019 Jan 15]. World Health Organization. Heart disease and stroke are the commonest ways by which tobacco kills people FACTSHEET 2018 INDONESIA [Internet]. 2018. Available from: http://www.searo.who.int/tobacco/data/ ino_rtc_reports [cited 2019 Jan 15]. Tan YL, Dorotheo U. The Tobacco Control Atlas: ASEAN Region, Fourth Edition [Internet]. Southeast Asia Tobacco Control Alliance (SEATCA). 2018. Available from: https://seatca.org/dmdocuments/SEATCA%20 Tobacco%20Control%20Atlas%20ASEAN%20Region%204th%20Ed%20Sept%202018.pdf [cited 2019 Jan 15]. World Health Organization. WHO Framework Convention On Tobacco Control [Internet]. 2003 Available from: https://www.who.int/tobacco/framework/ WHO_FCTC_english.pdf [cited 2019 Jan 15]. Mohamed Nor N, Abdullah N, Rampal L, Noor Z. An optimal cigarette tax in malaysia. Int J Econ Manag. 2013;7:205–20. Available from: http://www.ijem. upm.edu.my/vol7no2/bab02.pdf [cited 2019 Jan 15]. Smoking and Health Act Foundation. Cigarette Prices in Canada [Internet]. 2018. Available from: https://nsraadnf.ca/wp-content/uploads/2018/03/180302_ map_and_table.pdf [cited 2019 Jan 5]. Danubrata E, Reinard S. Indonesia Tobacco Bill Would Open Tap for Ads Aimed at Kids, Health Official Says [Internet]. 2017. Available from: https://www.reuters. com/article/us-indonesia-tobacco/indonesia-tobaccobill-would-open-tap-for-ads-aimed-at-kids-healthofficial-says-idUSKBN18S47O [cited 2019 Feb 26]. Jha P. The health, poverty, and financial consequences of a cigarette price increase among 500 million male smokers in 13 middle income countries: compartmental model study. BMJ. 2018;361:k1162. Available from: doi:10.1136/bmj.k1162. Nichter M, Padmawati S, Danardono M, Ng N, Prabandari Y, Nichter M. Reading culture from tobacco advertisements in Indonesia. Tob Control. 2009;18(2):98107. Available from: doi:10.1136/tc.2008.025809. Reynolds C. Tobacco advertising in Indonesia: “The defining characteristics for success”. Tob Control. 1999;8(1):85-8. Available from: doi:10.1136/ tc.8.1.85. Ng N, Weinehall L, Öhman A. ‘If I don’t smoke, I’m not a real man’—Indonesian teenage boys’ views about smoking. Health Edu Res. 2006;22(6):794-804. Available from: doi:10.1093/her/cyl104. Arnez M. Tobacco and Kretek: Indonesian drugs in historical change. ASEAS. 2009;2(1):49-69. Available from: https://www.ssoar.info/ssoar/handle/document/36276 [cited 2019 Jan 16]. United Nations Treaty Collection. Convention on the Rights of the Child [Internet]. 1989. Available from: https://treaties.un.org/pages/ViewDetails. aspx?src=IND&mtdsg_no=IV-11&chapter=4&lang=en [cited 2019 Jan 16]. Office of the United Nations High Commissioner for Human Rights. Fact Sheet No. 31, The Right to Health [Internet]. 2008. Available from: https://www.ohchr. org/Documents/Publications/Factsheet31.pdf [cited 2019 Jan 15]. Senthilingam M. Chain-smoking Children: Indonesia’s Ongoing Tobacco Epidemic [Internet]. CNN. 2017. Available from: https://www.cnn.com/2017/08/30/ health/chain-smoking-children-tobacco-indonesia/ index.html [cited 2019 Jan 15]. Huwein, N. 2-year-old Indonesian Boy Smokes 40 Cigarettes a Day, Drinks Mochachino [Internet]. The Straits Times. 2018 Aug 17. Available from: https://www. straitstimes.com/asia/se-asia/2-year-old-indonesianboy-smokes-40-cigarettes-a-day-drinks-mochachino [cited 2019 March 5]. Meyersohn H, Harris D. From Age 2 to 7: Why are Children Smoking in Indonesia? [Internet]. ABC News. 2011 Sep 9. Available from: https://abcnews. go.com/Health/age-children-smoking-indonesia/ story?id=14464140 [cited 2019 March 5]. Dhumeries M. The Number of Children Smoking in Indonesia is Getting Out of Control [Internet]. Pri. 2016. Available from: https://www.pri.org/stories/numberchildren-smoking-indonesia-getting-out-control [cited 2019 Jan 15]. Otañez M, Glantz SA. Social responsibility in tobacco production? Tobacco companies’ use of green supply chains to obscure the real costs of tobacco farming. Tob Control. 2011;20(6):403-11. Available from: doi:10.1136/tc.2010.039537. Ramos AK. Child labor in global tobacco production: A human rights approach to an enduring dilemma. Health Hum Rights. 2018;20(2):235-48. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC6293346/ [cited 2019 Jan 15]. Abdullah A, Stillman F, Yang LI, Luo H, Zhang Z, Samet J. Tobacco use and smoking cessation practices among physicians in developing countries: A literature review (1987-2010). Int J Environ Res Public Health. 2014;11(1):429-55. Available from: doi:10.3390/ ijerph110100429. Ng N, Prabandari YS, Padmawati RS, Okah F, Haddock CK, Nichter M, et al. Physician assessment of patient smoking in Indonesia: A public health priority. Tob Control. 2007;16(3):190-6. Available from: doi:10.1136/ tc.2006.018895. Golechha M. Health promotion methods for smoking prevention and cessation: A comprehensive review of effectiveness and the way forward. Int J Prev Med. 2016;7(1):7. Available from: doi:10.4103/20087802.173797. Prabandari YS, Nichter M, Nichter M, Padmawathi RS, Muramoto M. Laying the groundwork for tobacco cessation education in medical colleges in Indonesia. Educ Health (Abingdon). 2015;28(3):169-75. Available from: doi:10.4103/1357-6283.178602.

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Although dialogue between physicians and patients in Indonesia about the dangers of tobacco use is limited, it is key to inducing

CALL TO ACTION

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The problem can also be addressed from the perspective of child labour. It is estimated that thousands of child workers in Indonesia are involved in tobacco production for the country’s largest tobacco companies.15 British American Tobacco and Philip Morris International, the largest tobacco companies, generate $1.2 billion in unpaid children’s labour cost.21 Children working on these farms are at high risk for occupational hazards such as lacerations from equipment, exposure to chemicals, extreme weather conditions, and more. Due to the sensitive nature of a child’s developmental period, they are also at a high risk of “green tobacco sickness,” caused by dermal absorption of nicotine from the leaves of the tobacco plant. This is a form of nicotine poisoning that causes dizziness, vomiting, dehydration, and anorexia.22 Exposure to pesticides and herbicides may also increase the risk of chemical poisoning, cancer, reproductive health issues, and permanent neurological damage.22

change at the individual level.23-25 Smoking cessation efforts require more than just population health campaigns and taxation; they also require communal and sociopolitical efforts.25 Until recently, physicians were not tested on their proficiency in smoking intervention materials. An independent assessment of the medical college curriculum concluded that “very little time had been devoted to the [education of the] harms [of smoking and] … no training had been provided… on how to talk to patients about smoking or how to assist them in their efforts to quit.”26 It was only in 2012 when the Indonesian Doctors Association introduced counselling skills on smoking cessation into the National Competency Standards for Physicians. Furthermore, education on smoking cessation programs was introduced into the medical school curriculum in 2015. This is the first attempt to integrate tobacco control throughout all four years of medical school in Southeast Asia.26 Physician voice, therefore, is instrumental in policy decisions, which has led to Indonesia becoming a leading regional medical authority in tobacco cessation education.26

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A RT I S T RUBY ZHENG

CRITICAL REVIEW Pacritinib: A novel therapeutic agent for treating myelofibrosis

KASHYAP PATEL

Bachelor of Health Sciences (Honours) Class of 2020, McMaster University Correspondence: patelk69@mcmaster.ca

ABSTRACT Selective inhibitors are an important advancement in clinical medicine, providing a method to target proteins within signal transduction pathways. One such inhibitor, pacritinib, targets Janus Kinase 2 (JAK2) to treat patients with myelofibrosis (MF). In MF patients diagnosed with a specific point mutation (JAK2V61F), the JAK/STAT pathway is over-activated, leading to an increase in cell proliferation rates. Pacritinib restores normal JAK/STAT activity by targeting aberrant activity of JAK2V61F mutant proteins and inhibiting cell proliferation in bone marrow tissue. In recent studies, pacritinib has shown better results at treating MF than the best available therapy. Though pacritinib is a potentially effective treatment option, it does not address all aspects of MF and should be supplemented with other treatments.

INTRODUCTION

The following review will discuss the mechanisms behind the pathophysiology of MF, current treatments, and promising novel treatments targeting the JAK2/STAT pathway. In particular, recent studies report that the novel agent pacritinib has increased efficacy in treating MF over other therapeutic modalities.

PATHOPHYSIOLOGY

The drug that is currently used to treat MF with splenomegaly is ruxolitinib, a potent and selective JAK1/2 inhibitor. By inhibiting the JAK/STAT pathway, ruxolitinib downregulates target genes that promote cell growth and proliferation. A study conducted in 2012 compared the efficacy of ruxolitinib treatment for MF to best available treatments, which include anti-neoplastic agents and glucocorticoids. To compare treatments, they monitored the reduction in spleen size and MF-related symptoms.7 Ruxolitinib reduced spleen length by 56% on average, whereas the best available treatment group demonstrated a 4% increase in length at 48 weeks.7 The patients in the ruxolitinib group also reported a decrease in MF symptoms over time.7 Although ruxolitinib was superior to the best available treatment in reducing spleen size, both treatments had similar survival rates. Ruxolitinib is currently approved by the Food and Drug Administration and Health Canada to treat MF, and is the first MF agent to be commercially available.8,9

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Another MF treatment is allogeneic hematopoietic cell transplantation (HCT).10 This procedure has potential to be a long-term solution for MF, with minimal chance of relapse. In one study, 36 of 56 MF patients who received allogeneic HCT and achieved both engraftment and chimerism survived between 0.5 to 11.6 (median, 2.8) years posttreatment.10 Most of these patients enrolled in this trial after conventional treatments proved ineffective.10 The

M E D U CATO R

JAK2 is a tyrosine kinase that propagates and amplifies signals in a cell. It does so by catalyzing the transfer of a phosphate group from adenosine triphosphate donors to tyrosine residue receivers on proteins.4 JAK2 mutations have been implicated in MF and other myeloproliferative neoplasms. The most prevalent mutation, JAK2V617F, causes JAK2 to become constitutively active, escaping auto-inhibition and causing uncontrolled signal transduction.4,5 The activated JAK2 proteins phosphorylate the signal transducer and activator of transcription (STAT) proteins.6 Phosphorylation activates the STAT proteins, leading to their active transport into the nucleus where they enhance the transcription of target genes.6

CURRENT TREATMENTS

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Myelofibrosis (MF) is a rare bone marrow cancer that develops from genetic mutations in the hematopoietic stem cell population.1 Around 50-60% of MF cases have a Janus Kinase 2 ( JAK2) mutation, suggesting a correlation between the pathogenesis of MF and JAK2 mutants.2 The point mutation JAK2V61F, which is a conversion of valine to phenylalanine at position 617, is found in most MF patients.2 However, the etiology of JAK2 mutations that lead to myeloproliferative neoplasms remains unclear.1 These neoplasms continue to grow as scar tissue forms in the bone marrow. Scarring can disrupt normal blood cell production and cause anemia. In its early stages, MF is difficult to detect. However, as the bone marrow undergoes fibrosis, patients manifest symptoms such as weakness, bone pain, shortness of breath, and frequent infections.3 MF is diagnosed by the presence of bone marrow fibrosis in bone samples.3 Other methods of diagnosing MF include a complete blood count and palpating to detect enlargement of the spleen.3

The JAK/STAT pathway responds to growth factors, increasing the expression of genes that induce cell growth, differentiation, and apoptosis.6 This pathway is constitutively inhibited; the target genes are expressed in the cell only when the pathway is activated. The dysregulation of this pathway by mutations such as JAK2V61F can lead to the formation of myeloproliferative tissue, which can later become tumorigenic and lead to enlargement of the spleen (splenomegaly).6 Neoplasm growth is usually a slow process in MF. Consequently, symptoms are not observed by the patient until the scar tissue becomes prominent in the region and begins affecting blood cell production.

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paper noted that infections were implicated in most of the non-relapse deaths that occured within 6 months of treatment: pneumonia and other infections caused 13 out of 20 deaths. Thus, effective infection-prevention strategies need to be developed for stem cell transplant treatment. Although HCT is associated with risks, researchers believe that this avenue shows promise for long-term survival of MF patients.

pathway as ruxolitinib, which has been linked to inhibition of dendritic cell function and the downregulation of regulatory T cells.14 Consequently, serious complications can arise, including tuberculosis, an increase in hepatitis B titres, and the reactivation of the herpes simplex virus.14 Thus, it is important to research the effects of pacritinib on the immune system to develop preventative measures against infections.

MF is a complex disease. One treatment cannot be used as a standardized protocol for cases with varying severity and prognostic factors. Therefore, different treatments are administered in an orderly fashion to find the most effective candidate.

Currently, MF treatments target the JAK/STAT pathway. Though this pathway is an important target in treating the disease, there are other mechanisms that contribute to MF pathophysiology. Peripheral mechanisms contribute to the symptomatology of MF, and targeting them could lead to better patient outcomes and increased quality of life.14 However, focusing on treating the cause of the symptom can be more effective in improving long-term quality of life, than simply finding a short-term solution that alleviates the symptoms. Thus, drugs that target the peripheral mechanisms behind bone marrow dysmorphia need to be developed.14

M E D U CATO R

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FUTURE DIRECTIONS

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In 2018, Mascarenhas et al. published a study comparing the efficacy of pacritinib, a JAK2 inhibitor, to the best available treatments, including ruxolitinib.11 The results indicated that pacritinib is more effective at reducing spleen length and the total symptom score in MF patients. Furthermore, the side effects of pacritinib were minimal and did not generally cause discomfort. Though these results are promising, they may not be generalizable to all MF patients, given the small sample size of 33 patients. In a phase 3 trial, pacritinib was more effective at treating symptoms than current MF treatment, but the survival rates were not significantly different between groups.12 Moreover, phase 1 and 2 trials indicated that pacritinib treatment may incur lower risk of producing treatment-emergent conditions, such as thrombocytopenia and anemia, than other JAK2 inhibitors.13 Treatment with pacritinib has no associated significant cardiac or hematologic treatment-emergent events.13 Furthermore, this novel treatment may offer increased efficacy and decreased side-effects in comparison to ruxolitinib in certain patient populations.13 The reduced risk of adverse effects could increase patient compliance and the likelihood of treatment continuity. One common aspect of MF is anemia, which requires the patient to undergo red blood cell transfusions.11 The study by Mascarenhas et al. indicated that patients treated with pacritinib required fewer transfusions than those who were treated with ruxolitinib. This decrease in transfusion burden is a clinically significant outcome, because anemia is the root cause for some other symptoms.11 By mitigating the severity of anemia in MF patients, pacritinib may also decrease the development of other complications. Since MF patients become increasingly susceptible to infections as they undergo treatment, further research needs to be conducted on infection risk-reduction strategies. The weakened immune systems of MF patients undergoing treatment prevents a robust response against infectious agents, leading to serious adverse outcomes including tissue damage and death.14 Pacritinib may also lead to adverse immunological changes because it targets the same

It is evident that research focusing on the cause of the symptoms and the peripheral pathways of MF is required. Pacritinib is only a promising solution for one dysregulated pathway in MF. Further research needs to be conducted to validate these findings in order for pacritinib to be approved by healthcare authorities. The development of new and more selective JAK1/2 inhibitors can be a possible solution to MF, but in some cases, these inhibitors require supplementation with more potent treatments. The use of JAK inhibitors to treat MF seems to provide a short-term solution to the problem, but tolerance to JAK inhibitors can render these drugs less effective. Therefore, it is important to create a combined treatment plan that addresses the treatment challenges of MF in a systematic way.

CONCLUSION The prevalence of rare blood cancers is increasing in Canada, and research into anticancer treatments is rapidly gaining importance.3 MF is a debilitating disease that continues to affect thousands around the world, and specific JAK inhibitors show great promise in battling myeloproliferative conditions. The next challenge for researchers is to develop sufficient evidence for a treatment protocol for MF that can improve prognosis while increasing treatment access. . H

H LL

Dr. Chris Hillis is an Assistant Professor in the Department of Oncology at McMaster and a malignant hematologist at the Juravinski Cancer Centre. EDITED BY JIM XIE & ALBERT STANCESCU

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14.

Myelofibrosis facts. Leukemia & Lymphoma Society [Internet]. 2012. Available from: https://www.lls.org/sites/default/files/file_assets/FS14_Myelofibrosis_Fact%20Sheet_Final9.12.pdf [cited 2019 Jan 19]. Canadian Cancer Society. Idiopathic myelofibrosis [Internet]. Available from: http://www.cancer.ca/en/cancer-information/cancer-type/leukemia/leukemia/idiopathic-myelofibrosis/?region=on [cited 2019 Jan 19]. Reilly J, McMullin M, Beer P, Butt N, Conneally E, Duncombe A, et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol. 2012;158(4):453-71. Available from: doi:10.1111/j.13652141.2012.09179.x. Levine R, Wadleigh M, Cools J, Ebert B, Wernig G, Huntly B, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. 2005;7(4):387-397. Available from: doi:10.1016/j.ccr.2005.03.023. McLornan D, Percy M, McMullin MF. JAK2 V617F: A single mutation in the myeloproliferative group of disorders. Ulster Med J. 2006;75(2):112. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC1891745/ [cited 2019 Feb 12]. Lee H, Daver N, Kantarjian H, Verstovsek S, Ravandi F. The role of JAK pathway dysregulation in the pathogenesis and treatment of acute myeloid leukemia. Clin Cancer Res. 2012;19(2):327-35. Available from: doi:10.1158/1078-0432.CCR-12-2087. Harrison C, Kiladjian J, Al-Ali H, Gisslinger H, Waltzman R, Stalbovskaya V, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med. 2012;366(9):787-98. Available from: doi:10.1056/NEJMoa1110556. Lal A. Primary myelofibrosis treatment & management: Approach considerations, ruxolitinib, other chemotherapeutics [Internet]. 2017. Available from: https://emedicine.medscape.com/article/197954-treatment [cited 2019 Jan 19] Government of Canada. Summary safety review - Ruxolitinib - Assessing the potential risk of liver injury [Internet]. 2018. Available from: https://www.canada.ca/en/health-canada/services/drugs-health-products/ medeffect-canada/safety-reviews/ruxolitinib-potential-risk-liver-injury.html [cited 2019 Feb 12]. Deeg H. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood. 2003;102(12):3912-8. Available from: doi:10.1182/blood-2003-06-1856. Mascarenhas J, Virtgaym E, Stal M, Blacklock H, Gerds A, Mesa R, et al. Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: A sponsor-independent international study. Ann Hematol. 2018;97(8):1369-74. Available from: doi:10.1007/s00277-018-3309-6. Mesa RA, Vannucchi AM, Mead A, Egyed M, Szoke A, Suvorov A, et al. Pacritinib versus best available therapy for the treatment of myelofibrosis irrespective of baseline cytopenias (PERSIST-1): An international, randomised, phase 3 trial. Lancet Haematol. 2017;4(5):e225-36. Available from: doi:10.1016/S2352-3026(17)30027-3. CTI Biopharma. Pacritinib [Internet]. 2017. Available from: http://www.ctibiopharma.com/pipeline/pacritinib/ [cited 2019 Feb 7]. Bryan JC, Verstovsek S. Overcoming treatment challenges in myelofibrosis and polycythemia vera: The role of ruxolitinib. Cancer Chemother Pharmacol. 2016;77(6):1125-42. Available from: doi:10.1007/s00280016-3012-z.

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A RT I S T RUBY ZHENG

CRITICAL REVIEW

Understanding regulatory B cell development with single cell analyses

SAMANTHA VISVA 1 & DR. JOHN-PAUL OLIVERIA 2 1Bachelor of Health Sciences (Honours) Class of 2020, McMaster University Correspondence: visvas@mcmaster.ca 2 Assistant Clinical Professor, Division of Respirology, Department of Medicine, McMaster University Correspondence: oliveria@stanford.edu

ABSTRACT There is very little research concerning human regulatory B cells and this may in part be due to their inconsistent responses to immunosuppressi e cyto ines such as L . he purpose of this critical re iew is to e amine our current un erstan in of regulatory B cell development, such as time points of differentiation, and how in silico computer modelling can improve this un erstan in . pecifically, ioinformatic analysis of the chan es in cell surface mar ers an si nallin molecules can help guide our understanding of the timing of cell-fate decisions and regulatory B cell differentiation. Tracking regulatory B cell trajectory with bioinformatics and in silico methods may improve our understanding of their role in many neurodegenerative diseases such as multiple sclerosis.

BREG DEVELOPMENT

While B cells are most commonly known for their contributions to humoural immunity, a subset of B cells called regulatory B cells (Bregs) are recognized for their role in preventing autoimmunity.1 While central tolerance eliminates strongly self-reactive lymphocytes, some lymphocytes may bypass these mechanisms, necessitating additional safeguards.2 Bregs impart some peripheral tolerance functions by releasing immunomodulatory cytokines, such as IL-10, to suppress autoreactive immune responses.3 IL-10 carries out immune suppression by inhibiting proinflammatory cytokines, expression of co-stimulatory molecules, antigen presentation, and by affecting B cell development and function.1 Signals stimulating the production of IL-10 are poorly understood, but possible candidates include TLR ligands, dendritic cell-derived IFN-β and CD40L, cell surface markers, and the STAT3 signalling pathway.1-4 IL-10-independent mechanisms for immune suppression largely rely on the proliferation of regulatory T cells (Tregs) rather than the suppression of pathogenic T cells.4 For example, some Breg cytokines modulate CD4+ T cell functions when activated and promote the conversion of CD4+ T cells into Foxp3+ Tregs through the release of TGF-β.4

Differential hypotheses about the origin and development of IL-10-producing Bregs exist. Current studies show that any B cell can acquire regulatory properties, supporting the notion that mature B cells may not be in their terminally differentiated state.4 Proposed models of Breg differentiation include:4 rise to different Breg subsets.

2. Single-lineage Bregs: a single progenitor gives rise

to different Breg subsets, based on their expression of a single transcription factor. 3. Induced Bregs: with the appropriate microenvironment, any B cell has the potential to differentiate into a Breg cell. The third model is supported by research showing that treatment with different cytokines, such as IL-10, induces B cell differentiation into different Breg subsets.4,5 In an inflammatory response, IL-10 is upregulated by activation of BCRs; TLRs including TLR2, TLR4, and TLR9; and costimulatory molecules such as CD40 and CD86/ CD80.5-10 These findings demonstrate that increased levels of IL-10 can be induced by environmental stimuli.

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To elaborate, different pathways are involved in BCR, CD40, and TLR stimulation. BCR signalling is required for B cell production of IL-10 by activating proximal kinases and phospholipase C-β2 to initiate store-operated Ca2+ entry (SOCE).5,11 CD40 signalling activates STAT3, NFβB, and extracellular-signal regulated kinases.11 In a parallel pathway, TLRs are essential in inducing IL-10 production in naive B cells by altering the chromatin structure at the IL-10 locus to facilitate transcription.11 Histone deacetylase 11 and IRF4 are involved in regulating the transcription of the IL-10 gene to stimulate downstream molecules such as NFAT proteins, which interact with other transcription factors including AP-1, IRF4, GATA-binding protein 3, c-Maf, and the “master transcription factor” in plasma cell differentiation, Blimp1 (Refer to Figure 1).11 However, these parallel pathways are highly regulated to avoid generalized immunosuppression and non-selective IL-10 secretion.5

M E D U CATO R

Perhaps the heterogeneity of Breg functions can be attributed to differential signals received during Breg development.1 However, it is unclear if these functions are specific to a Breg subset, whether signals presented during Breg development lead to specific functions, and how functions interact to induce immunosuppression.1 The powerful immunosuppressive abilities of Bregs suggest therapeutic potential in immunerelated diseases such as multiple sclerosis (MS).2 This review will present our current understanding of Breg development and how in silico modelling methods and bioinformatics have the potential to bridge the aforementioned knowledge gaps. In silico methods such as CLUSTER algorithms are computer-generated mathematical datasets that attempt to mirror biological systems, whereas bioinformatics uses computer-aided strategies to analyze the empirical data from experimental techniques such as mass cytometry.

1. Multi-lineage Bregs: individual progenitors give

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INTRODUCTION

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Figure 1: Signalling pathway for IL-10 production via TLRs, CD40, SOCE, and their associated transcription factors.

The third model suggests that although Bregs are phenotypically distinct, they do not express ubiquitous lineage-specific markers. Rather, they are characterized by the production of IL-10 to control powerful T cellmediated responses. Certain cell types might also possess additional mechanisms of suppression.3-5 There may be different pathways involved with the differentiation of B cells to Bregs. Bregs share many phenotypic markers with transitional, marginal zone, marginal zone precursor, memory, and B1 B cells. These findings suggest that the environment of developing B cells is critical in their differentiation into Bregs.12 However, it is still unclear how these Bregs migrate to their respective tissue microenvironments, and how cells from these phenotypic subsets become Bregs, as these cells do not seem to constitute their own lymphocyte lineage.12

M E D U CATO R

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BIG DATA ANALYSIS

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There is a paucity of knowledge concerning Breg development and differentiation.13 While in silico analysis may help to bridge these knowledge gaps, there is little research that explicitly mentions Breg development.13 Current literature suggests that human B lymphopoiesis mirrors that of murine models as it occurs through certain developmental stages, such as pro-B cells, pre-B cells, and immature B cells before leaving the bone marrow. Throughout development, cells become more restricted to their cell type, and using single-cell technology to analyze cellular features (e.g. phenotypic proteins, transcription factors, regulatory enzymes, cell-state indicators, and regulatory signaling molecules) helps to detect the underlying relationships that drive differentiation.13 To further illustrate the importance of such features,

this review will examine two primary articles that use in silico analysis and bioinformatics to understand how cell surface changes directly impact Breg development. Bendall et al. used single-cell mass cytometry and a Wanderlust clustering algorithm to organize single cells onto a continuum to predict the B cell trajectory from hematopoietic stem cell to naïve B cells using their respective surface markers.13 A single sample of bone marrow has demonstrated that cells asynchronously transition through these stages, suggesting that hematopoiesis is a continuous process and confirms our current understanding of B cell development from pro- to immature B cells.13 This data reveals signalling changes corresponding to cell fate decisions, cell-cycle status (i.e. survival, proliferation, and apoptosis), and somatic recombination to paint a bigger picture of B lymphopoiesis.13 The data also revealed previously unknown stages of pro-B cells characterized by CD34, CD38, CD24, and TdT expression.13 Furthermore, the study discovered the precise timing of genomic rearrangement in sub-populations of pro-B cells, which is associated with IL-7-induced STAT5 signalling activation.13 These developmental processes are not a discrete set of steps, but rather a continuous process marked by coordination points and trends.13 However, without branch points, the model of Bendell et al. suggests that all cells follow the same transition from hematopoietic stem cell to immature B cell. Following the induced hypothesis of Breg development, where cells can be derived from any developmental stage given the right environment, this model is limited.14 Probability state modeling (PSM) is an approach that produces an analysis of antigen up- and downregulation

in chronological order from cytometry data.15 Bagwell et al. used PSM in bone marrow samples to examine B cell stages before and after CD19 upregulation.15 Prior to CD19 upregulation, there are at least two coordination points, marking three stages: P1, hematopoietic stem cell; P2, common lymphoid progenitor; and P3, pro-B cell.15 Subsequent to CD19 upregulation, there are three coordination points, forming four stages: B1, pre-B cell; B2, early B cell; B3, immature B cell; and B4, transitional B cell.15 Transitions between different stages are marked by the upregulation and downregulation of different cell markers. As many of these cell surface markers are also expressed on Bregs, a certain combination of these markers may reflect Breg progression. However, as CD10 and CD19 expression may reflect some stochasticity, there is some variability concerning the labelling of this progression.15

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

The maintenance of peripheral tolerance is essential, and Bregs perform regulatory functions to suppress immune responses by secreting IL-10 and TGF-β. No transcription factors have been specifically associated with Breg development; however, the Treg differentiation pathway may provide insight on the unique lineage of Bregs. There has been evidence that Breg subsets may share similar gene expression and cytokine profiles, and this relationship should be further studied. While there is limited research concerning Breg development, bioinformatics and in silico methods show immense promise in addressing knowledge gaps and may have even broader implications in understanding autoimmunity. REVIEWED BY JOSHUA F.E. KOENIG Joshua F.E. Koenig is currently a PhD Student in the Medical Sciences program at McMaster University. Joshua studies the pathways responsi le for eneratin hi h affinity antibodies which mediate allergic reactions to food under the supervision of Dr. Manel Jordana. EDITED BY: DANIEL RAYNER & KEVIN ZHAO

Ray A, Wang L, Dittel BN. IL-10-independent regulatory B-cell subsets and mechanisms of action. Int Immunol. 2015;27(10):531-6. Available from: doi:10.1093/intimm/dxv033. Figgett WA, Vincent FB, Saulep-Easton D, Mackay F. Roles of ligands from the TNF superfamily in B cell development, function, and regulation. Semin Immunol. 2014;26(3):191-202. Available from: doi:10.1016/j. smim.2014.06.001. Cambier JC, Gauld SB, Merrell KT, Vilen BJ. B-cell anergy: From transgenic models to naturally occurring anergic B cells? Nat Rev Immunol. 2007;7(8):633. Available from: doi:10.1038/nri2133. Bocian K, Kiernozek E, Domagała-Kulawik J, Korczak-Kowalska G, Stelmaszczyk-Emmel A, Drela N. Expanding diversity and common goal of regulatory T and B cells. I: Origin, phenotype, mechanisms. Arch Immunol Ther Exp. 2017;65(6):501-20. Available from: doi:10.1007/s00005-017-0469-3. Lykken JM, Candando KM, Tedder TF. Regulatory B10 cell development and function. Int Immunol. 2015;27(10):471-7. Available from: doi:10.1093/intimm/dxv046. Gray D, Gray M, Barr T. Innate responses of B cells. Eur J Immunol. 2007;37(12):3304-10. Available from: doi:10.1002/eji.200737728. Lampropoulou V, Hoehlig K, Roch T, Neves P, Gómez EC, Sweenie CH, et al. TLR-activated B cells suppress T cell-mediated autoimmunity. J Immunol. 2008;180(7):4763-73. Available from: doi:10.4049/jimmunol.180.7.4763. Fillatreau S, Sweenie CH, McGeachy MJ, Gray D, Anderton SM. B cells regulate autoimmunity by provision of IL-10. Nat Immunol. 2002;3(10):944-50. Available from: doi:10.1038/ni833. Mauri C, Gray D, Mushtaq N, Londei M. Prevention of arthritis by interleukin 10–producing B cells. J Exp Med. 2003;197(4):489-501. Available from: doi:10.1084/jem.20021293. Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol. 2009;182(12):745972. Available from: doi:10.4049/jimmunol.0900270. Baba Y, Matsumoto M, Kurosaki T. Signals controlling the development and activity of regulatory B-lineage cells. Int Immunol. 2015;27(10):487-93. Available from: doi:10.1093/intimm/dxv027. Tedder TF. B10 cells: A functionally defined regulatory B cell subset. J Immunol. 2015;194(4):1395-401. Available from: doi:10.4049/jimmunol.1401329. Bendall SC, Davis KL, Amir EA, Tadmor MD, Simonds EF, Chen TJ, et al. Single-cell trajectory detection uncovers progression and regulatory coordination in human B cell development. Cell. 2014;157(3):714-25. Available from: doi:10.1016/j.cell.2014.04.005. Spitzer MH, Nolan GP. Mass cytometry: Single cells, many features. Cell. 2016;165(4):780-91. Available from: doi:10.1016/j.cell.2016.04.019. Bagwell CB, Hill BL, Wood BL, Wallace PK, Alrazzak M, Kelliher AS, et al. Human B- cell and progenitor stages as determined by probability state modeling of multidimensional cytometry data. Cytometry B Clin Cytom. 2015;88(4):214-26. Available from: doi:10.1002/cyto.b.21243.

critical review

Given the lack of research on Breg development, bioinformatics has become a widely sought out solution. In silico and gene analysis can provide a greater understanding of the signals that drive Breg differentiation and activation. This analysis would be applicable for research on Bregs and can create healthy developmental trajectories to pinpoint irregularities in disease processes such as MS.13 For instance, the Th1 plaque formation and demyelination pathogenesis of MS has been oversimplified in the past; now that recent findings have shifted the focus to B cells, computer models may inform improved therapeutic approaches that harness Bregs to ameliorate autoimmune diseases.

CONCLUSION

M E D U CATO R | A P R I L 2019

22

INTERVIEW SPOTLIGHT

DR. JAMES MACKILLOP

Clearing The Smoke On Cannabis

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EDWARD CUI1 & DANIEL RAYNER2

Bachelor of Health Sciences (Honours) Class of 2021, McMaster University 2 Bachelor of Health Sciences (Honours) Class of 2022, McMaster University

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It’s been an evolution. I was always interested in psychology and I wanted to be a clinical psychologist, so that’s what I studied in graduate school. Initially, I wasn’t sure where I wanted to specialize. I worked in a laboratory doing schizophrenia research and I decided that it was not the direction I wanted to go. At the time, I was really interested in binge drinking among young adults; I was interested in studying alcohol misuse and that’s what I explored in graduate school. From there, I broadened my interests to other drug and behavioral addictions, including gambling disorders and compulsive eating. Only recently have I started focusing on the other [therapeutic] side of the coin: the medical applications of cannabis, which is in the context of the new CMCR. One of the things I love about being an addictions researcher is that it is an intersection of many different fields [such as] … behavioral genetics, … psychology [and] … cognitive neuroscience. Addiction has real-world impacts in terms of healthcare delivery, crime, and the economy, so all of these different disciplines have their own perspectives on addiction. Therefore, addiction is an incredibly multidisciplinary area that allows you to look at a significant social and health

concern through a lot of different lenses. [You] gain different perspectives based on the one you choose. H

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The second misconception is that medicinal cannabis is relatively benign and is healthier and safer than other medications because it’s a plant product. However, there are lots of natural things that are unsafe and unhealthy. For

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In my opinion, there are two families of misconceptions. There are many conditions for which people use medicinal cannabis. If you look at the Health Canada documentation, I think that there are more than 25 possible conditions listed, and if you search for medicinal cannabis use on the internet, you’ll find much longer lists. Recently, I was shown a site identifying over 200 different conditions. One of the misconceptions is that just because someone says you could use medicinal cannabis to treat something then there’s good evidence that it would actually be helpful, or that these lists, even from Health Canada, have the same amount of evidence from one [condition] to another. The reality is that the scientific literature is very lopsided; there are some conditions for which there is reasonably good evidence, and then there are conditions for which we have no evidence. In healthcare, you generally don’t want to recommend things for which you have no evidence apart from anecdotes or observational data. [These data] are certainly clues but are not the kind that one would ever use to get approval from Health Canada or the FDA. So I think the first misconception is [the belief ] that the evidence behind indications are equal.

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Historically, one of the obstacles has been that when you are trying to study an illegal product, it’s unlike studying alcohol or tobacco where there are quality assurance standards and manufacturing standards. If you tell me that you drank a Molson beer, I know how much ethanol is in that drink, so I can be fairly sure of [your intake]. If you bought some

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M E D U CATO R

At the CMCR, we’re supporting a variety of different pilot research initiatives. These include early stage trials looking at cannabis [treatment] for specific conditions. In other cases, it’s more observational research. For example, we’re conducting evaluations of patients in clinic who may be using cannabis, medically, or non-medically, to see how that interacts with their treatment prognosis. In other cases, there are laboratories investigating new therapeutic indications for cannabis and specific combinations of cannabinoids and their [associated] risks. For example, we’re looking at new combinations [of cannabinoids] as possible treatments for pain but we’re also looking at how cannabis smoke may have adverse consequences on lung function. We’re really trying to look at the whole spectrum of research, from basic science to clinical science, to move forward in terms of knowing where the best evidence is.

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interview spotlight

The interesting thing about medicinal cannabis use in Canada is that there has [recently] been a skyrocketing increase in the number of people who’ve sought a physician authorization for medicinal cannabis. Over the last four years, we’ve seen close to a 3000% increase in the number of people who have sought an authorization, and I believe that number is now over 300,000 Canadians. This increase is not because the associated evidence has also skyrocketed. The reality is that the evidence hasn’t changed all that much over the last couple years —that’s just the nature of health research. The other reality is that specifically in the context of medicinal cannabis, the evidence is not as strong as we would like in a number of areas. Most authoritative reviews have suggested that there is moderately consistent evidence for some conditions, such as nausea in chemotherapy patients and muscle spasticity in those with multiple sclerosis. However, for a lot of other conditions, the kind of evidence that we would look for, especially gold-standard randomized control trials, haven’t been conducted. This causes a real disconnect between the research being conducted and what people are actually using medicinal cannabis for. We feel like there is a real need for much more coordinated, dedicated, clinical and pre-clinical research on cannabis.

cannabis off the street and smoked it, I don’t really know what’s in it. I can “guess-timate” some levels of THC [or] we could take a sample and test it, although that’s actually quite challenging. It’s been a more opaque world out there in terms of contraband cannabis because there are variable levels of THC and there can be other products laced in. The more general issue with cannabis is that THC, the compound people are most familiar with because of its psychoactive effect, is not the only component. There are literally hundreds of other compounds and over a hundred different endocannabinoids/ phytocannabinoids, which are the plant compounds that actually act on our internal endogenous cannabinoid system. The best known is THC, but cannabidiol (CBD) is the other one people hear a lot about. Thus, in that illegal market, we have very little knowledge about what people are consuming. With legal medicinal cannabis and now legal recreational cannabis, we’re going to have a much better sense for what’s being consumed and what the possible consequences could be. For example, we may discover that there are more adverse consequences for individuals using THC products, or perhaps less harm for people using high CBD or lower THC:CBD ratios. The other thing is that we are going to have much better access to products that we can study. If you want to do trials or experimental research, you have to administer these substances under controlled conditions. I think that hopefully, with legalization, there will be an easier system for getting access to cannabis products in order to better study it in the laboratory and the clinic.

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example, you wouldn’t encourage someone to go out and eat mushrooms that they’ve self-foraged. The reality is that natural does not mean safe and we should think of medicinal cannabis as any other drug. Unfortunately, for virtually all drugs used to treat medical conditions, there are benefits we are looking for —the on-target therapeutic effects— and then there are the side effects. One of the things we encourage people to realize is that there are two sides of the coin when it comes to medicinal cannabis; in some cases it may be worth it, but just like any other drug, there is a costbenefit ratio. H

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In terms of the existing medicinal cannabis framework in Canada, we don’t really know what the recent legalization is going to do. One possibility is that medicinal cannabis and recreational cannabis will exist side-by-side and there won’t be much difference. The other possibility is that a lot of the licensed manufacturers that produce medicinal cannabis move over to the much larger recreational market and may produce fewer products in demand from this minority medicinal market —things like high-CBD products. Thus, there may be a change in the availability of the product based on the change in legislation. There are so many questions surrounding the legalization because we don’t know whether the overall prevalence of recreational and medicinal cannabis users will change and whether there will be changes within subpopulations. One interesting thing is that we haven’t seen a reduction in the rate of individuals seeking medicinal cannabis leading up to legalization. It seems like if people simply wanted access [to cannabis], they would just wait for legalization to happen. The fact that people are still seeking authorizations and meeting with physicians suggests that there is still going to be a robust segment of the population that wants to use medicinal cannabis. Another conjecture is that maybe the medical users will simply say, “I don’t need to pay more [for medicinal cannabis] or pay for physician visits,” because those are out-of-pocket and typically unreimbursed expenses, and instead buy recreational cannabis. If we had suddenly seen a plateau or a decrease in the number of people seeking authorizations, those would be people who see the official announcement of legalization as a signal that they’ll be able to get [cannabis] without an authorization. I tend to think that there will still be a distinct [medicinal] market but we don’t really know. This is why we’re doing lots of research to study how attitudes and behaviours change over the course of legalization.

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The opioid epidemic is, in some ways, a not-so-obvious but still very relevant reason why we created the CMCR. One of [the] things that the opioid crisis has revealed is how dangerous opioids are in terms of their abuse liability. Unforeseen consequences can happen when potent psychoactive drugs enter widespread medical practice with an underappreciation for their risks in the industry, among physicians and patients. It’s not too long a line to draw to expect a similar set of challenges when it comes to medicinal cannabis. You have a skyrocketing trajectory of use. We have a culture and industry that are fairly favourable toward the medical benefits. I would say that we often have an underappreciation of associated risks. Now, along with the legalization of cannabis for non-medicinal purposes, we have a major change that will provide even greater access to the general population. What we very much hope is that we don’t have to learn the lessons from the opioid epidemic twice. There are good reasons to think that that won’t happen. One of the things that makes the risk profile of cannabis lower than that of other drugs is that it has virtually no toxicity in terms of life-threatening levels of consumption. You can certainly overdose on cannabis. You can consume too much and have very unpleasant symptoms, such as delirium and psychosis, which should not be trivialized. But, unlike opioids, the risk of overdose leading to death is virtually nil. So, that kind of lethality dimension is not present. However, that doesn’t mean that there won’t be other unforeseen consequences. Part of our focus is trying to be a vocal proponent for knowing the risks of cannabis and investigating the potential benefits. I want to emphasize that we’re neither pro-cannabis nor anti-cannabis. We’re pro-research and we’re really trying to promote an evidencebased understanding of cannabis. H P

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The day-to-day experience is probably not the most glamorous, I would say. It involves mostly either being in meetings, writing and analyzing data, or writing results, which probably doesn’t seem very interesting. But, the great part about the work that we do is the fact that we are very trans-disciplinary in the CMCR. I’m a clinical psychologist, but probably half the affiliated faculty are physicians, many of whom are clinician-scientists, meaning those who are both seeing patients and doing research. And then we have a lot of PhD scientists who are doing more basic research. A lot of the meetings and studies we’re designing involve talking to people who are doing very different things and have different ways of thinking about the world. It means that we can ask some fascinating questions.

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OPINION

The Medicalization Of Childbirth A necessary system for safety or a lack of evidence-based practice?

LAUREN FILBEY Bachelor of Science in Nursing Class of 2020, McMaster University Correspondence: filbeyl@mcmaster.ca

ABSTRACT There has been an alarming trend in Canadian hospitals to over-medicalize the process of childbirth. The attribution of pathology to childbearing has led to an increased use of medical interventions that elevates healthcare costs and postoperative risk without improving the birthing experience for mothers and newborns. Nurses occupy an optimal position for addressing this problem because of the significant duration of contact they have with patients and their professional competency in non-pharmacological approaches. This is reflected in the positive outcomes linked to the use of continual labour support, an intervention largely performed by nurses and midwives. INTRODUCTION Medicalization is the process of defining a human condition as a pathology that should be managed with a medical framework consisting of diagnosis and treatment.1 However, pregnancy and the process of delivery are neither inherently pathological nor a disease state. Prior to the 18th century, childbirth was entrenched within the realm of midwifery.2 As critical health issues related to labour were identified, physicians became more involved in the childbirthing sphere.2 Medical interventions provide life-saving measures for childbirth that should not be devalued. For example, from 20032009, over half of maternal deaths worldwide could be attributed to preventable complications such as sepsis, hemorrhage, or hypertensive disorders.3 However, situations that warrant medical services rather than natural birthing strategies have not been firmly established, contributing to the overuse of medical interventions. The incorrect attribution of pathology to childbirth fosters the overuse of medical interventions including inductions, vacuumassisted deliveries, and caesarean sections (CS).4-8 The rate of CS in Canada has risen 10% since 1995 to a current total of approximately 25% of all births.5,9 A cross-sectional analysis concluded that labour is induced in 10% of all first-time mothers without appropriate medical indication.10 Additionally, vacuumextraction deliveries have increased by 56% in Canada since 1991.8

Excessive use of medical interventions during delivery are justified on the pretext of safety but are associated with decreased maternal autonomy, increased negative clinical outcomes, and escalating healthcare costs.2,5-7 Canadians should call for systems-level action to provide care that prioritizes the well-being of women and newborns. OVERUSE OF THE SUPINE POSITION The practice of placing mothers in a supine position during delivery is commonly used despite its association with negative clinical outcomes.11 The supine position oers optimal accessibility for the healthcare provider which has contributed to its popularity amongst clinicians.7,12 However, since maternal position during labour impacts the process and outcomes of childbearing, the decision therefore should be based on evidence rather than convenience.6 A number of studies demonstrated lower length of labour, self-reported pain, amount of assistance needed, and risk of abnormal fetal heart rates when delivering in the upright position.13 In comparison, women who labour in a supine position report higher rates of dissatisfaction with their birth and increased perineal trauma.7,14-16 Given these results, the standard position for delivery should be reconsidered and mothers should be made aware of the numerous positions amenable to birth. BARRIERS TO MOVEMENT The use of medical interventions often restricts movement, confining women to the supine position. This practice conflicts with the World Health Organization’s recommendations for intrapartum care which suggests that mobility is a critical factor in shaping a positive childbirth experience.17 Hormonal studies have found that increased time spent in the supine position increased release of catecholamines, which are

hormones associated with emotional responses of stress and fear.18 Two commonly used interventions that restrict movement are electronic fetal heart rate monitoring (EFM) and induction. EFM is widely used with the aim of identifying fetal deterioration.19 However, its capacity to detect true fetal distress remains quite low.19 Since its installation in hospitals, there has not been a substantial decrease in fetal morbidity.20 The usage of EFM largely limits a woman’s capacity to change position and often keeps her confined to bed, directly limiting her options of feasible birthing positions. Induction is intended to promote labour in women past 41 weeks of gestation to prevent complications associated with carrying a fetus past term. However, surveys from developed nations have found that up to 25% of deliveries were induced despite not surpassing gestational term.21 Pharmacological induction of labour often requires the insertion of an IV, which complicates movement and promotes stasis, further inclining women to labour in the supine position.22 INCREASING CS RATES IN CANADIAN WOMEN

process, and deliver babies with higher APGAR scores.11,27 Nurses are often at the patient bedside during delivery and therefore play a critical role in encouraging women in labour to assume more control in the birthing process. Nursing education around the benefits of upright birthing positions and continuous labour support during the intrapartum period could help improve the birthing experience for mothers and newborns. CONCLUSION The process of pregnancy and childbirth should not be considered inherently pathological or high-risk. The medicalization of childbirth is an unnecessary trend that is increasing in Canada without medical indication. Over-medicalization of childbirth creates negative subjective experiences and clinical outcomes for mothers and newborns and places an economic burden on the Canadian healthcare system. Ultimately, medical approaches to childbirth must be re-evaluated to allow current practices to reflect evidence-based research. Canadians should call for systems-level action to encourage care that facilitates the well-being of women and newborns. REVIEWED BY: JAMIE SASSI

Jamie is a 2nd year student in the BHSc Midwifery program at McMaster University. She is a research assistant for a project investigating the impact of midwifery services in underserved populations. She is also the co-chair of the c aster nterprofessional tu ent olla orati e, a student-run organization that promotes interprofessional collaboration.

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When necessary, CS can save the lives of mothers and babies and minimize the risk of serious complications.4 As previously discussed, the rates of CS in Canada have recently escalated significantly. The World Health Organization has identified a CS rate greater than 15% to be futile; this threshold raises concerns that many CS are medically unnecessary.4,5,9 A CS can result in severe acute and chronic complications. Acute complications include intra- and post-operative bleeding, wound infections or sepsis, and even death.4,23 Long-term complications include menstrual irregularities, ectopic pregnancy, abnormal placentation, and pelvic adhesions that generate recurrent pain.24 The escalating usage of CS suggests that clinicians are not fully considering the gravity of this procedure and its ramifications for mothers.

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Economic burdens must also be considered in the scrutiny of increasing CS rates. In fact, a CS in Canada can be 45% more expensive than a vaginal delivery.5,25 The current CS practices place increased economic stress on the already strained Canadian healthcare system.5

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It is recognized that CS rates in Canada have been steadily rising; however, causative factors have not been widely identified. Fear of malpractice lawsuits engendering a culture of defensive medicine has been implicated in this trend, as it inclines physicians to perform CS on complex birthing situations.23 Further, declining birth rates among North American women could be encouraging financially-motivated physicians to supplement their incomes by providing excessive care in the form of unnecessary CS.26

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THE ROLE OF THE NURSE IN THE BIRTHING PROCESS

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Evidence demonstrates that continuous support for labouring women from nurses promotes high rates of satisfaction in women and decreases the need for mechanical or surgical interventions.11,27 Women who received continuous labour support were more likely to experience spontaneous vaginal births, experience less pain, feel more active in the decision-making

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Merriam-Webster’s Collegiate Dictionary. 11th ed. Springfield, MA: Merriam-Webster Incorporated; 2003. 1162 p. Cahill HA. Male appropriation and medicalization of childbirth: an historical analysis. J Adv Nurs. 2001;33(3):334-342. Available from: doi:10.1046/j.1365-2648.2001.01669.x. Say L, Chou D, Gemmill A, Tuncalp O, Moller AB, Daniels J, et al. Global causes of maternal death: A WHO systematic analysis. Lancet Glob Health. 2014;2(6):e323-33. Available from: doi.10.1016/SS2214-109X(14)70227-X. Kingdon C, Downe S, Betran, AP. Non-clinical interventions to reduce unnecessary caesarean section targeted at organisations, facilities and systems: Systematic review of qualitative studies. PLoSONE. 2018;13(9):1-16. Available from: doi:10.137/journal/pone.0203274. Bermudez-Tamayo C, Johri M, Chaillet N. Budget impact of a program for safely reducing caesarean sections in Canada. Midwifery. 2018;60:20-6. Available from: doi:10.1016/j. midw.2018.01.22.022. Diorgu FC, Steen MP, Keeling JJ, Mason-Whitehead E. Mothers and midwives perceptions of birthing position and perineal trauma: An exploratory study. Women Birth. 2016;29(6):518523. Available from: doi:10.1016/j. wombi.2016.05.002. De Jonge A, Teunissen TAM, Lagro-Janseen ALM. Supine position compared to other positions during the second stage of labor: A meta-analytic review. J Psychosom Obstet and Gynecol. 2004;25(1):35-45. Available from: do i:10.1080/01674820410001737423. Canadian Institute for Health Information (CIHI). Giving birth in Canada: A regional profile. Ottawa: CIHI; 2004. 11 p. Canadian Institute for Health Information (CIHI). Patient cost estimator: Methodological: Notes and glossary. Ottawa: CIHI; 2015. 15 p. Report No.:9. Davey MA, King J. Caesarean section following induction of labour in uncomplicated first births – A population-based cross-sectional analysis of 42,950 births. BMC Pregnancy and Childbirth. 2016;16(92). Available from: doi:10.1186/ s12884-016-0869-0. Chow J. Canadian Maternity and Pediatric Nursing. 1st ed. Philadelphia: Wolters Kluwer; 2013. 1968 p. Boyle M. Childbirth in bed: The historical perspective. Pract Midwife. 2003;3(11):214. Available from: https://europepmc.org/ abstract/med/12026562. [cited 2019 Mar 6]. da Silva F, de Oliveira SM, Bick D, Osava RH, Tuesta EF, Riesco ML. Risk factors for birthrelated perineal trauma: Cross-sectional study in a birth centre. J Clin Nurs. 2012;21(1516):2209-18. Available from: doi:10.1111/ j.1365-2702.2012.04133.x. de Jong PR, Johanson RB, Baxen P, Adrians VD, Van der Westhuisen S, Jones PW. Randomised

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trial comparing the upright and supine positions for the second stage of labour. Br J Obstet Gynaecol. 1997;104(5):567-71. Available from: doi:10.1111/j.1471-0528.1997.tb11534.x. Waldenstrom U, Gottvall K. A randomized trial of birthing stool or conventional semi recumbent position for second-stage labor. Birth. 1991;18(1):5-10. Available from: doi:10.1111/j.1523-536X.1991.tb00045.x. Marttila M, Kajanoja P, Ylikorkala O. Maternal half-sitting position in the second stage of labour. J Perinatal Med. 1983;11(6):286-89. Available from: doi:10.1515/jpme.1983.11.6.286. World Health Organization. WHO recommendations: intrapartum care for a positive childbirth experience. Geneva: World Health Organization; 2018. 210 p. Report No.: 978-92-4-155021-5 Ondeck M. Healthy birth practice #2: Walk, move around, and change position throughout labour. J Perinat Educ. 2014;24(4):188-93. Available from: doi:10.1891/1058-1243.23.4.188. Nageotte MP. Fetal heart rate monitoring. Semin Fetal Neonatal Med. 2015;20(3):144-8. Available from: doi:10.1016/j.siny.2015.02.002. Freeman RK. Intrapartum fetal monitoring - A disappointing story. N Engl J Med. 1990;322(9):624-6. Available from: doi:10.1056/NEJM199003013220910. Caughey AB, Sundaram V, Kaimal AJ, Cheng YW, Gienger A, Little SE, et al. Maternal and neonatal outcomes of elective induction of labor. Rockville (MD): Agency for Healthcare Research and Quality (US); 2009. 257 p. Report No.: 09-E005. Luckas M, Bricker L. Intravenous prostaglandin for induction of labour. Cochrane Database Syst Rev. 2000;(4):CD002864. Available from: doi:10.1002/14651858.CD002864. Dubay L, Kaestner R, Waidmann T. The impact of malpractice fears on cesarean section rates. Health Econ. 1999;18(4):491-522. Available from: doi:10.1016/S0167-6296(99)000041. Moro F, Marvelos D, Pateman K, Holland T, Hoo WL, Jurkovic D. Prevalence of pelvic adhesions on ultrasound examination in women with a history of Cesarean section. Ultrasound Obstet Gynecol. 2015;45(2):223-8. Available from: doi.10.1002/uog/14628. Halpern S. SOGC joint policy statement on normal childbirth. J Obstet Gynecol Can. 2009;31(7):602-40. Available from: doi:10.1016/S1701-2163(16)34236-0. Gruber J, Owings M. Physician financial incentives and cesarean section delivery. RAND J Econ. 1996;27(1):99-123. Available from: doi:10.2307/2555794. Hodnett ED, Gates S, Hofmeyr GJ, Sakala C. Continuous support for women during childbirth. Cochrane Database of Syst Rev. 2013;7. Available from: doi:10.1002/14651858.

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GLOBAL PERSPECTIVE “Be the Bridge” Collaboration: Our journey 28

PRIYANKA JANI, ANDREA WASYLECZKOARON, RUTH LING, ERIKA RAYCROFT Bachelor of Science in Nursing Class of 2020, McMaster University

ABSTRACT

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global perspective

Students in the McMaster School of Nursing, like in other Health Sciences programs, learn about evidence-based practice in a variety of hospital settings. However, best practice must also be provided at a systems level in the community, guided by the principles of primary health care. During a third-year community health course, we were placed in the South Sherman neighbourhood, a low-income, high-priority area in Hamilton. Within this community, we learned that improving health requires looking beyond the healthcare system. Therefore, we developed an intervention to address the gap between services and residents in the area. After a successful pilot project, our initiative is now becoming a full-scale partnership between McMaster students and the Hamilton community members who act as our hosts and teachers.

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We completed our community placement at the 541 Eatery and Exchange on Barton Street. The eatery is a social justice initiative with a unique “button system” in which customers can order food and, if they choose, donate $1 to place a button in the countertop jar. Subsequent customers may use these buttons to purchase affordable, locally sourced, and freshly made meals. The button system allows members of the South Sherman neighbourhood to access quality food with reduced financial stress.This eatery draws customers from across the city and offers dignity to patrons from all walks of life, who order from the same menu and often share the same tables in conversation. As we formed relationships and interacted with the community, we noticed a high prevalence of health issues. This area has a lower median income relative to other communities located in Hamilton, which contributes to a significantly decreased life expectancy.1,2 Ten years ago, the Hamilton Spectator’s ‘Code Red’ report identified key factors that contribute to these health concerns, such as poverty, inadequate access to healthcare, and lack of education. These social determinants were related to higher rates of morbidities (e.g. cardiovascular diseases, diabetes, and cancer) and ultimately higher rates of mortality.3 Newly revised ‘Code Red’ statistics report that most health indicators have worsened.4 By being placed in a ‘high risk’ community, we had a first-hand glimpse of how these social determinants of health contributed to poor health outcomes for this population. For example, an individual living in poverty could not afford proper housing or medication to manage their disorders. Although health and social services exist to address the needs of the population, they remain inaccessible to many due to barriers such as low health literacy, lack of trust in professionals, low personal agency, previous experiences, and social stigma.5 Among these barriers, we identified health literacy as a common challenge to this population.

HEALTH LITERACY Health literacy, according to the World Health Organisation, is defined as “the cognitive and social skills which determine the motivation and ability of individuals to gain access to, understand and use information in ways which promote and maintain good health.”6 We entered the South Sherman neighbourhood ready to educate the population about the theoretical and clinical aspects of health in order to increase healthcare access in the area. However, this proved to be a more difficult task than expected, as we were taking the wrong approach. Once we stopped trying to teach and started to listen and learn from the community firsthand, we discovered that there was a disconnect between the healthcare system and the people that it is trying to serve. In order to bridge the divide between our training and the actual health needs of this marginalized population, we needed to foster bi-directional teaching between the two communities. We needed to learn the language, expertise, contextual knowledge, and stories of the community in order to identify an effective approach to address the problem.7-10 As such, our initiative is guided by participatory research approaches such as Participatory Action Research, and Asset-Based Community Development.11,12 Most evidence-based approaches within this body of literature require students to venture outside their privileged (university) communities and listen to people’s stories in the environments where they live, work, and play. As we integrated ourselves into the South Sherman neighbourhood and listened to these stories, we considered how to extend our impact beyond the confines of a single course.

“BE THE BRIDGE” COLLABORATION

Through our professional community practice, we witnessed the many factors that impact health outcomes, with health literacy being a primary factor. After our placement in the South Sherman community, we gained a better understanding of what makes it difficult for these individuals to navigate the healthcare system. In response, we created the program “Be the Bridge” which would target some of the remaining barriers to healthcare access and foster health literacy. As with most population health interventions, the benefits can be profound but it can be difficult to see changes in a matter of months. Through the collaboration with South Sherman community hosts, students were able to develop a stronger understanding of the struggles and barriers of their community partners, which diminished the biases the students once held. Students became more apt to listen and more narratively and culturally competent. We hope to ignite this change within every student who participates in “Be the Bridge.” REVIEWED BY NINA CAVEY, MSC. Nina Cavey is a faculty member at McMaster University’s School of Nursing with a diverse background in primary healthcare and global health, mental health, research coordination and curriculum development. Her graduate work on spirituality and schizophrenia earned her the prestigious Council of Ontario Universities’ Masters Award of Excellence.

global perspective

From our newfound experiences, we developed “Be the Bridge,” a formal collaboration between McMaster students and marginalized urban community members. To minimize stigma, we called community members “hosts,” highlighting their expertise in their respective communities. We realized that in order to construct a functional bridge, we needed an equal partnership between the two communities —a mutual development of health literacy. All parties involved needed to become building blocks in this living relational bridge —to Be the Bridge— to make services accessible to a priority urban population. In doing so, we can utilize experiential learning to foster empathy and develop healthcare professionals who understand the social determinants of health. We ran a small pilot project involving two McMaster students paired with one South Sherman community host. This relationship involved discussions about various topics such as health issues, personal experiences, and the South Sherman community. From their exchanges, we gathered informal data revealing that there were challenges involving the host questioning the students’ intentions and time constraints. Challenges notwithstanding, we considered the project feasible and worthwhile. We created a leadership team and are now establishing a more formal collaboration process that pairs McMaster student volunteers with urban community host volunteers. We expect to have the initiative operational by October 2019. Eventually, we hope that the model and vision of this program will become versatile enough to be utilized across multiple populations with similar features to the McMaster and South Sherman communities.

CONCLUSION

EDITED BY WENDY FU & DANIEL KIM

DeLuca P, Kanaroglou P. Code Red: Explaining average age of death in the city of Hamilton. AIMS Public Health. 2015;2(4):730-45. Available from: doi:10.3934/publichealth.2015.4.730.eCollection 2015. Statistics Canada. City of Hamilton Health Unit (Health Region), Ontario and Ontario (table) [Internet]. 2013 Dec 12. Available from: http://www12.statcan.gc.ca/health-sante/82-228/index. cfm?Lang=E [cited 2019 Mar 6]. 3. Buist S, DeLuca P, Johnston N. Code Red Hamilton [Internet]. The Hamilton Spectator. 2010. Available from http://thespec-codered.com/?page_id=8 [cited 2019 Mar 6]. 4. Buist S. Code Red: 10 years later [Internet]. The Hamilton Spectator. 2019 Feb 28. Available from https://www.thespec.com/news-story/9187352-code-red-10-years-later/ [cited 2019 Mar 6]. 5. Moravac CC. Reflections of homeless women and women with mental health challenges on breast and cervical cancer screening decisions: Power, trust, and communication with care providers. Front Public Health. 2018;6:30. Available from: doi:10.3389/fpubh.2018.00030. 6. World Health Organization. Track 2: Health literacy and health behaviour [Internet]. 2019. Available from https://www.who.int/healthpromotion/conferences/7gchp/track2/en/ [cited 2019 Mar 6]. 7. European Centre for Disease Prevention and Control. A rapid evidence review of interventions for improving health literacy: Insights into Health Communication [Internet]; 2012 May. Available from https://ecdc.europa.eu/sites/portal/files/media/en/publications/Publications/1205-TER-Improving-Health-Literacy.pdf [cited 2019 Mar 6]. 8. Hartzler A, Pratt W. Managing the personal side of health: How patient expertise differs from the expertise of clinicians. J Med Internet Res. 2011;13(3):e62. Available from: doi:10.2196/jmir.1728. 9. Sordo M, Tokachichu P, Vitale C, Maviglia S, Rocha R. Modeling contextual knowledge for clinical decision support. AMIA Annu Symp Proc. 2018:1617-24. Available from https://www.ncbi.nlm.nih.gov/ pmc/articles/PMC5977672/ [cited 2019 Mar 6]. 10. Charon R. The principles and practice of narrative medicine. New York, NY: Oxford University Press; 2017. 11. Larson C, Schlundt D, Patel K, Goldzweig I, Hargreaves M. Community participation in health initiatives for marginalized populations. J Ambul Care Manage. 2009;32(4):264-70. Available from: doi:10.1097/JAC.0b013e3181ba6f74. 12. Mathie A, Cunningham G. From clients to citizens: Asset-based community development as a strategy for community-driven development. Development In Practice. 2003;13(5):474-86. Available from: https://www.jstor.org/stable/4029934 [cited 2019 Mar 6]. 1. 2.

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ARTIST Laura Nguyen

CRITICAL REVIEW

What is the hidden curriculum, And how does it affect nursing students?

SIMON FARQUHARSON Bachelor of Science in Nursing, Class of 2019 McMaster University Correspondance: farquharsonse@gmail.com

ABSTRACT The hidden curriculum can be defined as that which is taught to students unintentionally by the culture, structure, and people of their educational setting. Although most authors agree on its importance, little is written about how the hidden curriculum affects nursing students in both university and clinical placements. The purpose of this review is to take a broad look at the research on the hidden curriculum in an attempt to better understand its current value and future potential, as it affects nursing students and the profession. A brief history of the hidden curriculum is provided in relation to nursing education, followed by a review of the literature with a specific focus on the variety of educational and clinical applications in which it plays important roles. These topics arose from interactions with peers, nurses, non-faculty staff, and other community members, all of which had potential impacts on the students. Ultimately, the hidden curriculum is an understudied, underappreciated component of education, and is one in which students play a major personal role in developing. Both faculty and students need to understand the power and importance of this tool, as it has the capacity to shape the future of the nursing profession.

BACKGROUND

The concept of a hidden curriculum is old. The specific term dates back to at least the 1960s and has been applied to healthcare education for several decades thereafter.3 Over the years, four types of curricula have been described: 1. The formal curriculum: what the school officially claims to teach in their published course outline or manual.4

REVIEW FINDINGS In the roughly 40 years since the study of hidden curricula was introduced into nursing literature, there have been few relevant publications. The lack of research is surprising given that until recently, nursing is a field that has relied primarily on hidden curricula in the form of peer teaching and on-the-job apprenticeships.10-12 Nursing in Canada only started to become a profession in the 1920s, and the transition into modern theoretical teaching began largely in the 1940s.11 However, even through the 1970s, much of the theoretical curriculum had little transferability into practice and focused instead on rote memorization.13 Student learning was often not the priority for hospitals, and debating their educational needs against the hospitals’ needs remained a persistent theme in every major Canadian nursing report until the 1970s.14 In the few times when the hidden curriculum was discussed in nursing literature, it traditionally carried a negative connotation, and the discussion focused on mitigating its undesirable outcomes.9,15,16 Indeed, the hidden curriculum has many negative outcomes due to the fact that the surrounding educational culture is difficult to control; however, it would be irresponsible to dismiss it as entirely unwanted for these reasons.4 Lately, literature on hidden curricula have primarily discussed students’ experiences in hospital placements, but there are many other areas within nursing education that involve hidden curricula which deserve our attention.9

Hidden Curricula within the School

critical review

McMaster Professor Geoff Norman, one of the theoretical founders of problem-based learning, recently said, “If you examine student outcomes, 3% of the difference is due to curricula, 7% to teachers, and 90% to students. And that’s in K-12 education; I suspect that curricula play even less of a role in health professions.”1 A longitudinal study in medical education came to the same conclusion: the greatest variability in student outcomes arises from the students, and the least from the curriculum.2 So, if a program’s curriculum matters so little, what is it that differentiates one school’s nursing graduates from another? While the full answers are complex, a notable proportion of the differences may be found not in the stated curriculum, but in the “hidden” curriculum.

lesson.7 Indeed, the values and attitudes transmitted through the hidden curriculum appear to have a greater impact on students than the formal curriculum.8 However, it is also a topic filled with controversy among educators. At times, the prevailing wisdom has been to combat the hidden curriculum, at times to ignore it, and at other times to mitigate its presence.4,5,9

Just as each university has its own students, staff, history, and culture, so too does each nursing school have its own hidden curriculum.9 And with each hidden curriculum comes a unique set of strengths and challenges that students must face on their path to becoming nurses.

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The concepts of power and privilege in the hidden curricula are addressed by a Canadian article and supported by a study from 2. The informal curriculum: the unscripted, or ad hoc, Iran.9,17 Both pieces highlight how misuse of the staff ’s power communication between faculty and students, usually in over students, or treating students differentially, can influence their development into nurses and inadvertently teach them between instances of formal curricula.4 to behave similarly in the future to their patients.9,17 Further 3. The null curriculum: the topics or lessons that are “conspicuous qualitative studies from Iran and Pakistan also discuss how by their absence,” such as how a topic deliberately left untouched unrealistic demands and a lack of resources in their learning environment increased the anxiety and stress of nursing students sends the message that it must be unimportant.5 and contributed to breaches of academic integrity.17,18 4. The hidden curriculum: a combination of factors involving the organization’s structure and culture that affect student learning.4 On the positive side, the previous Iranian study also highlighted instances where students felt encouraged to act altruistically due Overall, the hidden curriculum arises from the culture of the to positive interactions with school staff.17 Students also reported educational setting, the identity of its students, and the informal that being immersed in a new and challenging environment with interactions among peers and non-faculty personnel. As one different people and cultures helped them develop independence of the earliest authors in the field of nursing noted, the hidden and expand their perspectives as new nurses.17 Another qualitative curriculum is “taught by school, not by any teacher.”6 study from Australia investigated the experiences of peer teachers and learners for simple tasks such as taking vital signs, and found The hidden curriculum is a fundamental component of what is that this near-peer interaction also played a role in professional taught at school, and even as early as 1938, it was recognized that socialization and camaraderie.16 collateral learning was often more important than the intended

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Norman G. The birth and death of curricula. Adv Health Sci Educ Theory Pract [Internet]. 2017 [cited 2019 Mar 1];22:797–801. Available from: https://www.ncbi.nlm.nih. gov/pubmed/29189964 DOI: 10.1007/s10459-017-9790-1 Hecker K, Violato C. How much do differences in medical schools influence student performance? A longitudinal study employing hierarchical linear modeling. Teach Learn Med [Internet]. 2008 [cited 2019 Mar 1];20:2, 104-113. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18444195 DOI: 10.1080/10401330801991915 Lawrence C, Mhlaba T, Stewart KA, Moletsane R, Gaede B, Moshabela M. The hidden curricula of medical education: a scoping review. Acad Med [Internet] 2018 [cited 2019 Mar 1];93(4):648-656. Available from: https://www. ncbi.nlm.nih.gov/pubmed/29116981 DOI: 10.1097/ ACM.0000000000002004 Hafferty FW. Beyond curriculum reform: confronting medicine’s hidden curriculum. Acad Med [Internet]. 1998 [cited 2019 Mar 1] ;73(4):403-7. Available from https://www. ncbi.nlm.nih.gov/pubmed/9580717 Hafferty FW, O’Donnell JF. The hidden curriculum in health professional education. Lebanon, NH: Dartmouth College Press; 2015. Partridge B. The hidden curriculum of nursing education. Lamp 1983;40(8):30. Dewey J. Experience and education. Indianapolis: Kappa Delta Pi; 1938. Edwards H, Chapman H, Davis, LM. Utilization of research evidence by nurses. Nurs Health Sci [Internet]. 2002 [cited 2019 Mar 1];4:89-95. Available from: https://onlinelibrary. wiley.com/doi/abs/10.1046/j.1442-2018.2002.00111.x DOI:10.1046/j.1442-2018.2002.00111.x Chen R. Do as we say or do as we do? Examining the hidden curriculum in nursing education. Can J Nurs Res [Internet]. 2015 [cited 2019 Mar 1];47(3):7-17. Available from: https://www.ncbi.nlm.nih.gov/pubmed/29509469 DOI: 10.1177/084456211504700301 Ferguson KE, Jinks AM. Integrating what is taught with what is practised in the nursing curriculum: a multi-dimensional model. J Adv Nurs [Internet]. 1994 [cited 2019 Mar 1];20(4):687-95. Available from https://www.ncbi.nlm.nih. gov/pubmed/7822604 Mansell D. Forging the future: A history of nursing in Canada. MI, USA: Thomas Press/Ann Arbor; 2004. 219 p. Boschma G, Davidson L, Bonifacio N. Bertha Harmer’s 1922 textbook – the principles and practice of nursing: Clinical nursing from an historical perspective. J Clin Nurs [Internet]. 2009 [cited 2019 Mar 1];18: 2684-2691. Available from: https://www.ncbi.nlm.nih.gov/pubmed/19744019 DOI:10.1111/j.1365-2702.2009.02891.x Hipps O. The integrated curriculum: The emperor is naked. Am J Nurs [Internet]. 1981 [cited 2019 Mar 1];81(5), 976-980. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/6908812 DOI:10.2307/3424725 Bramadat IJ, Chalmers KI. Nursing education in Canada: historical ‘Progress’—contemporary issues. J Adv Nurs [Internet]. 1989 [cited 2019 Mar 1];14: 719-726. Available from: https://www.ncbi.nlm.nih.gov/pubmed/2674245 DOI:10.1111/j.1365-2648.1989.tb01636.x Cook SH. Mind the theory/practice gap in nursing. J Adv Nurs [Internet]. 1991 [cited 2019 Mar 1];16(12):14629. Available from: https://www.ncbi.nlm.nih.gov/ pubmed/1724255 McKenna L, Williams B. The hidden curriculum in near-peer learning: an exploratory qualitative study. Nurse Educ Today [Internet]. 2017 [cited 2019 Mar 1];50:77-81. Available from: https://www.ncbi.nlm.nih.gov/pubmed/28024234 DOI: 10.1016/j.nedt.2016.12.010 Karimi Z, Ashktorab T, Mohammadi E, Abedi H, Zarea K. Resources of learning through hidden curriculum: Iranian nursing students’ perspective. J Educ Health Promot [Internet]. 2015 [cited 2019 Mar 1];4:57. Available from: https://www.ncbi.nlm.nih.gov/pubmed/26430684 DOI: 10.4103/2277-9531.162368 Tharani A, Husain Y, Warwick I. Learning environment and emotional well-being: a qualitative study of undergraduate nursing students. Nurse Educ Today [Internet]. 2017 [cited 2019 Mar 1];59:82-87. Available from: https://www.ncbi.nlm. nih.gov/pubmed/28961508 DOI: 10.1016/j.nedt.2017.09.008 MacMillan K. The hidden curriculum: what are we actually teaching about the fundamentals of care? Nurs Leadersh (Tor Ont) [Internet]. 2016 [cited 2019 Mar 1];29(1):37-46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/27309640 Allan HT, Smith P, O’Driscoll M. Experiences of supernumerary status and the hidden curriculum in nursing: a new twist in the theory-practice gap? J Clin Nurs [Internet]. 2011 [cited 2019 Mar 1];20(5-6):847-55. Available from: https://www.ncbi.nlm.nih.gov/pubmed/21320207 DOI: 10.1111/j.1365-2702.2010.03570.x Jafree SR, Zakar R, Fischer F, Zakar MZ. Ethical violations in the clinical setting: the hidden curriculum learning experience of Pakistani nurses. BMC Med Ethics [Internet]. 2015 [cited 2019 Mar 1];16:16. Available from: https://www. ncbi.nlm.nih.gov/pubmed/25888967 DOI: 10.1186/s12910015-0011-2. Karimi Z, Ashktorab T, Mohammadi E, Abedi H. Influential factors on learning through the hidden curriculum in the perspective of undergraduate baccalaureate nursing students. J Adv Med Educ Prof [Internet]. 2014 [cited 2019 Mar 1];2(2):53-7. Available from https://www.ncbi.nlm.nih.gov/ pubmed/25512920 Karimi Z, Ashktorab T, Mohammadi E, Abedi HA. Using the hidden curriculum to teach professionalism in nursing students. Iran Red Crescent Med J [Internet]. 2014 [cited 2019 Mar 1];16(3):e15532. Available from: https://www.ncbi. nlm.nih.gov/pubmed/24829784 DOI: 10.5812/ircmj.15532 Hunter K, Cook C. Role-modelling and the hidden curriculum: new graduate nurses’ professional socialisation. J Clin Nurs [Internet]. 2018 [cited 2019 Mar 1];27(1516):3157-3170. Available from: https://www.ncbi.nlm.nih. gov/pubmed/29752850 DOI: 10.1111/jocn.14510 Azadi Z, Ravanipour M, Yazdankhahfard M, Motamed N, Pouladi S. Perspectives of nursing and midwifery students regarding the role of the hidden curriculum in patient education: a qualitative study. J Educ Health Promot [Internet]. 2017 [cited 2019 Mar 1];6:108. Available from: https://www. ncbi.nlm.nih.gov/pubmed/29296609 DOI: 10.4103/jehp. jehp_37_17

Hidden Curricula at Clinical Placements

DISCUSSION

Student nurses spend a large portion of It should be noted that most of the their program in clinical settings, which are research found on hidden curricula was perhaps even more important contributors international and multicultural, which to the hidden curriculum than the classroom. may not be generalizable to Canadian Here, they interact and cooperate with nursing. Several sources describe this field many members of the local community: as growing, but existing research has only staff nurses, doctors, clinical managers, scratched the surface. Areas for suggested allied health professionals, patients, and research include an increased focus on family members. These interactions with the impact that hidden curricula have on non-faculty individuals are almost always students’ futures as professionals; whether unscripted, making them the ideal avenue attempts to harness hidden curricula can be for both informal and hidden curricula successful; and a better understanding of the to predominate. Again, as with any other importance of contributing factors to hidden curriculum, there is considerable potential curricula. Before conducting investigations, for both negative and positive influences on it would be prudent to first develop a students. better understanding of hidden curricula in Canadian nursing schools. Also, future One Canadian article discussed an example references to the hidden curriculum should of hidden curriculum in which nurses have define the term clearly, as the waters are been socialized to wait for physician orders muddy surrounding its relation to the other 19 before providing nursing care. This practice types of curricula, particularly the informal reduces the quality of patient care and curriculum. reinforces the idea that nurses are ultimately 19 just following orders. In response, students In the end, just as any tool, the hidden are led to regard nursing as a technical curriculum can work to the benefit or rather than an intellectually stimulating detriment of a student. It is a culture which profession.19 The gap between nursing theory is ever-present and ever-changing depending and nursing practice is a long-debated topic on the people that it involves. It should not and is a major focus of research regarding be feared, fought against, or ignored. Rather, the hidden curriculum in nursing.9,10,15,20 This by understanding what a hidden curriculum gap is amplified when the clinical placements’ entails, teachers and learners can work with culture and values misalign with those of the it to fulfill their needs. universities, or when there is poor integration CONCLUSION between the two entities.10,20 Although one study from Pakistan reported that the hidden curriculum helped propagate ethical violations, the same study also noted that ethics was rarely taught in nursing school.21 Most of what the nursing students learned about ethics was also via a hidden curriculum.21 Several other international studies supported that hidden curricula not only helped nursing students learn ethics, but helped them build a professional identity by collaborating with staff and other students.17,22-24

The school one attends and the clinical placements one receives make a difference on learning outcomes, but not entirely for the reason one might expect. Ultimately, it seems that the culture of the learning community has more profound impacts than what is written in the course manual. Culture is both experienced and created: all students add to the culture of their school and placement and, thus, to the hidden curriculum.

As we become senior students, graduate, and go on to become more experienced nurses, Student nurses have been shown to we cannot forget that we are always teaching, learn a lot about communication style, whether it is formally or in a more “hidden” attention to patient differences, and ethical fashion. We are always influencing those considerations of patient teaching through around us and shaping the future of the unscripted interactions with patients and nursing profession. other nurses.25 These interactions with ACKNOWLEDGEMENTS other more established nurses were shown in a New Zealand study to be important I would like to acknowledge Ruth Chen components in developing the skills and for first sparking my interest in this subject, mechanisms needed to become competent Daniel Kim for encouraging me to write professionals.24 this piece, and JoAnn Saldua-Toomath REVIEWED BY JOANN for providing thorough and constructive feedback. S A L D U A - T O O M AT H JoAnn Saldua-Toomath received her BScN from Queen’s and her MScN from the University of Western Ontario. She has over 10 years of academic and 20 years of oncology, supportive and palliative care nursing experience. JoAnn is currently working towards her PhD, where she will be testing Newman’s Theory of Health as an Evolution of Consciousness within health services and delivery research. EDITED BY DANIEL KIM

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