Issue 39 by The Meducator

MARCH 2021 | ISSUE 39

UTERINE TRANSPLANTS T H E I M P L I CAT I O N S T H R O U G H S O C I O P O L I T I CA L & M E D I CA L C O N T E XT S

COMPUTER-AIDED DIAGNOSES T H E A P P L I CAT I O N S O F A RT I F I C I A L I N T E L L I G E N C E I N L U N G CA N C E R

SEPSIS SCREENING TOOLS A P P LY I N G CA P N O G RA P H Y F O R LA CTAT E - E N H A N C E D QSOFA SCORES

WWW.MEDUCATOR.ORG

table of CONTENTS

table of contents

MARCH 2021

ISSUE 39

01 INTRODUCTION 02 MEDPULSE 04 MEDBULLETINS 06 PATHOPROFILE 08 MEDUSTORY 10 IWCH ABSTRACTS 12 FORUMSPACE OPINION 14 The implications of uterine transplants through the sociopolitical and medical context 16 Evaluating the local status of minority maternal health through institutionalized disparities in Hamilton

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CRITICAL REVIEW 18 Artificial intelligence in diagnosing lung cancer: Applications and future development 22 CARs on the road: Who gets a seat? 26 Implementing capnography for lactateenhanced qSOFA scores: Sepsis diagnosis in the EMS setting

30 INTERVIEW SPOTLIGHT 33 CONTRIBUTORS COVER ARTIST ESRA RAKAB TOC ARTIST MANREET DHALIWAL

Welcome to Issue 39 of The Meducator! From novel approaches in vaccine development to advances in diagnostic technology, this year has shown us more clearly than ever the importance of collaboration in the increasingly complex field of health sciences. As conveyed in Esra Rakab’s celestial cover illustration, exploration and discovery serve as the cornerstones of scientific innovation. By learning through experience, we can make better informed decisions tomorrow from the information that we have unearthed. The COVID-19 pandemic has sparked curiosity in virology, epidemiology, and immunology, inspiring students to progress our understanding of these fields. Editors Albert and Yiming start Issue 39 off by exploring recent health-related developments across the globe in MedPulse, highlighting the plethora of research that has continued despite limitations the pandemic poses. Following MedPulse, editors Eric and Michal tell the story of Aubrey de Grey, a biomedical gerontologist who seeks to reverse the aging process. In Issue 39, The Meducator continues its collaboration with the International Women & Children’s Health (IWCH) Conference, as well as the McMaster Health Forum. This issue’s Forumspace examines the current staffing crisis in long-term care homes amidst the COVID-19 pandemic, while the IWCH abstracts explore the benefits of mHealth technologies, the impact of cannabis on female reproduction, and the relationship between menopause and mental health. We are also excited to feature three Critical Reviews and two Opinion columns. In a critical review on computer aided diagnostics, Justin Phung highlights the current role of artificial intelligence in identifying lung cancer nodules. Meanwhile, Katherine Taplin and Preetama Badyal examine the novel use of CAR T-cells in treating relapsed and refractory hematopoietic cancers. Transitioning towards a clinical context, Donny Li, Jeffrey Sun and Lucy Zhao evaluate the application of capnography devices when screening for sepsis. Editors Aisling and Jeffrey investigate the considerations that must be taken with the standardization of uterine transplants. Finally, Jeffrey also emphasizes the institutional disparities in Hamilton which influence minority maternal health.

introduction

INTRODUCTION ISSUE 39

dear reader,

This issue was the product of close collaboration between all members of our talented and passionate staff. We cannot express enough gratitude towards our hardworking team, the supportive McMaster community, and you, our engaged readers. We would also like to give special thanks to our executive team, Aaron, Catherine, David, Michal, Peri, Shadi, Sophie, Wendy, and Zahra, for their incredible student leadership. As this academic year comes to an end, we would like to extend a warm welcome to the incoming Editors-in-Chief, Michal Moshkovich and Sophie Zarb. We are confident that these two will not only uphold, but elevate, The Meducator’s ongoing legacy within the McMaster community. From the both of us, thank you for joining us on this journey this past year. M E D U CATO R

All the best,

DANIEL RAYNER

| MARCH 2021

KARISHMA MEHTA

Bachelor of Health Sciences (Honours) Class of 2022

MEDPULSE

AUTHORS: ALBERT STANCESCU & YIMING ZHANG ARTISTS: MADELINE CHAN & WENDY ZHANG

A New Blood Test to Detect Alzheimer’s Disease

table of contents

(Feb 2021, California, U.S.) Alzheimer's disease (AD) is a neurodegenerative disorder marked by the accumulation of beta-amyloid plaques in the brain. Recent advances have attempted to mitigate the difficulties of diagnosing AD prior to symptom onset using tools such as brain imaging and spinal fluid sampling. However, these techniques are invasive and expensive. In an attempt to circumvent this issue, a research team led by Dr. Adam Boxer developed a new technique to assess the risk of developing AD. By measuring blood concentrations of apolipoprotein E and beta-amyloid, this test is able to improve the accuracy of diagnosis by distinguishing AD from memory loss caused by other conditions.1 Future developments may use tau proteins to further improve the accuracy of test results.2

DNA Methylation Regulation Leads to Antidepressant-Like Effects (Feb 2021, Sao Paulo, Brazil) A study from the University of São Paulo showed that the inhibition of DNA methylation in the prefrontal cortex could exert an antidepressant-like effect. The experiment focused on the interaction between brain-derived neurotrophic factor (BDNF), a natural protein involved in neural plasticity that exhibits antidepressive effects, and DNA methyltransferase, a protein that reduces BDNF expression in the brain and increases in activity during stressful situations. Researchers used Wistar rats injected with two pharmacologically different DNA methyltransferase inhibitors and measured the neural protein transcript levels in the hippocampus and prefrontal cortex during a learned helplessness test.3 The study found that the inhibition of stress-induced DNA methylation in the prefrontal cortex exerted an antidepressant effect, a finding that may lead to the development of novel therapeutic antidepressants.4

California quail (US)

Senegal parrot (Senegal) Toco toucan (Brazil)

The New Virus on the Block (Feb 2021, Senegal) Since 2016, scientists have been monitoring the spread of H5N8, a highly pathogenic avian influenza (HPAI) in sub-Saharan Africa. Spreading across western Eurasia, the Middle East, and Nepal, the H5N8 influenza dispersed widely as waterbirds migrated from region to region.5 A pandemic was limited to Asian countries between 2016 and 2018, but it has since spread globally and continued to infect African populations in 2020. Recently, a new strain of HPAI has resurfaced in Africa— H5N1. January 2014 marked the first incidence of HPAI H5N1 in Canada, and October 2020 marked the first incidence in Senegal.6,7 While it has limited spread in humans, HPAI H5N1 spreads rapidly among avian species. In Senegal, more than 700 dead pelicans were found positive for H5N1.8 While vaccines are stockpiled in response for a potential pandemic outbreak, H5N1 continues to show sporadic activity and may present another pandemic in the future.6 “image: Freepik.com”. This map has been designed using resources from Freepik.

Toxic Ingredients Found in Select Hand Sanitizers (January 2021, Mexico & US) With >900 accidental poisonings involving hand sanitizer within January 2021, the United States Food and Drug Administration (FDA) has placed a countrywide “import alert” on all alcohol-based hand sanitizer imports from Mexico.11 Imported products contained traces of methanol, a toxic substance that is absorbable through the skin and poisonous when ingested. Repeated exposure may result in nausea, vomiting, and permanent damage to the nervous system. Roughly 84% of analyzed samples did not comply with the FDA regulations for safety, and over 50% contained harmful levels of methanol or 1-propanol. The FDA encourages public reports of any harmful effects from hand sanitizer products.12

The Kidney Disease Mobile App (Feb 2021, UK)

Eurasian hoopoe (UK)

introduction

New AI diagnostic tools are transporting the laboratory setting away from the clinic and into patients’ homes. Healthy.io, a new biotechnology company based in the UK, has developed an athome testing kit that can be used for early diagnosis of kidney disease.9 Using an absorbent pad and a phone camera, the AI mobile application uses a colorimetric analysis to provide readings equivalent to what laboratory analyses reveal. At-home screening for proteinuria has not only proven to be efficacious, but also preferred by patients; a survey found that 89% of patients (n = 999) preferred at-home tests over clinical visits.10 With 3500 patients having already received a testing kit, it is projected that over 500 000 patients will benefit from this technology over the next three years.9

Research Establishes Antibiotic Potential for Cannabis (January 2021, Australia)

Indian roller (India)

Changing the Face of Healthcare (Jan 2021, Singapore & India)

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References can found on our website: meducator.org

M E D U CATO R

The COVID-19 pandemic has led many countries into technical recessions, prompting governments to reallocate their financial resources. India’s economic growth prospects remain uncertain due to lengthy lockdown protocols, but new strategies are being proposed that would allocate 2.2 trillion rupees (~$30 billion USD) to develop the country's capacity to provide primary, secondary, and tertiary care. From these funds, 350 billion rupees will be used for COVID-19 vaccines, with the remaining being allocated to public infrastructure.15 In prioritizing healthcare facilities, these new plans may catalyze the Indian biotechnology sector, which was forecasted to grow to $100 billion USD by 2025.16 Only time will tell if India will become a lead innovator in the emerging healthcare treatment market.

Researchers at the University of Queensland have established an antibiotic application for synthetic cannabidiol (CBD). The study states that CBD disrupts bacterial activity through its ability to both penetrate and inhibit the production of bacterial biofilm, which are clusters of bacterial growths that attach to surfaces and other bacteria to evade immune detection and resist antibacterial treatments.13 As a result, CBD bypasses the biofilm’s natural defence system. This synthetic compound selectively produces antibacterial effects for numerous resistant strains of bacteria, including Streptococcus pneumoniae and Neisseria gonorrhoeae, and further tests have shown a low tendency for resistance towards CBD. With prominent antibacterial properties, researchers are exploring possible clincal applications of this cannabinoid.14 Rainbow lorikeet (Australia)

MEDBULLETIN MicroRNAs IMPROVING THE ARDS PATIENT ALZHEIMER’S EXPERIENCE

M E D U CATO R

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medbulletin table of contents

A THERAPEUTIC DISCOVERY

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CANNABINOIDS

ELUCIDATING THE EFFECTS OF CBD AND THC ON DRIVING

ADRIAN WONG

AD R IAN WO N G

Acute respiratory distress syndrome (ARDS) is a condition caused by tissue insults that can severely damage the respiratory system.1 Approximately 10% of intensive care patients, totaling 3 million people worldwide, suffer from ARDS,2 largely affecting patients with pneumonia, sepsis, and trauma.3 Patients with ARDS usually undergo supportive treatment, which often involves mechanical ventilation.4 However, mechanical ventilation can result in structural damage to the lung, termed ventilator-induced lung injury (VILI).5 A recent study suggests that microRNAs, which are small, non-coding RNA molecules involved in post-transcriptional regulation as well as the formation of many pulmonary diseases, may provide a new strategy for preventing VILI.3

With the increasing legalization of cannabis and use of medicinal cannabis worldwide,1,2 concerns regarding driving under the influence of cannabis (DUIC) have grown.1 Cannabis ingestion has been linked to poor performance on divided-attention tasks, decision-making, and sudden reactions.3 As such, DUIC has been associated with an increased risk of collision.3 However, most relevant studies have focused on cannabis containing tetrahydrocannabinol (THC), while the effects of cannabidiol (CBD), another prominent substance in cannabis products, have been given less attention.4

Bobba et al. hypothesized that microRNA-146a (miR-146a) may control the mechanisms in alveolar macrophages that lead to VILI, and tested that hypothesis using in vitro and in vivo models. In mouse models, they discovered that injurious mechanical ventilation caused a tenfold increase in miR-146a levels in alveolar macrophages, while miR-146a knockout mice lacking the microRNA subtype suffered greater lung injury. Nevertheless, the endogenous increase in miR-146a expression was insufficient to completely alleviate lung damage. Alveolar macrophages were then treated with lipid nanoparticles containing pre-miR-146a in both in vitro and in vivo conditions. miR-146a levels increased 100-fold in vitro and 10,000-fold in vivo, enough to prevent significant inflammation caused by pressure changes. In animal models, elevated miR-146a levels led to significant improvements in lung function.3

A recent study, conducted by the University of Sydney and Maastricht University, sought to delineate the effects of both THC and CBD on driving performance and cognition.5 Arkell et al. tested whether inhalation of cannabis containing 13.75 mg of only THC, only CBD, or a mix of THC and CBD (THC/CBD) affected driving performance in healthy adults who occasionally used cannabis. The primary outcome was standard deviation of lateral position (SDLP), which assesses control of a vehicle; a higher value indicates less control, with more weaving and swerving. From 40 to 100 minutes after consumption, the THC and THC/CBD groups saw an increase in SDLP of more than 2 cm (86.94 cm and 85.51 cm respectively) compared with placebo conditions (84.41 cm), while the CBD group (84.07 cm) did not see any significant changes. From 240 to 300 minutes after consumption, the difference in SDLP between all groups was negligible, indicating that THC had no effect during this time.5

This study builds on existing research indicating the alteration of microRNA expression by mechanical ventilation, suggesting that microRNAs may be involved in VILI pathogenesis.6 Moreover, miR-146a has been shown to regulate inflammation caused by mechanical ventilation in lung epithelial cells, indicating its potential as a treatment target.7 Overall, the findings of this study suggest that delivering miR-146a through lipid nanoparticles to supplement physiological levels may prove effective in ameliorating VILI and improving the ventilation treatment experience for ARDS patients.3

These findings indicate that while THC diminished short-term driving performance, CBD itself had no negative effect.5 Contrary to popular belief, CBD did not negate the effects of THC on driving performance.4,5 The findings of this study invite further research into the effects of THC and CBD on driving performance in regular cannabis users, including medicinal cannabis users, as well as research involving a greater range of cannabinoid doses.4,5

Watson TM, Mann RE. International approaches to driving under the influence of cannabis: a review of evidence on impact. Drug Alcohol Depend. 2016;169:148–55. Available from: j.drugalcdep.2016.10.023.

WHO Expert Committee on Drug Dependence. Cannabis plant and cannabis resin. Section 5: epidemiology. 2018. Available from: https://www.who.int/medicines/access/controlled-substances/Section5.CannabisPlant.Epidemiology.pdf?ua=1. [cited 2021 Feb 28]

Bos LDJ, Artigas A, Constantin J-M, Hagens LA, Heijnen N, Laffey JG, et al. Precision medicine in acute respiratory distress syndrome: workshop report and recommendations for future research. Eur Respir Rev. 2021;30(159):200317. Available from: doi:10.1183/16000617.0317-2020.

Fan E, Brodie D, Slutsky AS. Acute respiratory distress syndrome: advances in diagnosis and treatment. JAMA. 2018;319(7):698. Available from: doi:10.1001/jama.2017.21907.

Bobba CM, Fei Q, Shukla V, Lee H, Patel P, Putman RK, et al. Nanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates injury during mechanical ventilation. Nat Commun. 2021;12(1):289. Available from: doi:10.1101/796557.

Chow RM, Marascalchi B, Abrams WB, Peiris NA, Odonkor CA, Cohen SP. Driving under the influence of cannabis: a framework for future policy. Anesth Analg. 2019;128(6):1300–8. Available from: doi:10.1213/ANE.0000000000003575.

Fan E, Needham DM, Stewart TE. Ventilatory management of acute lung injury and acute respiratory distress syndrome. JAMA. 2005;294(22):2889. Available from: doi:10.1001/jama.294.22.2889.

Cole TB, Saitz R. Cannabis and impaired driving. JAMA. 2020; 324(21):2163. Available from: doi:10.1001/jama.2020.18544.

Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med. 2013; 369(22):2126–36. Available from: doi:10.1056/ NEJMra1208707.

Arkell TR, Vinckenbosch F, Kevin RC, Theunissen EL, McGregor IS, Ramaekers JG. Effect of cannabidiol and 9tetrahydrocannabinol on driving performance: a randomized clinical trial. JAMA. 2020;324(21):2177. Available from: doi:10.1001/jama.2020.21218.

Vaporidi K, Vergadi E, Kaniaris E, Hatziapostolou M, Lagoudaki E, Georgopoulos D, et al. Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2012;303(3):L199–207. Available from: doi:10.1152/ajplung.00370.2011.

Huang Y, Crawford M, Higuita-Castro N, Nana-Sinkam P, Ghadiali SN. miR-146a regulates mechanotransduction and pressureinduced inflammation in small airway epithelium. FASEB J. 2012;26(8):3351–64. Available from: doi:10.1096/fj.11-199240.

DEPRESSION

HUNTINGTON’S

INSIGHT INTO THE NEURONAL CIRCUITRY

HEAT SHOCK PROTEINS FOR TREATING HUNTINGTON’S

NUR I SONG Major depression is one of the most common mental health conditions in Canada, with an estimated 1.7 million adults experiencing at least one episode.1 Prevalence rates are highest among 18–25 year olds, with increased risk in females (twice the risk of males) and individuals with a family history of depression.2 With existing treatments, only about onethird of patients achieve full remission.3 Despite its prevalence and growing attention, the underlying neuronal mechanisms of depression are poorly understood.

Researchers led by Patrick van der Wel et al., from the University of Groningen in the Netherlands, have successfully revealed the structure of a heat shock protein (HSP), yielding insight into the treatment of Huntington’s.3 HSPs are highly conserved proteins with regulatory and protective roles in the cell.4 A notable class of HSPs is HSP40, which plays a critical role in regulating protein aggregation. The focus of van der Wel’s team was to visualize DnaJB8, a subtype of HSP40 known to bind to other proteins with elongated chains of glutamine amino acids, similar to the HTT protein in Huntington’s. Until recently, its structure has been unclear, preventing researchers from understanding the mechanism of HSPmediated protein deaggregation. Using solid-state NMR spectroscopy, van der Wel et al. successfully visualized HSP40. Based on its structure, researchers predict that DnaJB8 binds to protein aggregates, and activates another class of HSPs, HSP70, which inhibits further aggregation.

This discovery has important implications for future medications used to treat depression. A common current medication is Prozac, which regulates mood by inhibiting serotonin uptake, but results in sleep disturbance due to low serotonin levels. Shifting treatment focus to AgRP may yield more targeted treatments to mitigate such side effects. It is important to note that AgRP neurons are implicated in other physiological processes including stimulating metabolism and increasing food-seeking behaviour.5 Treatments targeting AgRP may therefore lead to side effects such as weight gain.5 With that said, further research is needed to elucidate to what extent AgRP neurons are implicated in depression as a result of chronic stress.

HTT - Huntingtin - Homo sapiens (Human) - HTT gene & protein [Internet]. Available from: https://www.uniprot.org/uniprot/ P42858. [cited 2021 Feb 28].

Fast Facts about Mental Illness [Internet]. CMHA National. Available from: https://cmha.ca/fast-facts-about-mental-illness. [cited 2021 Feb 28].

Roos RA. Huntington’s disease: A clinical review. Orphanet J Rare Dis. 2010; 5:40. Available from: doi:10.1186/1750-11725-40.

Albert PR. Why is depression more prevalent in women? J Psychiatry Neurosci. 2015; 40(4):219–21. Available from: doi:10.1503/jpn.150205.

New insight into protein structures that could treat Huntington’s disease [Internet]. ScienceDaily. Available from: https:// www.sciencedaily.com/releases/2021/02/210212113926.htm. [cited 2021 Feb 28].

Ionescu DF, Rosenbaum JF, Alpert JE. Pharmacological approaches to the challenge of treatment-resistant depression. Dialogues Clin Neurosci. 2015; 17(2):111–26. Available from: doi:10.31887/DCNS.2015.17.2/dionescu.

Li Z & Srivastava P. Heat-shock proteins. Curr Protoc Immunol. 2004; 58;1:A.1T.1-6. Available from: doi:10.1002/0471142735.ima01ts58.

Fang, X., Jiang, S., Wang, J. et al. Chronic unpredictable stress induces depression-related behaviors by suppressing AgRP neuron activity. Mol Psychiatry. 2021. Available from: doi:10.1038/s41380-020-01004-x.

Essner RA, Smith AG, Jamnik AA, Ryba AR, Trutner ZD, Carter ME. AgRP neurons can increase food intake during conditions of appetite suppression and inhibit anorexigenic parabrachial neurons. J Neurosci. 201; 37(36):8678–87. Available from: doi:10.1523/JNEUROSCI.0798-17.2017.

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M E D U CATO R

Researchers hypothesize that enhancing the activity of DnaJB8 or its analogues will reduce protein aggregation in Huntington’s patients, and alleviate symptoms. Although more research is required, insight into the mechanism has paved the way for future studies in the quest to cure Huntington’s.

Recent research by Fang et al. has found that agouti-related peptide (AgRP) neurons, a small group of neurons nestled in the arcuate nucleus of the hypothalamus, likely contribute to depression.4 When subjecting mice to chronic, unpredictable stress (resulting in an animal model of depression), AgRP neurons decreased in frequency of firing, and increased in firing irregularities. Moreover, when using a synthetic small molecule agonist to stimulate AgRP neurons, Fang et al. noted the reversal of standard depressive symptoms, such as inability to experience pleasure. As a result, Fang et al. have demonstrated both that chronic stress causes AgRP dysfunction, and that AgRP neurons are key to the neural circuitry underlying depression.

medbulletin

NURI S O N G Huntington’s disease is an autosomal dominant genetic disorder caused by the abnormal repetition of the DNA sequence CAG on the Huntingtin (HTT) gene.1 This trinucleotide mutation (with a minimum of 36 repeats) results in the aggregation of a faulty glutamine-based protein in the brain, causing a range of debilitating symptoms and, ultimately, death.2 The onset of Huntington’s disease ranges from 30 to 50 years old and patients suffer from dementia, behavioural and psychiatric disturbances, and involuntary motor movements known as chorea.2 Following pneumonia, the most common cause of death is suicide.2 Although a range of therapeutic interventions are available for Huntington’s patients, the pathophysiology of the condition remains unclear, and, as a result, there is no current cure.

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doi:10.35493/medu.39.6

NECROTIZING FASCIITIS Pathoprofile 1.

pathoprofile table of contents

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11.

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Bellapianta JM, Ljungquist K, Tobin E, Uhl R. Necrotizing fasciitis. J Am Acad Orthop Surg. 2009;17(3):174–82. Available from: doi:10.5435/00124635200903000-00006. Goh T, Goh LG, Ang CH, Wong CH. Early diagnosis of necrotizing fasciitis. Br J Surg. 2013;101(1). Available from: doi:10.1002/bjs.9371. Morgan MS. Diagnosis and management of necrotising fasciitis: A multiparametric approach. J Hosp Infect. 2010;75(4):249–57. Available from: doi:10.1016/j. jhin.2010.01.028. Schulz SA. Necrotizing fasciitis [Internet]. 2020. Available from: https://emedicine.medscape. c o m /a r t i c l e / 2 0 5 1 1 5 7 overview#a4. [cited 2021 Feb 3]. Davoudian P, Flint NJ. Necrotizing fasciitis. CEACCP. 2017;12(5): 245-50. Available from: doi:10.1093/bjaceaccp/ mks033. Kückelhaus M, Hirsch T, Lehnhardt M, Daigeler A. Nekrotisierende fasziitis der oberen und unteren extremität. Notfall Rettungsmed. 2017;20: 363-75. Available from: doi:10.1007/s10049-0170319-1. Wong C-H, Chang H-C, Pasupathy S, Khin L-W, Tan J-L, Low C-O. Necrotizing fasciitis: Clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg. 2003;85(8):1454-60. Available from: https://pubmed. ncbi.nlm.nih.gov/12925624/ [cited 2021 Feb 3]. Shimizu T, Tokuda Y. Necrotizing fasciitis. Intern Med. 2010;49(12):1051–7. Available from: doi:10.2169/ internalmedicine.49.2964. Wang J-M, Lim H-K. Necrotizing fasciitis: Eight-year experience and literature review. Braz J Infect Dis. 2014;18(2):137–43. Available from: doi:10.1016/j. bjid.2013.08.003. Schulz, SA. What are risk factors for necrotizing fasciitis? [Internet]. 2020. Available from: https://www.medscape.com/ answers/2051157-42838/ w h a t-a re - r i s k-fa c to rs -fo rnecrotizing-fasciitis [cited 2021 Feb 5]. Centers for Disease Control and Prevention. Necrotizing fasciitis: All you need to know [Internet]. 2019. Available from: https://www.cdc. gov/groupastrep/diseasespublic/necrotizing-fasciitis. html#:~:text=Group%20A%20 Strep%20Thought%20to%20 Be%20Most%20Common%20 Cause,-Bacteria%20that%20 live&text=Public%20health%20 experts%20believe%20 group,common%20cause%20 of%20necrotizing%20fasciitis. [cited 2021 Feb 3]. Stevens DL, Bryant AE. Streptococcus pyogenes : Basic biology to clinical manifestations [Internet]. 1st ed. Oklahoma City: University of Oklahoma Health Sciences Center; 2016. 1-29.

AUTHORS: MATTHEW LYNN & RIDA TAUQIR ARTIST: CARYN QIAN

INTRODUCTION Necrotizing fasciitis (NF), commonly known as flesh-eating disease, is a rare and life-threatening soft-tissue infection characterized by the rapid necrosis of subcutaneous tissue and fascia.1,2 There are four subtypes of NF, each classified based on the causative microorganism, with NF types I and II accounting for ~70-80% and ~20-30% of cases, respectively.3 Differing only in clinical manifestations and speed of pathogenesis, the pathophysiology of all types of NF is similar.3 Bacteria invades subcutaneous tissue, proliferates, and releases endotoxins and exotoxins, leading to expanding tissue necrosis, toxic shock syndrome (TSS), and death in 1545% of cases.4-6 DIAGNOSIS NF has the potential to spread aggressively and, thus, early diagnosis is vital in preventing mortality and morbidity.1 Multivariate analysis reveals that a delay of 24 hours in NF treatment can decrease the survival rate by 18%.2,7 However, in the early stages of NF, the paucity of pathognomonic signs often results in a misdiagnosis of cellulitis, erysipelas, or an abscess.2,8 Therefore, a high-degree of clinical suspicion is required to distinguish NF from other soft-tissue infections.1,2 Following clinical assessment, various tests may be performed to confirm diagnosis. The ‘finger test’ is among the most effective diagnostic procedures.2 A 2-cm incision is made and the surgeon inserts their index finger to probe the deep tissue; a test is NFpositive if the subcutaneous tissue easily dissects off of the deep fascia.1,2 A laboratory evaluation may also be used to identify characteristics of NF such as leukocytosis with a neutrophil predominance, and the elevation of acute phase reactants such as C-reactive protein and platelets. Radiological imaging can also be useful for a timely diagnosis.9 MRI scans exhibit a success rate of 93-100% in diagnosis by identifying necrosis and edema along the thickened fascial planes, and fascial fluid generated from liquefactive tissue necrosis.1,2 Furthermore, CT scans may display increased attenuation of subcutaneous fat, fascial thickening, soft-tissue edema, and tracking along fascial planes.1 RISK FACTORS Although NF can infect healthy individuals of all ages, immunocompromised patients are most

susceptible to the disease due to weakened immune defences against pathogens.1 In fact, diabetes mellitus is the most common comorbidity, presenting in 18-60% of cases.1,2 Additional immunocompromised states strongly associated with NF include liver cirrhosis, obesity, alcohol abuse, peripheral vascular disease, cancer, and advanced age.1,2 Intravenous drug use and surgical procedures also increase the risk of developing NF as they may lead to bacterial invasion and localized tissue damage.10 MECHANISM (TYPE II NECROTIZING FASCIITIS) Infection by group A Streptococcus (e.g. S. pyogenes) is the most common cause of NF.11 Unlike Clostridium bacteria, which enter directly through deep penetrating injuries, S. pyogenes enters the bloodstream and deep tissue through minor breaches in the epithelium, or penetrates through mucus membranes.12 Through the expression of the anti-phagocytic M protein, S. pyogenes avoids destruction by the host immune system and begins infecting the hypodermis.12,13 The anaerobic environment and the synergy between virulence factors and host proteins promotes bacterial growth and facilitates necrosis of the fascia by bacterial enzymes.13 Invasive bacteria then cause thrombosis of hypodermal nutrient vessels, leading to ischemia, infectious dissemination, skin necrosis, intense pain, or anesthesia.13 If NF continues to progress, exotoxins released by S. pyogenes (e.g. streptococcal pyrogenic exotoxin A, streptococcal superantigen, etc.) or M protein fragments may act as superantigens by overstimulating inflammatory T-cells resulting in TSS, organ failure, and death.12 Necrotic spread in the fascia progresses several inches per hour, with death resulting as soon as 12-24 hours after initial infection.12,14 TREATMENT Surgical debridement of affected tissues is the primary treatment for NF.13 This life-saving procedure is performed as early as possible, and often repeated 5 to 40 times depending on the clinical course of the infection.13 The initial debridement surgery typically involves a widedeep cut or multiple shallow cuts at the edge of the infected area, to release pus or hemorrhagic fluid and prevent further spread of the infection.13,15 Once an incision is made, infected tissue is

or TSS with NF and its treatment, nutritional supplementation is required to replace lost proteins and fluids.12 Several other treatments, including hyperbaric oxygen therapy (HBOT) and IV immunoglobulin (IVIg) therapy, have been proposed but remain controversial.16 HBOT, which involves inhalation of 100% oxygen, is said to decrease edema, infection spread, and increase antibiotic efficacy, but has yet to be strongly supported in clinical settings.17 Similarly, IVIg therapy is hypothesized to bind and inhibit exotoxins released by NF-causing bacteria; however, these observations remain restricted to small studies of critically-ill NF patients.16,18

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EDITED BY: NICK TELLER & TAAHA HASSAN

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

M E D U CATO R

17.

REVIEWED BY: DR. CHERYL MAIN

Misiakos EP, Bagias G, Patapis P, Sotiropoulos D, Kanavidis P, Machairas A. Current concepts in the management of necrotizing fasciitis. Front Surg. 2014;1(6):36. Available from: doi:10.3389/ fsurg.2014.00036. Health Link BC. Necrotizing fasciitis (flesh-eating disease) [Internet]. 2019. Available from: https://www.healthlinkbc.ca/ healthlinkbc-files/flesh-eatingdisease#:~:text=In%20some%20 cases%20death%20can,4%20 people%20infected%20with%20 it. [cited 2021 Feb 3]. Sun X, Xie T. Management of necrotizing fasciitis and its surgical aspects. Int J Low Extrem Wounds. 2015;14(4): 328-34. Available from: doi: 10.1177/1534734615606522 Sarani B. Necrotizing fasciitis [Internet]. 2018. Available from: https://rarediseases. org/rare-diseases/necrotizingfasciitis/#investigational-therapies [cited 2021 Feb 3]. Jallali N, Withey S, Butler PE. Hyperbaric oxygen as adjuvant therapy in the management of necrotizing fasciitis. Am J Surg. 2005;189(4):462-66. Available from: doi:10.1016/j. amjsurg.2005.01.012. Kadri SS, Swihart BJ, Bonne SL, Hohmann SF, Hennessy LV, Louras P et al. Impact of intravenous immunoglobulin on survival in necrotizing fasciitis with vasopressor-dependent shock: A propensity score–matched analysis from 130 US hospitals. Clin Infect Dis. 2017;64(7):877-85. Available from: doi:10.1093/cid/ciw871

pathoprofile

removed while carefully trimming potentially salvageable soft tissue, until healthy tissue is revealed.13 If debridement proves insufficient, patients may choose amputation, which could involve fewer procedures and reduced blood loss.15 Although no definitive requirements exist, amputation is often performed if there is extensive necrosis of underlying muscles, TSS, vascular insufficiency, or patient history of diabetes or hypotension.13 Treatment of NF with antibiotic therapies is minimally effective. However, using a combination of broad and narrow-spectrum antibiotics alongside surgical intervention can help prevent the spread of infection.13 Due to the possible development of large wounds

ARTIST KATELYN MOORE

IWCH ABSTRACTS Impact of Cannabis on Female Reproduction & Preimplantation Embryonic Development: A Review of the Literature DANIELLE CAMPAGNOLO, MBS 1 ; LAURA A. FAVETTA, PHD 1 1

Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph

tableabstracts of contents

Endocannabinoids are natural ligands of cannabinoid, vanilloid, and peroxisome proliferator-activated receptors. These ligands, alongside their receptors, enzymes, and signaling targets, form the endocannabinoid system (ECS). The ECS has been implicated in the functioning of the hypothalamic-pituitary-ovarian (HPO) axis and components of the ECS have been localized to the reproductive tissues. Further, it is involved in mammalian folliculogenesis, oocyte maturation and transport, and preimplantation embryo development. Exogenous cannabinoids such as delta-9-tetrahydrocannabinol (Δ9-THC — the main bioactive component in cannabis) have been known to cause dysregulation of the ECS as they bind to the same cannabinoid receptors as ECS ligands. Unfortunately, effects of cannabis use on human female reproduction and early stages of embryonic development remain largely uncertain due to ethical restrictions and study design heterogeneity. However, results from animal and in vitro studies have been useful in understanding cannabinoids’ impact on human reproduction and preimplantation embryonic development. Hence, in this review, data from various study types were analyzed to understand the effects of cannabis on maternal and fetal outcomes. Use of cannabis is likely to offset the balance of endocannabinoid signaling necessary for proper HPO axis function. Cannabis has also been shown to exhibit direct and irreversible reprotoxic effects on ovarian tissues and developing follicles. Studies on endocannabinoid tone in the reproductive tract also suggest that Δ9-THC is disruptive to oocyte tubal transport, sperm capacitation in the female reproductive tract, fertilization, and appropriate embryonic development. Given the recent legalization in Canada and the significant increase in Δ9-THC concentrations in cannabis over the past decade, understanding the consequences of its consumption on reproduction is of

The Use of eHealth and mHealth Technologies for Menopausal Transition Achievements and Knowledge Gap DANIEL D’SOUZA 1 , DR. PING ZOU, PHD 2 1

M E D U CATO R

| MARCH 2021

Faculty of Engineering and Health Sciences, McMaster University School of Nursing, Nipissing University

Menopause is the permanent cessation of menstrual cycles, marking the end of a female’s reproductive age. Menopause, perimenopause, and postmenopause may involve intense physical and psychological symptoms. eHealth has emerged as an alternative in delivering treatment and education to patients. Subsequently, the recent addition of mobile health (mHealth) as a subdivision of eHealth via personal mobile devices poses benefits for menopausal women. This project aims to review the literature for eHealth and mHealth design, and its efficacy among this demographic. To achieve this, several databases were reviewed for original quantitative studies about eHealth, mHealth, and menopause, yielding 15 results. The main findings were that both interventions were feasible in terms of usability, cost, and acceptance. Moreover, these interventions appeared to be more effective than conventional methods in addressing physical and psychosocial health outcomes. It is important to acknowledge that issues did arise in experimental design, such as inadequate patient and provider involvement. Therefore, while eHealth and mHealth represent viable platforms for healthcare delivery among menopausal women, further research and improvements to experimental design are required before they can be operationalized on larger scales. Future studies should aim to diversify sample populations in socioeconomic status and ethnicity, as well as lengthen followup periods to discern the true effect of these interventions.

Effects of mHealth Interventions on the Depression, Anxiety, and Quality of Life of Breast Cancer Patients SABRINA L. BALKARAN 1 , DR. PING ZOU, PHD 1 1

Department of Nursing, Nipissing University,

introduction abstracts

Introduction: Insufficient initiatives exist to support the psychological health of women upon receiving a breast cancer diagnosis. This systematic review explored the facilitators, barriers, and effects of mobile health (mHealth) interventions on the depression, anxiety, and quality of life of breast cancer patients. Methods: A total of 11 databases were searched for quantitative studies assessing the effectiveness of mHealth interventions on depression levels, anxiety levels, and the quality of life of breast cancer patients. Search terms included patient characteristics (i.e. breast cancer), intervention elements (i.e. mHealth), and outcome measures (i.e. depression). Results: Among 1232 articles, 29 studies met the selection criteria and were reviewed. Significant increases in the quality of life of patients were reported in 67% of studies that listed it as an outcome. In studies that listed depression and anxiety as an outcome, 62% reported significant decreases in anxiety, while 38% reported no changes. Additionally, 62% of included studies reported significant decreases in depression levels, while 38% reported no changes. Barriers to mHealth use included difficulty with navigating apps, as well as the patient desire for more content-specific catering of mHealth apps to their needs. Conclusions: mHealth interventions may be beneficial in improving the quality of life of breast cancer patients. Current information is insufficient to draw strong conclusions on whether mHealth interventions affect depression and anxiety in this demographic. Larger, multicenter studies should be conducted to strengthen the findings on quality of life and to inform on the effects of mHealth. Further studies should be conducted to address the barriers to mHealth application use.

Incident depression in midlife women attending a menopause clinic is associated with a history of childhood maltreatment ALISON K. SHEA, MD, PHD, FRCSC 1,2,3 , BENICIO N. FREY, MD, PHD 3,4 , NICOLE GERVAIS 1 , ANA LOPEZ 5 , LUCIANO MINUZZI, MD, PHD 3,4 Department of Obstetrics and Gynecology, Faculty of Health Sciences, McMaster University The Research Institute, St. Joeseph’s Healthcare 3 Department of Psychiatry and Behavioural Neurosciences, Faculty of Health Sciences, McMcaster University 4 Women’s Health Concerns Clinic, St. Joeseph’s Healthcare 5 Faculty of Health Sciences, McMaster University 1 2

M E D U CATO R | A P R I L 2015 M E D U CATO R | M A R C H 2 0 2 1

A growing body of literature has suggested that, for some women, the perimenopausal and early post-menopausal years are associated with an increased risk of depression symptoms and the development of first-onset and recurrent episodes of major depressive disorder. Although multiple risk factors have been identified, including stressful life events and lower socioeconomic status (SES), early life adversity may also have enduring effects on mental well-being later in life. The objective of this study was to characterize the influence of childhood maltreatment and incident depression among women experiencing bothersome menopausal symptoms. Findings from this cross-sectional cohort indicate that adverse childhood experiences, as measured by the Childhood Trauma Questionnaire (CTQ), were highly prevalent among women seeking care for bothersome menopausal symptoms (66%). Furthermore, a greater score on the CTQ was significantly associated with both major depressive episodes, as estimated using the Center for Epidemiologic Studies Depression Scale, and a greater burden of menopausal symptoms. This association persisted after adjusting for confounding. Our findings lend support to the growing body of literature suggesting that early life stress affects health well into adulthood.

11 13

FORUMSPACE

Staffing crisis: Addressing the high turnover rate of personal support workers in Ontario’s long-term care sector

doi:10.35493/medu.39.12

SAIF ALAM & ANASTASIA DRAKOS 1

M E D U CATO R

| MARCH 2021

forumspace table of contents

12 20

Bachelor of Science in Integrated Science (Honours) Class of 2022, McMaster University Bachelor of Health Sciences (Honours) Class of 2022, McMaster University

INTRODUCTION Personal support workers (PSWs) serve a valuable role within the health system, providing up to 80% of direct care to residents and clients in the home and community care (HCC) and long-term care (LTC) sectors.1,2 According to a report by the Ministry of LongTerm Care, as of 2018, 50 000 PSWs were employed within LTC facilities in Ontario, accounting for the majority of the workforce within this sector.3 The original purpose of the PSW role was to support residents with activities of daily living such as dressing, toileting, and bathing.4,5 However, in an effort to minimize healthcare costs and keep up with the rapidly aging population, there has been a recent shift towards implementing policies that support the idea of aging at home.4 The criteria for admission to LTC in Ontario was amended in 2010, with individuals now required to have “high or very high physical and cognitive challenges” to qualify for care.4,5 As a result, LTC home residents require a greater complexity of care, as reflected by the fact that an estimated 81% reportedly suffer from some form of cognitive impairment.3 To meet the increasing needs of residents in a sector that is severely understaffed, the role of PSWs has evolved to take on a greater responsibility in resident care and provide levels of support that are often beyond the scope of their training.4

Correspondence: alams22@mcmaster.ca, drakoa2@mcmaster.ca

LONG-STANDING FACTORS CONTRIBUTING TO PSW TURNOVER Short staffing is a long-standing issue that has plagued the LTC sector, placing an overwhelming workload on those working within these homes. A recent report by the Ontario Health Coalition highlighted insights gleaned from round table meetings with staff from eight LTC homes across the province.8 The majority of the homes included in this report identified shortages of at least one to two PSWs during every shift.8 The report also noted that understaffing within these facilities plays a significant role in the delay and absence of resident care, as PSWs are assigned too many tasks to complete during a single shift. The association between high levels of work-related stress and intent to leave has been supported by numerous studies.9,10 This raises the concern that PSW burnout is a significant factor that contributes to their high turnover rate.

A study by Perreira et al. found that PSWs employed in LTC homes across Ontario have significantly lower perceptions of support, safety, and work engagement when compared to those working in HCC settings.1 When working in end-of-life environments, many PSWs have reported symptoms of compassion fatigue and indicated minimal workplace support to assist them with coping.3,8,11 With respect to safety, the LTC sector has the highest number of staff injuries resulting in time lost among all healthcare As unregulated healthcare professionals, PSWs operate under the sectors.3 This further contributes to the staffing crisis, leading to direct supervision of a nurse practitioner (NP) and face limited greater workplace stress and more negative effects on the emotional autonomy, strict reporting requirements, low wages, and minimal well-being among staff.3 opportunities for further advancement.6,7 These factors contribute to the high staff turnover rates that exist for PSWs in LTC; 25% of Lastly, despite their importance in providing high-quality care PSWs leave the sector after just two years of work experience and for residents, PSWs are subject to salaries that are not far above 40% leave within the first year of graduation.3 minimum wage, leading the majority of these individuals to work multiple part-time jobs.12 The Ontario Health Coalition report This article will investigate the various factors that contribute to the noted that many PSWs left the LTC sector to work in retail outlets, high rate of PSW turnover, examine the COVID-19 pandemic and restaurants, or school boards, jobs that are far less onerous and the staffing crisis, and highlight possible interventions that may offer similar levels of compensation to that of a PSW.8 Although a improve staff retention within the LTC sector. $4.00 pay raise and $250.00 bonus were enacted to support PSWs throughout the COVID-19 pandemic, a more permanent solution is required to reflect the greater workload placed upon these individuals.12

ARTIST MADELINE CHAN

THE IMPACT OF COVID-19 AND PSW TURNOVER The COVID-19 pandemic has further exacerbated the workplace crisis that exists within the LTC sector, with PSWs leaving their jobs due to health and safety concerns and burnout.3,13 As a result, quality of care continues to suffer, further contributing to the disproportionate number of COVID-19 cases that exist within these facilities.

homes.20 Similarly, when compared to low empowerment care facilities, Berridge et al. observed a 44% and 64% increase in staff retention in medium and high empowerment LTC facilities, respectively.18

forumspace

Further insights from key stakeholders have revealed the need to focus on additional contributing factors, such as replacing temporary and part-time contracts with full-time employment positions, reducing the administrative burden, leveraging the use of technology, supporting A WINDOW OF OPPORTUNITY FOR CHANGE professional growth among staff, raising staff compensation, and The COVID-19 pandemic has created an opportunity to address standardizing minimum benefits and paid sick leaves.3,21 the issues of staff retention and ensure the highest quality-of-care is provided to residents. Current evidence suggests that interventions CONCLUSION centered around improving the culture of care, staff empowerment, The limited retention of PSWs within the LTC sector is a pressing and leadership practices may be critical towards increasing staff 14,15 health-systems issue, with implications that have led to a ripple effect retention. in LTC homes on both the working environment for staff and qualityImproving the culture of care is grounded in the notion of fostering a of-care for residents. Coordinating strategies and finding solutions to positive work environment in LTC homes. This can be accomplished these issues at the policy level helps bring upon the changes needed to by creating a climate where staff feel recognized for their contributions, achieve optimal care within these facilities. have a sense of connectedness with colleagues and residents, and dedicate an increased number of hours to hands-on care.15 Studies REVIEWED BY: DR. MICHAEL WILSON by Castle and McGilton et al. found that caregivers who cared for an Dr. Michael Wilson is the Assistant Director of the McMaster Health individualized subset of residents, and who developed meaningful Forum, an Associate Professor in the Department of Health Research relationships with those residents and other caregivers, had decreased Methods, Evidence, and Impact, a member of the Centre of Health Economics and Policy Analysis, and Investigator with the Program in Policy rates of turnover and absenteeism.16,17 Decision-Making. His research focuses on supporting the use of research evidence by health systems decision-makers, including policymakers and stakeholders such as community-based organizations.

Within the context of staff empowerment and leadership practices, existing literature further supports the adoption of educational training programs, greater autonomy, and integration in decision- EDITED BY: AARON WEN & SOPHIE ZARB making processes as key elements for retaining staff.14,18,19 A study conducted by Dreher et al. found a 43% increase in staff retention The McMaster Health Forum aims to generate action on pressing health- and social-systems based on the best available research evidence. More discussion surrounding challenges one month after implementing a 90-minute educational program on issues within the health system —namely, identifying and harnessing the potential of technology in longcompassion fatigue awareness and self-care skill strategies in nursing term care settings in Canada— can be found on mcmasterforum.org.

Lum J, Sladek J, Ying A, Payne LH. Ontario personal support workers in home and community care: CRNCC/PSNO survey results. Canadian Research Network for Care in the Community; 2010. Available from: https://www.ryerson.ca/content/dam/ crncc/knowledge/infocus/factsheets/InFocus-Ontario%20PSWs%20in%20Home%20and%20Community%20Care.pdf [cited 2021 Jan 25].

Ministry of Long-Term Care. Long-term care staffing study [Internet]. 2020. Available from: https://www.ontario.ca/page/long-term-care-staffing-study [cited 2021 Jan 25].

Berta W, Laporte A, Deber R, Baumann A, Gamble B. The evolving role of health care aides in the long-term care and home and community care sectors in Canada. Hum Resour Health. 2013;11:25. Available from: doi:10.1186/1478-4491-11-25.

Ontario Long Term Care Association. This is long-term care 2016 [Internet]. Available from: https://www.oltca.com/oltca/documents/reports/tiltc2016.pdf [cited 2021 Jan 25].

Czuba KJ, Kayes NM, McPherson KM. Support workers’ experiences of work stress in long-term care settings: A qualitative study. Int J Qual Stud Health Well-being. 2019;14(1):1622356. Available from: doi:10.1186/1478-4491-11-25.

Zagrodney K, Saks M. Personal support workers in Canada: The new precariat? Healthc Policy. 2017;13(2):31-9. Available from: doi:10.12927/hcpol.2017.25324.

Unifor. Caring in crisis: Ontario’s long-term care PSW shortage [Internet]. Ontario: Ontario Health Coalition; 2019. Available from: https://www.unifor.org/sites/default/files/documents/document/final_psw_report.pdf [cited 2021 Jan 26].

Meeusen VC, Van Dam K, Brown-Mahoney C, Van Zundert AAJ, Knape HTA. Understanding nurse anesthetists’ intention to leave their job: How burnout and job satisfaction mediate the impact of personality and workplace characteristics. Health Care Manage Rev. 2011;35(2):155-63. Available from: doi:10.1097/HMR.0b013e3181fb0f41.

10.

Leiter MP, Maslach C. Nurse turnover: the mediating role of burnouts. J Nurs Manag. 2009;17(3):331-9. Available from: doi:10.1111/j.1365-2834.2009.01004.x.

11.

Wiersma E, Marcella J, McAnulty J, Kelley ML. ‘That just breaks my heart’: Moral concerns of direct care workers providing palliative care in LTC homes. Can J Aging. 2019;38(3):268-80. Available from: doi:10.1017/S0714980818000624.

12.

Government of Ontario. Archived – COVID-19: Temporary pandemic pay [Internet]. Available from: https://www.ontario.ca/page/covid-19-temporary-pandemic-pay [cited 2021 Jan 26].

13.

Rossiter K, Godderis R. Essentially invisible: Risk and personal support workers in the time of COVID-19. Sociol Health Illn. 2020;42(8):e25-31. Available from: doi:10.1111/1467-9566.13203.

14.

Berridge C, Lima J, Schwartz M, Bishop C, Miller SC. Leadership, staff empowerment, and the retention of nursing assistants: Findings from a survey of U.S. nursing homes. J Am Med Dir Assoc. 2020;21(9):1254-9.e2. Available from: doi:10.1016/j. jamda.2020.01.109.

15.

Johnston L, Malcolm C, Rambabu L, Hockley J, Shenkin S. Supporting the resilience and retention of frontline care workers in care homes for older people: A systematic scoping review and thematic synthesis. medRxiv. 2020;2020.09.05.20188847. Available from: doi:10.1101/2020.09.05.20188847.

16.

Castle NG. Consistent assignment of nurse aides: association with turnover and absenteeism. J Aging Soc Policy. 2013;25(1):48–64. Available from: doi:10.1080/08959420.2012.705647.

17.

McGilton KS, Boscart VM, Brown M, Bowers B. Making tradeoffs between the reasons to leave and reasons to stay employed in long-term care homes: Perspectives of licensed nursing staff. Int J Nurs Stud. 2014;51(6):917–26. Available from: doi:10.1016/j.ijnurstu.2013.10.015.

18.

Berridge C, Tyler DA, Miller SC. Staff empowerment practices and CNA retention: Findings from a nationally representative nursing home culture change survey. J Appl Gerontol. 2018;37(4):419–34. Available from:

19.

Gaudenz C, De Geest S, Schwendimann R, Zúñiga F. Factors associated with care workers’ intention to leave employment in nursing homes: A secondary data analysis of the Swiss Nursing Homes Human Resources Project. J Appl Gerontol. 2019;38(11):1537-63. Available from: doi:10.1177/0733464817721111.

20.

Dreher MM, Hughes RG, Handley PA, Tavakoli AS. Improving retention among certified nursing assistants through compassion fatigue awareness and self-care skills education. J Holist Nurs. 2019;37(3):296–308. Available from: doi:10.1177/0898010119834180.

21.

Ministry of Long-Term Care. A better place to live, a better place to work: Ontario’s long-term care staffing plan [Internet]. Ontario, Canada: Government of Ontario; 2020. Available from: https://www.ontario.ca/page/better-place-live-better-placework-ontarios-long-term-care-staffing-plan [cited 2021 Jan 25].

| MARCH 2021

Perreira TA, Berta W, Laporte A, Ginsburg L, Deber R, Elliott G, et al. Shining a light: Examining similarities and differences in the work psychology of health support workers employed in long-term care and home and community care settings. J Appl Gerontol. 2019;38(11):1595-614. Available from: doi:10.1177/0733464817737622.

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OPINION

ARTIST ANNISA SIU

M E D U CATO R

| MARCH 2021

tableopinion of contents

Uterine Transplants:

Evaluating the Implications Through the Sociopolitical & Medical Context

INTRODUCTION There is an inevitable point where ethics meets medicine and the question of why becomes subject to debate. In 2019, the Cleveland Clinic became the first North American institution to successfully deliver offspring from a uterine transplant (UTx) and —while this suggests infinite implications for infertile and transgender women— the associated medical, emotional, and financial risks challenge the reasons for why it should be operationalized in hospitals.1,2 Reasons for undergoing UTx are two-fold: (1) having the ability to carry offspring and (2) furthering the anatomical transition process in male-to-female gender affirmation procedures.3 Emerging literature argues that there should be “an individual right of people to exercise control and shape their role in reproduction” and sexuality, while others say that the dire aftereffects leave the patient in a better state before UTx.3 In this piece, we dissect the benefits and disadvantages of having UTx and recommend whether or not it should be practiced. We argue that surgeons should be more conservative in their practices and defer their use of UTx procedures until further research is done to diminish procedural risks. UTERINE TRANSPLANTS FOR INFERTILE WOMEN To bear and parent offspring is a milestone deemed essential for many women and holds great significance in how many perceive their own worth.4 Women who have either a damaged uterus or Mayer-Rokitansky-Küster-Hauser Syndrome (abnormally developed uterine systems) are often subject to a life of infertility. Given the association between fertility and self-esteem, approximately 44% of women in this population tend to experience depression and anxiety, compared to

JEFFREY SUN1 & AISLING ZENG1 Bachelor of Health Sciences (Honours), Class of 2024, McMaster University 1

doi:10.35493/medu.39.14

28.7% among their fertile counterparts.4 Studies by Zaami et al. underscore the immense implications that UTx may serve for the 15% of the female population that is infertile.3 In 2014, Swedish clinical trials were the first to achieve uterine transplantation and subsequent delivery, after which 50 more transplants and 16 more UTx-births occurred worldwide.5 This data suggests that UTx may enable gestation and may make infertility impermanent, increasing fulfillment in life for many women globally.2,5 It is, however, important to acknowledge that the surgical and healing processes of UTx are highly complex and dangerous to patients’ health. Both the uterine donor and recipient must undergo months of counselling, psychological screening, as well as social and financial evaluations pre-operation.6 The uterus is then surgically removed from the donor via hysterectomy and transplanted into the recipient.6 A multitude of immunosuppressant drugs are administered orally to diminish the chances of transplant rejection.2 In the unlikely event that transplantation is successful, menstrual cycles begin as early as one month post-operation.6 After 6 to 18 months post-operation, a previously fertilized ovum from the recipient is implanted onto the uterine lining.7 Should pregnancy last until the third trimester, the fetus is delivered via cesarean section, followed by a hysterectomy to remove the transplant.3 Current arguments around UTx suggest that the adverse effects may outweigh the potential benefits, which include both medical adversities and psychological issues linked with overwhelming physiological distress. Complications that have arisen in UTx cases include uterine thrombosis, eclampsia, and intrauterine infection, which lead to embryo transfer failures,

complications in pregnancy, and immune rejection of the uterus even with immunosuppressive therapies.7,8 While the recipient may benefit from the possibility of pregnancy, live UTx donors experience increased risk of ovarian failure and dependence on hormonal therapy to treat early menopause.9 Recipients also experience enumerated psychological adverse effects, with Järvholm et al. reporting increased levels of anxiety in approximately 22% of patients due to failure in maintaining a pregnancy alongside the chemical damages of immunosuppressants.10,11 For these reasons, there is strong evidence that UTx may not be worth its potential benefits. While most patients are subject to adverse side effects, very few are successful in pregnancy. The reality for most UTx recipients is that they may need to endure these difficulties only to bear no children and have their uterus removed after two to three years. In these cases, surrogacy and adoption are almost objectively better choices for both mental and physical health.

However, in conjunction with previous arguments, UTx for transgender populations has been argued to pose more disadvantages compared to benefits. A significant reason is that uteri must be removed via hysterectomy two to three years after transplantation regardless, which may place transgender women at their original position of having no female reproductive attributes.3 Moreover, the aforementioned medical, financial, and emotional costs that transgender women are subjected to for an impermanent transplant may damage their physical and mental health more than if they were not a UTx patient.3 While it is extremely important for transgender women to transition and feel comfortable with themselves,

Unfortunately, the novel means of reproduction have become significant topics of controversy. For instance, uterine donation from deceased donors proposes ethical considerations as to whether a non-lifesaving transplant should be prioritized over the harvest of more essential organs.9 In many countries, UTx is either prohibited or considered taboo.3 Many legislatures place barriers upon the right to undergo this procedure, but this ultimately preserves the health and safety of potential recipients in the long term. Nonetheless, the importance of UTx for these populations is undisputed. Hence, we suggest that these practices should undoubtedly be improved, regulated, and made available in the future. REVIEWED BY: HARMEET GURM Harmeet Gurm is a MSc candidate in the Department of Pediatrics and Faculty of Health Sciences at McMaster University. Her research primarily focuses on investigating the impacts of cannabis compounds on the production of Th1/Th2-type cytokines during placental development in human pregnancy.

EDITED BY: PARNIKA GODKHINDI

References can be found on our website: meducator.org

M E D U CATO R | A P R I L 2015 M E D U CATO R | M A R C H 2 0 2 1

As females without uteri, transgender women also qualify for UTx and may benefit from its groundbreaking implications to revolutionize the gender affirmation process. In the Journal of Law & Biosciences, Alghrani underscores the potential that UTx may have in allowing a person assigned male at birth to gestate.14 There is ongoing political debate regarding the extent to which transgender women may legally and medically identify themselves as female —having the reproductive characteristics of cisgender women may give them greater autonomy to identify with the female gender. It is a constitutional right in many countries to self-identify with genders, and it only seems reasonable that UTx be practiced for these reasons.15

DISCUSSION & CLOSING REMARKS While UTx has potential to revolutionize many lives, it is objectively clear that significant research is needed before the standardization of UTx in healthcare. Given the present findings, it is advisable to defer the use of UTx in male-tofemale transition, as the psycho-emotional and medical risks outweigh the benefits of having an impermanent uterus. The same reasons follow for infertile, cisgender females as the chance of pregnancy is low and gestational surrogacy is a safer alternative. However, it is important to emphasize that current UTx trials involving deceased donors have succeeded in bearing offspring in one among three total cases.7 The prospects of these trials have significant implications for the future as it minimizes procedural risks, using already-deceased donors.

opinion introduction opinions

UTERINE TRANSPLANTS FOR TRANSGENDER WOMEN There is an evergrowing pressure for transgender women to have the civil right to live as any healthy cisgender female does: to have the anatomy to potentially gestate and bear children. Studies show that among the assigned male at birth population, 52.72 million globally experience gender dysphoria—the persistent discomfort of not conforming to the gender traditionally corresponding to one’s sex.12 Unfortunately, as Jones et al. state, most transgender persons do not find comfort in their gender identity until “surgical intervention [is used] to change their external genitalia and sexual characteristics.”12 These issues consequently manifest as declining mental health and increasing suicidality, with studies by McNeil et al. reporting suicidal thoughts and behaviours among 37% to 83% of varying transgender population samples.13

as Sparrow et al. argue: “the need to align with gender identity comes secondary to […] ensuring [the] safety” of the individual.16 It may be in the best interest of transgender women and surgeons to explore alternative options —such as hormonal therapy, speech-feminization therapy, and vaginoplasty— until more research is done to make UTx a safer procedure.3,17

15 17

doi:10.35493/medu.39.16

Opinion

Healthcare Disparities Evaluating The Local Status of Minority Maternal Health in the Context of Institutionalized Disparities in Hamilton JEFFREY SUN

M E D U CATO R

| MARCH 2021

tableopinion of contents

Bachelor of Health Sciences (Honours), Class of 2024, McMaster University sun72@mcmaster.ca

ARTIST KATELYN MOORE

INTRODUCTION While it holds true that visible minorities often benefit less than average from healthcare systems in North America, there is yet to be consensus on the extent to which racism and other institutionalized issues play a role in leaving them at a serious disadvantage.1-3 A 2018 study by Dr. Elizabeth Howell reports that African American women face severe maternal morbidity at rates two-fold that of non-Hispanic white women, which in light of the Black Lives Matter movement, brings to question the integrity of the maternal care system and the professionals who work within it.1,2 Many health problems faced by Black, Indigenous, and People of Colour (BIPOC) have not only been a result of racial prejudice, but also disparities beyond the control of individual healthcare providers.4,5 In his anthology of essays, Disease, Life, and Man, Rudolf Virchow underscores the origins of disease as rather originating from structural flaws in health states dictated by the democratic polity.3 Although racism contributes greatly to healthcare inequality, significant disparities also stem from socioeconomic barriers that impede minority access to healthcare. The purpose of this article is to examine the institutional disparities influencing health accessibility for BIPOC women, and analyze its effects on the maternal health of racial minorities with an emphasis on Hamilton, Ontario. INSTITUTIONAL DISPARITIES Rarely are “the social institutions on which [health] depends [...] approached with the same understanding” as the physiological determinants, according to Lynn Freedman of Columbia University.6 It is often the case that visible minorities suffer the effects of “weathering” —chronic stress from intense work conditions— putting them at greater risk for onset of diabetes and hypertension later in life.7 Studies by Geronimus et al. show that Black women between the ages of 40-50 have telomeres that appear 7.5 years older than White women of the same age, suggesting that minority women are more likely to endure age-related pregnancy risks from weathering.7 Weathering-caused hypertension can evolve into preeclampsia (maternal hypertension) which in turn escalates into eclampsia (hypertensive seizures) and venous thromboembolisms.8,9 Collectively, these conditions overwhelm the cardiovascular system of the mother and impair the ability of placental

vasculature to supply nutrients for fetal development, constituting higher maternal and infant mortality rates.10 The greater likelihoods of developing these conditions are not typically caused by the provision of the care itself but rather by their weathering workplace conditions. The 2016 Ontario census reported a 3.7-fold higher labour employment rate among visible minorities compared to their White counterparts. 11,12 Despite this, they are only paid an average annual income of $33 300 CAD— well below the average Ontario annual income of $60 300 CAD in 2016.13 These wage differences place minorities at greater pressure to work longer hours to afford basic essentials. This prevents women especially from being able to afford medications, receive adequate nutrition, and seek maternity leave or consultations to address their health-related needs.14,15 Potential health concerns can go undiagnosed, thereby increasing the incidence and mortality rates of medical conditions experienced among these demographics.10 DISPARITIES AS APPLIED TO HAMILTON DEMOGRAPHICS Studies by Darling et al. in the Hamilton region demonstrate that pregnant persons of lower socioeconomic status and education levels receive inadequate prenatal care compared to the demographic majority.16 Furthermore, the economic condition of Hamilton itself is worse than the average across Ontario.17 Census data from 2015 revealed that 35.5% of Hamilton residents have earned at most a high school diploma.17,18 As a result of this, these residents are more likely to seek labourintensive professions with diminished flexibility in working conditions and fewer excused leaves.17 These factors contribute to 83.6% of Hamilton residents earning a post-tax income lower than the provincial average of $60 800 CAD (2015) and 16.7% of residents living below the low-income cut off— putting these residents in the poverty demographic.12,13,19 Given that visible minorities are already at a financial disadvantage compared to non-minority populations, these data suggest that BIPOC in Hamilton may have particularly diminished access to essential healthcare— especially during pregnancy when flexibility in working conditions is essential. Moreover, Hamilton women are already twice as likely to report stress and poor mental health compared to their male counterparts, according to a 2018 report by the Hamilton Community Foundation. While

these are precursors to weathering-related risks, most health services are concentrated in the downtown area, which is geographically inaccessible to many women.20 The outcome of Hamilton-situated pregnancies are contingent on a series of financial and geographical issues exacerbated by minority status, creating a cycle of disadvantage for BIPOC women that puts them at an insurmountable health risk. With that said, more research is needed on the particular disparities that minorities face in maternal care given that much of the analysis extrapolates federal statistics to a municipal scale.

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Howell E. Reducing disparities in severe maternal morbidity and mortality. Clin Obstet Gynecol. 2018;61(2):387-99. Available from: doi:10.1097/GRF.0000000000000349. Howard J. Women dying from pregnancy and childbirth is still a problem in the US, CDC report shows [Internet]. 2020. Available from: https://www.cnn.com/2020/01/30/ health/maternal-mortality-statistics-cdc-study/ [cited 2021 Feb 22]. Williams D, Rucker T. Understanding and addressing racial disparities in health care. HCFR. 2000;21(4):75–90. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/ PMC4194634/ [cited 2021 Feb 22]. Virchow R, Rather LJ. Disease, life, and man. Stanford:Stanford University Press; 1958. Yamin AE, Boghosian T. Democracy and health: Situating health rights within a republic of reasons. Yale J Health Policy Law Ethics. 2020;19(2):103-40. Freedman LP. Achieving the MDGs: Health systems as core social institutions. Development. 2005;48(1):19–24. Available from: doi:10.1057/palgrave.development.1100107. Geronimus AT, Hicken M, Keene D, Bound J. “Weathering” and age patterns of allostatic load scores among Blacks and Whites in the United States. Am J Public Health. 2006;96(5):826– 33. Available from: doi:10.2105/AJPH.2004.060749. Peres GM, Mariana M, Cairrão E. Pre-Eclampsia and eclampsia: An update on the pharmacological treatment applied in Portugal. J Cardiovasc Dev Dis. 2018;5(1):3. Available from: doi:10.3390/jcdd5010003. Simcox LE, Ormesher L, Tower C, Greer IA. Pulmonary thrombo-embolism in pregnancy: Diagnosis and management. Breathe. 2015;11(4):282–9. Available from: doi:10.1183/20734735.008815. Pereira RD, De Long NE, Wang RC, Yazdi FT, Holloway AC, Raha S. Angiogenesis in the placenta: the role of reactive oxygen species signaling. Biomed Res Int. 2015;2015:814543. Available from: doi:10.1155/2015/814543. Statistics Canada. Census Recensement: Labour Force Status [Internet]. Available from: https://www12.statcan.gc.ca/census-recensement/2016/dp-pd/dt-td/Rp-eng.cfm? TABID=2&Lang=E&APATH=3DETAIL=0%DIM=0&FL=A&FREE=0&GC=0&GID=1341 679&GK=0&GRP=1&PID=110692&PRID=10&PTYPE=109445&S=0&SHOWALL=0& SUB=0&Temporal=2017&THEME=124&VID=0&VID=0&VNAMEE=&VNAMEF=&D1=0&D 2=0&D3=0&D4=0&D5=0&D6=0 [cited 2021 Feb 28]. Statistics Canada. Census Program [Internet]. Available from: https://www12.statcan. gc.ca/census-recensement/index-eng.cfm [cited 2021 Feb 28]. Government Of Canada. Table 3 Median after-tax income, Canada and provinces, 2013 to 2017 [Internet]. 2019. Available from: https://www150.statcan.gc.ca/n1/dailyquotidien/190226/t003b-eng.htm [cited 2021 Feb 28]. Kahn RS, Wise PH, Kennedy BP, Kawachi I. State income inequality, household income, and maternal mental and physical health: cross sectional national survey. BMJ. 2000;321(7272):1311-5. Available from: doi:10.1136/bmj.321.7272.1311. United States of America Department of Labor. Job flexibilities and work schedules — 20172018 data [Internet]. 2019. Available from: https://www.bls.gov/news.release/pdf/flex2. pdf [cited 2021 Feb 28]. Nussey L, Hunter A, Krueger S, Malhi R, Giglia L, Seigel S, et al. Sociodemographic characteristics and clinical outcomes of people receiving inadequate prenatal care: A retrospective cohort study. J Obstet Gynaecol Can. 2020;42(5):591–600. Available from: doi:10.1016/j.jogc.2019.08.005. Government of Canada Census Division. Census Profile, 2016 Census Hamilton, Census Ontario [Internet]. 2019. Available from: https://www12.statcan.gc.ca/censusrecensement/2016/as-sa/fogs-spg/Facts-cma-eng.cfm?LANG=Eng&GK=CMA&GC=537 &TOPIC=10 [cited 2021 Feb 28]. Statistics Canada. Census Profile [Internet]. Available from: https://www12.statcan.gc.ca/ census-recensement/2016/dp-pd/prof/details/page.cfm?Lang=E [cited 2021 Feb 28]. Low Income - Hamilton Community Foundation [Internet]. Hamilton Community Foundation. Community Foundations of Canada; 2016. Available from: https://www. hamiltoncommunityfoundation.ca/vital-signs/low-income-2018/ [cited 2021 Mar 3]. Ogrodnik M, Atienza A, Ma A, Sharma S, Socha A. Women and girls in Hamilton. [Internet]. Hamilton: Research Shop; 2018. 7–10 p. Available from: https://www. hamiltoncommunityfoundation.ca/wp-content/uploads/2019/01/McMaster-ResearchShop-Report-Hamilton-Community-Foundation-1.pdf [cited 2021 Feb 28]. Amutah-Onukagha N. AAMC Maternal Health Equity Series [Internet]. 2020 Available from: https://www.aamc.org/system/files/2020-04/sa-healthequity-AprilWebinar-04-17-20. pdf. [cited 2021 Feb 28].

introduction opinion

CONCLUDING EVALUATIONS A crucial component in the understanding of racial disparities in maternal health is the lack of integrity in community infrastructure to provide equal opportunity and pay for pregnant persons to better access vital healthcare. To address these issues, both government and healthcare systems require a greater interdisciplinary understanding of racism and the institutionalized disparities that perpetuate innaccessibility to healthcare among female minorities. The aforementioned evaluations underscore the need to improve youth education in female health so that those socioeconomicallydisadvantaged may develop an increased awareness of the healthcare services that should be available to them. As well, news and social media should supplement government support by communicating to minority women about their right to healthcare and quality of which they should expect to receive.21 The City of Hamilton should implement these improvements, as its general economic-backslide compared to average statistics in Ontario puts its female residents at greater disadvantage to seek and benefit from maternal care services. Doing so can address the current institutional disparities, as well as allow for more equitable healthcare.

REVIEWED BY: NICODA FOSTER & NAHELA NOWSHIN

Nahela Nowshin is a PhD candidate in the Department of Health, Aging, and Society at McMaster University, currently working on a research project related to the sexual reproduction and health rights (SRHR) of “last-mile” adolescents in the global context. Her research interests include social justice, poverty, SRHR and the social determinants of health.

EDITED BY: HANNAH SILVERMAN & JERRY DU

M E D U CATO R | A P R I L 2015 M E D U CATO R | M A R C H 2 0 2 1

Nicoda Foster is a PhD candidate in the Department of Health, Aging, and Society at McMaster University. Her research primarily focuses on health equity, social justice, health system measurement and performance, as well as community engagement and participation.

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ARTIST JEFF ZHANG

CRITICAL REVIEW Artificial intelligence in diagnosing lung cancer: Applications and future developments

doi:10.35493/medu.39.18

JUSTIN PHUNG

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

ABSTRACT Computer-aided diagnosis (CAD) systems lie at the intersection of medicine and computer science. Over the last couple of decades, consistent research and technological advances have resulted in a steady improvement of CAD systems that are capable of assisting in the detection and diagnosis of various diseases. However, several limitations prevent CAD from being implemented in clinical practice. The primary purpose of this review is to provide a general overview of CAD systems in the context of lung cancer, as well as assess the critical challenges that CAD must overcome. Such challenges include data privacy and sharing laws, radiologist workflow integration, and the lack of a standardized performance evaluation. Thus, coordination between radiologists, researchers, and medical institutions will play a pivotal role in shaping the future development of CAD systems in healthcare.

Much of the existing literature is focused on CADe systems, involving the detection of nodules or lesions. Zhang et al. noted in their appraisal that there have been many reviews about CADe systems, but few regarding CADx systems.5 CADe and CADx are often regarded separately, with most research focused on individually optimizing either system.14

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Although the purpose of CAD is to assist radiologists in the detection of lung nodules, CAD has not been implemented

Despite the clear impact of CAD on lung nodule detection, its performance varies significantly depending on the study. Generally, a research study’s CAD system can be evaluated through several metrics including accuracy, precision, sensitivity, specificity, true positive rate, and false positive rate.2 Although the establishment of databases like the LIDCIDRI has provided a large repository of training images that have steadily improved sensitivity and specificity, CAD systems remain inconsistent depending on the method and training dataset.12 For example, one model trained on the LIDC-IDRI dataset was a multi-view CNN, a 3D model that encodes for richer spatial information. Its error rate was 5.41%, and the sensitivity and specificity rates were 90.49% and 99.91%, respectively.12 Conversely, another study conducted by Nishio et al. utilized the deep CNN method on a clinical dataset; their highest reported accuracy score was 68.0%.13 Overall, the CAD effectiveness varies depending on the method and training dataset used.

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Although there are variations in how CAD systems function, most undergo five general steps: acquisition, preprocessing (increasing the precision and accuracy of algorithms), segmentation (separating the study region from other organs and tissues in radiographic images), nodule detection (marking the location of pulmonary nodules in the image), and elimination of false positives.4 CAD systems are further divided into computer-aided detection (CADe) and computer-aided diagnosis (CADx).3 This distinction is critical as their functions differ: CADe systems detect potential lesions and reveal abnormalities in medical images, whereas CADx systems primarily serve to characterize, classify, and distinguish lesions.5

EVALUATING EFFECTIVENESS OF CAD CAD can potentially reduce radiologists’ workloads and enhance their performances. Reading time is significantly shorter with CAD used as a concurrent reader compared to when the reading is done after interpretation by a radiologist.4 Moreover, CAD has been shown to improve the performance of experienced and inexperienced radiologists.9 Kligerman et al. determined that CAD can improve a radiologist’s ability to accurately detect lung nodules that were initially missed, while Sahiner et al. further demonstrated that it can help detect small size nodules under five millimetres, which are easily overlooked by inspection alone.10,11 As such, CAD consistently improves performance among thoracic radiologists and can play a critical role in the detection of lung nodules.

critical review

CONTEXT The applications of artificial intelligence (AI) in the field of medicine have made much headway in recent years, especially with regards to detection and diagnosis of diseases using computer-aided diagnosis (CAD) systems. AI utilizes computers to simulate human intelligent processes, including learning, reasoning, and thinking.1 In particular, convolutional neural networks (CNNs), a subset of AI, can automatically extract image features after training on labelled samples.1,2 Given the availability of large datasets and increased computing power, CNN-based CAD systems have produced promising results for many tasks, including image classification, correct image detection, and segmentation, proving themselves capable of replacing current CAD systems based on manual input.3

in routine clinical practice, with research efforts still focused primarily on improving performance.4 Currently, computerized tomography (CT) scans are the most common imaging modality for radiomics analyses, especially for diagnosing lung cancer, due to their high spatial resolution, cost-effectiveness, wide availability, and noninvasiveness.5,6 CNNs have been successfully developed to detect pulmonary nodules and lesion segmentation through training on publicly available databases and testing on various datasets such as the Lung Image Database Consortium and Image Database Resource Initiative (LIDC-IDRI).7,8

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Cong L, Feng W, Yao Z, Zhou X, Xiao W. Deep learning model as a new trend in computer-aided diagnosis of tumor pathology for lung cancer. J Cancer. 2020;11(12):3615-22. Available from: doi:10.7150/jca.43268. Gao J, Jiang Q, Zhou B, Chen D. Convolutional neural networks for computer-aided detection or diagnosis in medical image analysis: An overview. Math Biosci Eng. 2019;16(6):6536-61. Available from: doi:10.3934/mbe.2019326. Lee SM, Seo JB, Yun J, Cho YH, Vogel-Claussen J, Mark L, et al. Deep learning applications in chest radiography and computed tomography. J Thorac Imaging. 2019;34(2):75-85. Available from: doi:10.1097/RTI.0000000000000387. Al Mohammad B, Brennan PC, Mello-Thoms C. A review of lung cancer screening and the role of computer-aided detection. Clin Radiol. 2017;72(7):433-42. Available from: doi:10.1016/j.crad.2017.01.002. Zhang G, Yang Z, Gong L, Jiang S, Wang L, Cao X, et al. An appraisal of nodule diagnosis for lung cancer in CT images. J Med Syst. 2019;43(7):181. Available from: doi:10.1007/s10916-019-1327-0. Chen B, Zhang R, Gan Y, Yang L, Li W. Development and clinical application of radiomics in lung cancer. Radiat Oncol. 2017;12(1):154. Available from: doi:10.1186/s13014-017-0885-x. Benzaquen J, Boutros J, Marquette C, Delingette H, Hofman P. Lung cancer screening, towards a multidimensional approach: Why and how? Cancers (Basel). 2019;11(2):212. Available from: doi:10.3390/cancers11020212. Armato SG 3rd, McLennan G, Bidaut L, McNittGray MF, Meyer CR, Reeves AP, et al. The Lung Image Database Consortium (LIDC) and Image Database Resource Initiative (IDRI): A completed reference database of lung nodules on CT scans. Med Phys. 2011;38(2):915-31. Available from: doi:10.1118/1.3528204. Marten K, Seyfarth T, Auer F, Wiener E, Grillhösl A, Obenauer S, et al. Computer-assisted detection of pulmonary nodules: Performance evaluation of an expert knowledge-based detection system in consensus reading with experienced and inexperienced chest radiologists. Eur Radiol. 2004;14(10):193038. Available from: doi:10.1007/s00330-0042389-y. Kligerman S, Cai L, White CS. The effect of computer-aided detection on radiologist performance in the detection of lung cancers previously missed on a chest radiograph. J Thorac Imaging. 2013;28(4):244-52. Available from: doi:10.1097/ RTI.0b013e31826c29ec. Sahiner B, Chan HP, Hadjiiski LM, Cascade PN, Kazerooni EA, Chughtai AR, et al. Effect of CAD on radiologists' detection of lung nodules on thoracic CT scans: Analysis of an observer performance study by nodule size. Acad Radiol. 2009;16(12):1518-30. Available from: doi:10.1016/j.acra.2009.08.006. Kang G, Liu K, Hou B, Zhang N. 3D multi-view convolutional neural networks for lung nodule classification. PLoS One. 2017;12(11):e0188290. Available from: doi:10.1371/journal.pone.0188290. Nishio M, Sugiyama O, Yakami M, Ueno S, Kubo T, Kuroda T, et al. Computer-aided diagnosis of lung nodule classification between benign nodule, primary lung cancer, and metastatic lung cancer at different image size using deep convolutional neural network with transfer learning. PLoS One. 2018;13(7):e0200721. Available from: doi:10.1371/journal.pone.0200721. Ozdemir O, Russell RL, Berlin AA. A 3D probabilistic deep learning system for detection and diagnosis of lung cancer using low-dose CT scans. IEEE Trans Med Imaging. 2020;39(5):1419-29. Available from: doi:10.1109/TMI.2019.2947595. Liu B, Chi W, Li X, Li P, Liang W, Liu H, et al. Evolving the pulmonary nodules diagnosis from classical approaches to deep learning-aided decision support: Three decades' development course and future prospect. J Cancer Res Clin Oncol. 2020;146(1):153-85. Available from: doi:10.1007/s00432-019-03098-5. Abouelmehdi K, Beni-Hssane A, Khaloufi H, Saadi M. Big data security and privacy in healthcare: A review. Procedia Comput Sci. 2017;113(1):73-80. Available from: doi:10.1016/j.procs.2017.08.292. Bossuyt PM, Reitsma JB, Bruns DE, Gatsonis CA, Glasziou PP, Irwig L, et al. STARD 2015: An updated list of essential items for reporting diagnostic accuracy studies. BMJ. 2015;351(1):h5527. Available from: doi:10.1136/bmj.h5527. Savitha G, Jidesh P. Advances in Intelligent Systems and Computing. Singapore: Springer; 2019. 11-23 p. Ather S, Kadir T, Gleeson F. Artificial intelligence and radiomics in pulmonary nodule management: Current status and future applications. Clin Radiol. 2020;75(1):13-9. Available from: doi:10.1016/j. crad.2019.04.017. Yanase J, Triantaphyllou E. The seven key challenges for the future of computer-aided diagnosis in medicine. Int J Med Inform. 2019;129(1):413-22. Available from: doi:10.1016/j.ijmedinf.2019.06.017.

However, a study by Ozdemir et al. suggests that coupling CADe and CADx systems can result in improved performance.14 Using an open-source dataset, CADe and CADx systems were developed simultaneously, allowing for an optimized system which can reduce the false positive rate and serve as an end-to-end automated diagnostic tool for lung cancer.14 ETHICAL AND PRACTICAL LIMITATIONS Several limitations currently plague the field of CAD and hinder its development. Data scarcity is one such challenge, as properly and reliably training a CAD system is resource-intensive. Labeling tools must be made available to radiologists to create high-quality datasets, and although databases are expanding, a higher volume of data is required to improve functionality.15 There are several work-arounds, such as transfer learning —a machine learning method that involves pre-training on a large dataset, followed by fine-tuning on another dataset— that has been demonstrated to show improved accuracy despite the lack of labeled images.13 Supervised learning could also be utilized on a small portion of the dataset to train networks, followed by unsupervised learning that classifies the remaining unlabeled data.15 However, the primary concern pertains to legal and ethical issues surrounding data privacy. Numerous data confidentiality laws govern the use of patient images in academic settings, and medical institutions may face fines if personal health information is compromised.3 Despite the need for extensive high-quality images to train CNNs, healthcare organizations may be deterred from contributing to a shared learning dataset as the possibility of mishandling medical images and facing litigation is not worth the risk. Nevertheless, data security in healthcare continues to improve, and new privacy-preserving models such as deidentification and anonymization are crucial to safeguarding and managing patient records.16 Once the security of privacyenhancing technologies is strengthened, the risks associated with uploading and sharing patient data can be drastically reduced, and de-identified patient data can be used for

research with the approval of a research ethics board. Thus, a vast number of medical facilities may be incentivized to collaborate and contribute to a shared training dataset for CAD systems. Another challenge that must be addressed is the diagnostic accuracy of CAD. The performance of CAD systems is steadily improving, but still varies with the study or method. The lack of a standardized performance assessment for CAD systems adds to the problem. Although at least one measure of accuracy is recommended by the Standards for Reporting of Diagnostic Accuracy Studies, the specific measures are not clearly stated and measures reported in published articles remain inconsistent depending on the application of the CAD system (e.g. segmentation or classification).17 By establishing a well-defined standard such that the most important metrics are consistently reported in the literature, comparing different CAD systems becomes easier and more reliable, which would provide a direction for future researchers to build on past studies. In particular, Gao et al. highlighted eight common evaluation metrics that can be used to form a standard, including accuracy, precision, sensitivity, specificity, and true and false positive rates.2 CAD systems that perform well against other systems can then be replicated; for example, the optimal deep CNN method that yields high results across several metrics can be further investigated by researchers on alternate datasets.18 Thus, developing a standardized evaluation of various CAD systems is necessary to unify research efforts. Finally, coordination between radiologists and researchers is needed to integrate CAD into clinical practice. Despite its potential to improve radiologist performance, CAD systems remain absent in clinical settings as they fail to integrate with radiologists’ workflow.19 As a result, CAD systems are likely to be regarded as low priority compared to their clinical tasks.2,19 Nevertheless, combining the knowledge of radiologists and computer analysis can enhance CAD system performance.5 Radiologists have a strong understanding of the diagnostic process and can identify the strengths and areas of improvement

of current CAD systems. The implementation of a feedback system would offer insight and guidance to academic researchers developing practical CAD systems.20 CONCLUSION Artificial intelligence has the potential to improve patient outcomes by detecting, classifying, and diagnosing pulmonary nodules. Although substantial progress in CAD research has been made, there are still significant barriers to widespread clinical implementation. Current research suggests that developing CADe and CADx simultaneously can optimize performance. High-quality databases are required to train CAD systems, while privacy and security are crucial to ethically and legally share patient data for research. Furthermore, the lack of a standardized performance assessment tool has persistently made comparison between published literature difficult. Successful collaboration between professionals in the field of medicine and computer science is necessary to improve the effectiveness of CAD systems and, by extension, patient care.

REVIEWED BY: DR. DAVID KOFF Dr. David Koff is a Professor of radiology and Chair of the Department of Radiology at McMaster University. He leads research projects on radiation risk, the validation of technology, and applications of artificial intelligence to medical imaging. He is currently the Chair of Canada Safe Imaging (CSI), an initiative he launched to promote radiation safety in Canada.

EDITED BY: NICK TELLER & TAAHA HASSAN

critical review M E D U CATO R | MARCH 2021

doi:10.35493/medu.39.22

CRITICAL REVIEW CARs on the road: Who gets a seat? KATHERINE TAPLIN1 & PREETAMA BADYAL 1 Bachelor of Health Sciences (Honours) Class of 2024, McMaster University

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critical review table of contents

ABSTRACT Chimeric antigen receptor (CAR) T-cell therapy is a form of immunotherapy that has shown potential for inducing complete remission in relapsed/refractory hematopoietic cancers. Depending on the patient’s therapeutic needs, CAR T-cells may be constructed using different cytoplasmic and extracellular domains to alter their affinity, persistence, and proliferation. While the therapy holds promise, the conventional use of CAR T-cell therapy is limited by the occurrence of side effects, substantial rates of relapse, and manufacturing logistics. The objective of this review is to discuss the potential of CAR T-cell therapies, as well as patient characteristics which may influence its efficacy.

INTRODUCTION

Engineering T-cells became commonplace in the mid-2000s, with first generation chimeric antigen receptors (CARs) developed in 1993.¹ Currently approved CAR T-cell therapies are developed from the patient’s own T-cells.² These cells are engineered to express specific T-cell receptors targeted to an antigen on the surface of cancerous cells, allowing the immune system to identify previously unrecognizable immunomodulatory cancer cells.2,3 CAR T-cells most commonly use a single-chain variable fragment (scFv) on the CAR to bind to cancerous antigens.4 When this binding occurs, a signal is generated and transmitted through the CAR cytoplasmic domain, consisting of costimulatory and signalling domains, activating the CAR T-cell.² Once activated, the T-cells initiate cytotoxic functions which can yield cancer cell elimination.² Currently, the United States Food and Drug Administration (FDA) has approved CAR T-cell therapies for the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and lymphomas in children and young adults.¹ Although this treatment has shown promising results, the procedure has been shown to cause adverse effects. The objective of this review is to present the benefits, challenges, and variations in success rates across demographics of patients receiving CAR T-cell therapies.

ADVANTAGES OF CAR T-CELL THERAPY

Inducing Complete Remission CAR T-cell therapies have shown great promise for treating relapsed/refractory hematopoietic cancers by inducing complete remission in patients for whom chemotherapy is no longer

ARTIST BEVERLY NG effective. There are two main CAR T-cell therapies approved by the FDA: Yescarta and Kymriah.5 The CAR T-cells used in these treatments target the CD19 antigen found on B-cell cancers like ALL and B-cell lymphomas. 6 In a clinical trial, Kymriah was administered to 93 patients with refractory B-cell lymphomas, with 52% of patients responding to the treatment and 40% achieving complete remission.7 In a clinical trial to test the efficacy of Yescarta, 101 patients with a type of refractory lymphoma received an infusion.8 The overall response rate after one year was 82%, out of which 58% achieved complete remission.8 These studies demonstrate the efficacy and potential for future CAR T-cell therapies. Reducing Off-Tumor Toxicities One of the challenges in developing efficient cancer treatments is reducing toxicity to non-cancerous cells.9 Many chemotherapeutic drugs target highly active pathways involved in the cell cycle that are not specific to cancer cells, thereby killing healthy cells and worsening the patient’s prognosis.¹0 In comparison, CAR T-cell therapies offer a degree of specificity that is absent from conventional treatments. CAR T-cells can be constructed using various scFv domains to recognize a particular antigen on cancerous cells, such as CD19 found on B-cell cancers.¹1 Thus, CAR T-cell therapy has potential to significantly reduce off-tumor toxicities. However, off-tumour toxicities are still commonplace in patients who receive CAR T-cell therapies, which requires additional treatments to manage associated adverse effects. One common example seen with CD19 CAR T-cell therapy is the ablation of B-cells, which renders the patient immunodeficient.12 This occurs because the CD19 antigen found on hematological cancers are also found on normal B-cells.6 These patients can be treated through periodic administration of intravenous immunoglobulins to replace the antibodies no longer being produced. Nevertheless, there are other off-tumor toxicities for which further research is needed to determine the mechanisms involved and the appropriate treatments.12 Variability of CAR T-Cells Depending on the therapeutic needs of patients, CAR T-cells can be altered at the scFv and the cytoplasmic domain to modulate affinity, persistence, and proliferation.4 Using mouse tumor models, Liu et al. observed that CAR T-cells constructed using lower affinity scFvs had fewer off-tumour responses, increasing their therapeutic index.13 Studies suggest that high affinity scFvs may hinder CAR T-cells’ ability to discriminate between cancer cells and healthy cells.13 CD19 CAR T-cells with higher affinity scFvs for their target antigen have greater anti-tumor activity.12

Additionally, in a study comparing the functionality and persistence of CAR T-cell cytoplasmic domains, Zhao et al. concluded that CAR T-cells with a CD28 cytoplasmic domain expand more efficiently than those with a 4-1BB domain, leading to more rapid cytotoxic effects.¹4,¹5 However, 4-1BB CAR T-cells demonstrate a higher persistence, generating long-term tumor immunity and reducing the risk of cancer relapse.¹³,¹6 These two instances highlight the complex interrelationships at play in cancer immunology, complicating the development of an efficacious CAR T-cell therapy.¹7

SETBACKS IN CAR T-CELL THERAPY

The incidence and severity of adverse effects can be greatly diminished with knowledge of CRS management and early intervention. A recent study suggests that lymphoma patients over 18 years of age display a lower incidence of severe CRS compared to a population under 18 years of age.²² In contrast, another study suggests the opposite pattern in patients with R/R ALL, where higher rates of CRS have been reported in the adult population.²³ These findings suggest a variance in the extent of CRS observed within different cancer types and a need for further research to clarify the relationship between age and CRS severity.

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Immune Effector Cell-associated Neurotoxicity Syndrome Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), a form of neurotoxicity, is the second most prominent adverse effect associated with CAR T-cell therapy.²4 ICANS presents as an encephalopathy, resulting in confusion, aphasia, cerebral edema, and motor weakness, potentially leading to comas, seizures, and death.8 The occurrence of ICANS associated with CD19 CAR T-cell therapy varies between 23-67% among

patients with lymphoma, and between 40-62% in patients with leukemia.¹5 As CAR T-cell therapy is a relatively novel immunotherapy, the mechanism of ICANS development is currently not well understood.²5 However, there are two prevailing theories regarding its development. The first pertains to the disruption of the blood-brain barrier (BBB). Patients who develop ICANS have high levels of pro-inflammatory cytokines known to interact with endothelial cells of the BBB, which protects the brain from circulating toxins and pathogens.²6-²8 Increased cytokine levels may lead to BBB permeabilization, allowing cytokines to enter the brain.²7 The second theory is related to the expression of CD19 on brain cells. In a study by Parker et al., a population of healthy cells in the brain were found to express CD19.²9 Since these cells express the same target antigen as the cancerous cells, CAR T-cells may mistakenly target or damage them.²9

critical review introduction

Cytokine Release Syndrome A primary adverse effect of CAR T-cell therapies is cytokine release syndrome (CRS), marked by elevated serum cytokine levels.¹5 Cytokines are small proteins released by immune cells acting as chemical messengers.¹8 Following their interactions with cancerous cells, activated CAR T-cells release pro-inflammatory cytokines.¹5, ¹9 Symptoms of CRS include fever, myalgia, hypotension, and hypoxia, with severe cases resulting in hemodynamic compromise, capillary leak, arrhythmias, renal failure, and various other complications.¹9 These life-threatening symptoms are also typically seen in early onset CRS, occurring within three days of CAR T-cell infusion.¹5 Studies done on Bcell malignancies have shown that factors such as a high bone marrow tumor burden and higher CAR T-cell dosages pose a greater risk for developing severe CRS through rapid CAR Tcell expansion.²0,²¹

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CAR T-cell designs and dosages may also influence the risk of developing ICANS. CAR T-cells with a CD28 cytoplasmic domain have greater proliferation, but lead to a greater incidence of ICANS.¹5,³¹ Additionally, higher doses of CAR T-cells have been associated with an increased risk of neurotoxicity.²7,³0 Further research on ICANS may help identify high-risk patients preemptively to allow for appropriate adjustments in CAR Tcell design and dosage.³¹ Treatment Logistics Financial costs, storage, handling, and timeline of treatment all hinder the widespread clinical administration of CAR T-cell therapy. There is a concern regarding the financial burden that the treatment imposes on patients.¹5 For patients with ALL, an infusion of Kymriah is over $200,000 USD more expensive than the average 100-day hematopoietic stem cell transplantation treatment (HSCT).³²,³³ Nonetheless, it is important to recognize that, unlike Kymriah treatments, autologous HSCT is not curative for ALL. In a 2014 trial conducted by Maude et al., 63% (n = 30) of patients treated with Kymriah remained in remission during a follow-up period of 24 months.³4 As a result of this cost barrier, this treatment is not financially accessible to the general population. This furthers an ongoing economic debate regarding the cost-effectiveness of CAR T-cell therapies, especially due to its novelty compared to conventional cancer treatments.³² Moreover, the production of CAR T-cells is resource intensive, requiring genetic manipulation, quality control, and final cryopreservation of the expanded T-cell product prior to infusion.¹5 Additional equipment, training, and infrastructure are also needed for the administration and post-treatment monitoring of patients. Future efforts should address the implementation in impoverished communities and hospital systems with minimal funding.

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CAR T-Cell Relapse There are two types of relapses that occur with CAR T-cell therapy. Negative CAR T-cell relapse occurs due to the loss of the target antigen on the tumor (e.g. CD19), allowing cancer cells to evade CAR T-cells.³5 Positive CAR T-cell relapse occurs due to poor persistence and proliferation of CAR T-cells despite the tumor expressing the target antigen.5 With further use of CAR T-cells, relapse has become an apparent obstacle, with up to 50% of patients relapsing within one year.³6

In a clinical study, CD19 CAR T-cells were administered to patients with R/R ALL, with 45% of those who achieved complete remission relapsing.³7 While positive relapse accounted for 6% of cases, negative relapse was 39%, making it a primary research focus.³7 In the case of ALL, potential treatment options include targeting the expression of CD22 on the cancer cells rather than CD19, and developing CAR T-cells with receptors able to target both CD19 and CD22.

CONCLUSION

At this stage, CAR T-cell therapy can be considered effective for inducing complete remission in hematopoietic cancer patients. Given that CRS and ICANS are heightened in patients with higher disease burden and associated comorbidities, CAR T-cell therapy administration should consider the patient’s own treatment needs. Additional research is needed to better understand the mechanisms and management of multiple off-tumor toxicities. Reducing their incidence may be accomplished through alterations to individual CAR T-cell designs. Furthermore, there are a number of handling and economic challenges associated with CAR T-cell therapies. These therapies offer a promising future for those afflicted with R/R ALL and lymphomas, but its cost and patient safety concerns restrict its implementation in clinical settings. REVIEWED BY: DR. JONATHAN BRAMSON Dr. Jonathan Bramson is a Professor in the Department of Pathology and Molecular Medicine as well as the Vice Dean of Research in the Faculty of Health Sciences at McMaster University. His research focuses on the development of immunological strategies that target cancer, using methods such as synthetic biology to direct T-cells against tumor targets.

EDITED BY: HANNAH SILVERMAN & JERRY DU

1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

18. 19. 20. 21. 22. 23.

24. 25. 26. 27. 28. 29. 30.

32. 33. 34. 35. 36. 37. 38.

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Styczynski, J. A brief history of CAR-T cells: From laboratory to the bedside. Acta Haematol Pol. 2020;51(1):2-5. Available from: doi:10.2478/ahp-2020-0002. Mohanty R, Chowdhury CR, Arega S, Sen P, Ganguly P, Ganguly N. CAR T cell therapy: A new era for cancer treatment (Review). Oncol Rep. 2019;42(6):2183-95. Available from: doi:10.3892/ or.2019.7335. Simon B, Harrer DC, Schuler-Thurner B, Schuler G, Uslu U. Arming T cells with a gp100-specific TCR and a CSPG4-specific CAR using combined DNA-and RNA-based receptor transfer. Cancers (Basel). 2019;11(5):2-13. Available from: doi:10.3390/cancers11050696. Benmebarek M, Karches C, Cadilha BL, Lesch S, Endres S, Kobold S. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019;20(1283):1-21. Available from: doi:10.3390/ ijms20061283. Virchow R, Rather LJ. Disease, life, and man. Stanford:Stanford University Press; 1958. Guedan S, Calderon H, Posey AD Jr., Maus MV. Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev. 2019;12:145-52. Available from: doi:10.1016/j.omtm.2018.12.009. Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380(1):45-56. Available from: doi:10.1056/NEJMoa1804980. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel CAR T cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-44. Available from: doi:10.1056/NEJMoa1707447. Emens LA. Chemotherapy and tumor immunity: An unexpected collaboration. Front Biosci. 2008;13:249-57. Available from: doi:10.2741/2675. Darzynkiewicz Z. Novel strategies of protecting non-cancer cells during chemotherapy: Are they ready for clinical testing? Oncotarget. 2011;2(3):107-8. Available from: doi:10.18632/ oncotarget.249. Hay AK, Turtle CJ. Chimeric antigen receptor (CAR) T cells: Lessons learned from targeting of CD19 in B cell malignancies. Drugs. 2017;77(3):237-45. Available from: doi:10.1007/s40265-0170690-8. Rafiq S, Hackett CS, Brentjens RJ. Engineering strategies to overcome the current roadblocks in CAR T-cell therapy. Nat Rev Clin Oncol. 2020;17(3):147-67. Available from: doi:10.1038/ s41571-019-0297-y. Wang K, Wei G, Liu D. CD19: A biomarker for B cell development, lymphoma diagnosis and therapy. Exp Hematol Oncol. 2012;1(36):1-7. Available from: doi:10.1186/2162-3619-1-36. Liu X, Jiang S, Fang C, Yang S, Olalere D, Pequignot EC, et al. Affinity-tuned ErbB2 or EGFR chimeric antigen receptor T cells exhibit an increased therapeutic index against tumors in mice. Cancer Res. 2015;75(17):3596-607. Available from: doi:10.1158/0008-5472.CAN-15-0159. Zhao Z, Condomines M, Van der Stegen SJC, Gunset G, Plotkin J, Sadelain M. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015;28(4):415-28. Available from: doi:10.1016/j.ccell.2015.09.004. Santomasso B, Bachier C, Westin J, Rezvani K, Shpall EJ. The other side of CAR T-Cell therapy: Cytokine release syndrome, neurologic toxicity, and financial burden. American Society of Clinical Oncology Educational Book. 2019;39:433-44. Available from: doi:10.1200/EDBK_238691. McLellan AD, Ali Hosseini Rad SM. Chimeric antigen receptor T cell persistence and memory cell formation. Immunol Cell Biol. 2019;97(7):664-74. Available from: doi:10.1111/imcb.12254. Nie Y, Lu W, Chen D, Tu H, Guo Z, Zhou X, et al. Mechanisms underlying CD19-positive ALL relapse after anti-CD19 CAR T cell therapy and associated strategies. Biomark Res. 2020;8(18):1-17. Available from: doi:10.1186/s40364-020-00197-1. Spear TT, Evavold BD, Baker BM, Nishimura MI. Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy. Cancer Immunol Immunother. 2019;68(11):1881-9. Available from: doi:10.1007/s00262-019-02401-0. Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27-37. Available from: doi:10.1097/AIA.0b013e318034194e. Murthy H, Iqbal M, Chavez JC, Kharfan-Dabaja MA. Cytokine release syndrome: Current perspectives. Immunotargets Ther. 2019;8:43-52. Available from: doi:10.2147/ITT.S202015. Hay KA, Hanafi L-A, Li D, Gust J, Liles WC, Wurfel MM, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130(21):2295-306. Available from: doi:10.1182/blood-2017-06-793141. Wang Z, Han W. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. Biomark Res. 2018;6(4). Available from: doi:10.1186/s40364-018-0116-0. Cao J, Wang H, Gao W, You J, Wu L, Wang Z. The incidence of cytokine release syndrome and neurotoxicity of CD19 chimeric antigen receptor–T cell therapy in the patient with acute lymphoblastic leukemia and lymphoma. Cytotherapy. 2020;22(4):214-26. Available from: doi:10.1016/j.jcyt.2020.01.015. Sheth VS, Gauthier J. Taming the beast: CRS and ICANS after CAR T-cell therapy for ALL. Bone Marrow Transplant. 2020. Available from: doi:10.1038/s41409-020-01134-4. Neelapu SS. Managing the toxicities of CAR T-cell therapy. Hematol Oncol. 2019;37(1):48-52. Available from: doi:10.1002/hon.2595. Rice J, Nagle S, Randall J, Hinson HE. Chimeric antigen receptor T cell-related neurotoxicity: Mechanisms, clinical presentation, and approach to treatment. Curr Treat Options Neurol. 2019;21(8):40. Available from: doi:10.1007/s11940-019-0580-3. Gust J, Hay KA, Hanafi LA, Li D, Myerson D, Gonzalez-Cuyar LF, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7(12):1404-19. Available from: doi:10.1158/2159-8290.CD-17-0698. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-48. Available from: doi:10.1056/NEJMoa1709866. Obermeier B, Daneman R, Ransohoff RM. Development, maintenance and disruption of the bloodbrain barrier. Nat Med. 2013;19(12):1584-96. Available from: doi:10.1038/nm.3407. Parker KR, Migliorini D, Perkey E, Yost KE, Bhaduri A, Bagga P, et al. Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies. Cell. 2020;183(1):126-42. Available from: doi:10.1016/j.cell.2020.08.022. Gust J, Taraseviciute A, Turtle CJ. Neurotoxicity associated with CD19-targeted CAR-T cell therapies. CNS Drugs. 2018;32(12):1091-101. Available from: doi:10.1007/s40263-018-0582-9. Siegler EL, Kenderian SS. Neurotoxicity and cytokine release syndrome after chimeric antigen receptor T cell therapy: Insights into mechanisms and novel therapies. Front Immunol. 2020;11(1973):1-8. Available from: doi:10.3389/fimmu.2020.01973. Hay A, Cheung M. CAR T-cells: costs, comparisons, and commentary. J Med Econ. 2019;22(7):61315. Available from: doi:10.1080/13696998.2019.1582059. Maziarz RT, Guérin A, Gauthier G, Heroux J, Zhdanava M, Wu EQ, et al. Five-year direct costs of acute lymphoblastic leukemia pediatric patients undergoing allogeneic stem cell transplant. Int J Hematol Oncol. 2016;5(2):63-75. Available from: doi:10.2217/ijh-2016-0001. Maude SL, Frey N, Shaw PA, Aplenc R, Barett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507-17. Available from: doi:10.1056/NEJMoa1407222. Xu X, Sun Q, Liang X, Chen Z, Zhang X, Zhou X, et al. Mechanisms of relapse after CD19 CAR T-Cell therapy for acute lymphoblastic leukemia and its prevention and treatment strategies. Front Immunol. 2019;10(2664):1-15. Available from: doi:10.3389/fimmu.2019.02664. Ma S, Li X, Wang X, Cheng L, Li Z, Zhang C, et al. Current progress in CAR-T cell therapy for solid tumors. Int J Biol Sci. 2019;15(12):2548-60. Available from: doi:10.7150/ijbs.34213. Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129(25):3322-31. Available from: doi:10.1182/blood-2017-02-769208.

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A RT I S T KIEN NAGALES

CRITICAL REVIEW Implementing capnography for lactate-enhanced qSOFA scores: Sepsis diagnosis in EMS settings

doi:10.35493/medu.39.26

DONNY LI1 , JEFFREY SUN1 , LUCY ZHAO1 Bachelor of Health Sciences (Honours) Class of 2024, McMaster University

ABSTRACT Sepsis is a life-threatening condition that occurs when the body produces a pro-inflammatory immune response to infection, leading to a decrease in blood flow that results in organ failure and death. Sepsis has the ability to kill within hours, and is responsible for 20% of deaths globally. However, current diagnostic techniques in the pre-hospital setting are limited by time and resources. It has recently been found that sepsis screening tools like qSOFA and lactate biomarkers used within the hospital could supplement diagnostic needs within the EMS setting. With research showing that lactate levels can be indirectly and instantaneously measured via capnography by EMS personnel, this technique may complement existing sepsis screening tools to achieve faster diagnosis. This article investigates the current flaws of sepsis diagnosis within the EMS setting and evaluates the benefits of the implementation of qSOFA and lactate technology.

Septic shock, being the most severe stage of sepsis, has been clinically noted to occur under two conditions: when hypotension is sustained even after fluid resuscitation, and when serum lactate levels are above 2 mmol/L.17 This claim is also supported by Shankar-Hari et al., who have also found that the combination of lactate levels above 2 mmol/L and low blood pressure may be a marker for sepsis.1 As a result, the lactate-enhanced qSOFA score (LqSOFA) has been developed as a novel in-hospital screening tool calculated by adding an additional point to qSOFA in patients who meet the lactate threshold above 2 mmol/L. LqSOFA has demonstrated better performance than SIRS, SOFA, and qSOFA prognostic tools, and increased qSOFA’s sensitivity from 47.6% to 65.5%.21-23 Currently, lactate testing is widely used in the hospital setting as laboratory testing is required to analyze the blood samples. However, a capnography test conducted by EMS personnel can also provide an indirect, but accurate measure of lactate levels. Capnography devices in ambulances can measure a patient’s end-tidal carbon dioxide (etCO2) levels —the amount of carbon dioxide released at the end of an exhaled breath.24 This functions on the basis that when glucose and oxygen are metabolized, carbon dioxide is diffused from

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EXISTING SEPSIS SCREENING TOOLS The use of sepsis screening tools has been strongly advocated for by researchers and clinicians in the pre-hospital setting, with the goal of earlier initiation of fluid resuscitation and antibiotic administration. A variety of EMS screening tools have been proposed to date, but due to the lack of a Canadian EMS regulatory body, no standardized sepsis protocol

LACTATE DETECTION IN SEPSIS DIAGNOSIS In recent years, a novel method of pre-hospital sepsis screening has been introduced that uses serum lactate levels to improve sepsis identification.17 Lactate is produced by hypoxic cells and tissues as a byproduct of anaerobic metabolism. Generally, lactate levels are tested in a hospital setting via blood sampling, whereby high concentrations of lactate are suggestive of sepsis. The biological system behind the correlation between sepsis and lactate levels is still unclear, but scientists suspect they are linked through four main mechanisms: (1) sepsis causes tissue hypoperfusion, resulting in an increase of anaerobic cell respiration and consequently elevated lactate levels;18 (2) cases of sepsis may result in liver and kidney dysfunction, resulting in lowered lactate clearance;17 (3) sepsis releases endogenous epinephrine, stimulating beta-2 receptors in skeletal muscle cells which promote the upregulation of glycolysis, generating excess pyruvate which is converted to lactate;19 and (4) tissue hypoperfusion from sepsis may lead to mitochondrial dysfunction, resulting in an upregulation of non-mitochondrial energy production.20

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Given that patient survival depends on timely treatment, it is crucial for healthcare workers in the pre-hospital setting to detect sepsis prior to arrival at the emergency department (ED). Approximately 8–10% of patients who have an infection are diagnosed with sepsis by emergency medical services (EMS), yet approximately 50% of sepsis patients at the ED arrive via EMS, emphasizing the need for enhanced sepsis screening tools.4 Bayer et al. state that given the lack of sepsis-specific biomarkers, a practical scoring system could potentially improve patient outcomes.5 Although currently being used outside of the EMS setting, recent studies suggest that the quick Sequential Organ Failure Assessment (qSOFA) test and lactate markers can potentially improve sepsis detection rates.3 This article examines the shortcomings in current pre-hospital sepsis diagnostic methods and explores how qSOFA and lactate detection technologies may be used to promote early sepsis identification by EMS providers.

While there lacks research on pre-hospital sepsis diagnosis, extensive research exists on the efficacy of existing inhospital screening tools. The main sepsis diagnostic tools include, Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), and qSOFA, with their specific criteria described in Table 1.6

critical review

INTRODUCTION There is inadequate emphasis on the importance of early sepsis diagnosis in the medical community. Defined as a “life-threatening organ dysfunction caused by a dysregulated host response to infection,” sepsis is responsible for almost 20% of deaths globally.1, 2 Current treatment effectiveness for sepsis depends heavily on how quickly treatment is initiated: broad-spectrum antibiotics should be administered within the first hour of diagnosis, followed by intravenous fluids within three hours, then the use of vasopressors to increase blood pressure.3

exists. Rather, regional EMS centres design their operating procedures in collaboration with medical authorities at the provincial and federal levels.

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Shankar-Hari M, Phillips GS, Levy ML, Seymour CW, Liu VX, Deutschman CS, et al. Sepsis Definitions Task Force. Developing a new definition and assessing new clinical criteria for septic shock: For the third International Consensus Definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):775-87. Available from: doi:10.1001/jama.2016.0289. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the Global Burden of Disease Study. Lancet. 2020;395(10219):200-11. Available from: doi:10.1016/S0140-6736(19)32989-7. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock. Crit Care Med. 2016;43(3):304-77. Available from: doi:10.1007/s00134-017-4683-6. Smyth MA, Brace-McDonnell SJ, Perkins GD. Identification of adults with sepsis in the prehospital environment: A systematic review. BMJ Open. 2016;6(8). Available from: doi:10.1136/bmjopen-2016-011218. Bayer O, Schwarzkopf D, Stumme C, Stacke A, Hartog CS, Hohenstein C, et al. An early warning scoring system to identify septic patients in the prehospital setting: The PRESEP score. Acad Emerg Med. 2015;22(7):868–71. Available from: doi:10.1111/acem.12707. Koch C, Edinger F, Fischer T, Brenck F, Hecker A, Katzer C, et al. Comparison of qSOFA score, SOFA score, and SIRS criteria for the prediction of infection and mortality among surgical intermediate and intensive care patients. World J Emerg Surg. 2020;15(63). Available from: doi:10.1186/s13017-020-00343-y. Chakraborty RK, Burns B. Systemic Inflammatory Response Syndrome. StatPearls Publishing; 2020. Available from https://www.ncbi. nlm.nih.gov/books/NBK547669/ [cited 2021 Jan 21]. Kaukonen KM, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629-38. Available from: doi:10.1056/NEJMoa1415236. Seymour CW, Liu VX, Iwashyna TJ, Brunkhorst FM, Rea TD, Scherag A, et al. Assessment of clinical criteria for sepsis: For the third International Consensus Definitions for sepsis and septic shock (Sepsis-3). JAMA. 2016;315(8):762-74. Available from: doi:10.1001/jama.2016.0288. Kovach CP, Fletcher GS, Rudd KE, Grant RM, Carlbom DJ. Comparative prognostic accuracy of sepsis scores for hospital mortality in adults with suspected infection in non-ICU and ICU at an academic public hospital. PLoS One. 2019;14(9). Available from: doi:10.1371/ journal.pone.0222563. Peng Y, Zhang W, Xu Y, Li L, Yu W, Zeng J, et al. Performance of SOFA, qSOFA and SIRS to predict septic shock after percutaneous nephrolithotomy. World J Urol. 2020. Available from: doi:10.1007/s00345-020-03183-2. Costa RT, Nassar AP Jr, Caruso P. Accuracy of SOFA, qSOFA, and SIRS scores for mortality in cancer patients admitted to an intensive care unit with suspected infection. J Crit Care. 2018;45:52-7. Available from: doi:10.1016/j. jcrc.2017.12.024. Lambden S, Laterre PF, Levy MM, Francois B. The SOFA score—development, utility and challenges of accurate assessment in clinical trials. Critical Care. 2019;23(1):74. Available from: doi:10.1186/s13054-019-2663-7. Freund Y, Lemachatti N, Krastinova E, Van Laer M, Claessens YE, Avondo A, et al. French Society of Emergency Medicine Collaborators Group. Prognostic accuracy of Sepsis-3 criteria for in-hospital mortality among patients with suspected infection presenting to the emergency department. JAMA. 2017;317(3):301-8. Available from: doi:10.1001/jama.2016.20329. Jiang J, Yang J, Mei J, Jin Y, Lu Y. Head-tohead comparison of qSOFA and SIRS criteria in predicting the mortality of infected patients in the emergency department: A meta-analysis. Scand J Trauma Resusc Emerg Med. 2018;26(1). Available from: doi:10.1186/ s13049-018-0527-9. Critical Care Summit. New sepsis definitions and qSOFA - Craig Coopersmith MD, FACS, FCCM. [Video] 2016. Available from https:// www.youtube.com/watch?v=3kNbW_T-vrA [cited 2021 Jan 21]. Lee SM, An WS. New clinical criteria for septic shock: serum lactate level as new emerging vital sign. J Thorac Dis. 2016;8(7):1388-90. Available from: doi:10.21037/jtd.2016.05.55. Foucher CD, Tubben RE. Lactic Acidosis. Florida: StatPearls Publishing; 2020. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK470202/ [cited 2021 Jan 21]. Levy B, Desebbe O, Montemont C, Gibot S. Increased aerobic glycolysis through 2 stimulation is a common mechanism involved in lactate formation during shock states. Shock. 2008;30(4):417-21. Available from: doi:10.1097/SHK.0b013e318167378f.

cells and into the blood as waste products.25 Decreased blood flow from sepsis results in elevated levels of metabolic waste in the bloodstream.26 As such, etCO2 levels are inversely proportional to lactate levels.26 Hunter et al. developed a general guideline for EMS personnel to follow, showing that etCO2 levels below 25 mmHg are strongly correlated with serum lactate levels above 4 mmol/L.27 Wiryana et al. further validate these findings, demonstrating a strong correlation between etCO2 and lactate levels.28 DISCUSSION As the severity of sepsis is exacerbated by delayed treatment, its early recognition in the pre-hospital setting is paramount to increasing patient survival rates. Current EMS sepsis protocols lack standardization and result in poor recognition of sepsis among EMS teams. Thus, the implementation of a pre-hospital screening tool that is simple, accurate, and timeefficient is crucial to patient survival. Through evaluating the existing systems in place for sepsis identification, it should be underscored that the speed of qSOFA tests can be complemented by the accuracy provided by lactate measurements, thus making it an ideal candidate for pre-hospital sepsis screening. The qSOFA tool is heavily criticized for its poor sensitivity; yet, when measured in combination with lactate as a biomarker, its performance is improved. Research consistently demonstrates that LqSOFA scores can predict in-hospital mortality more accurately than qSOFA, SOFA, and SIRS.29-31 As discussed previously, capnography may serve as a novel lactate measuring technology for EMS personnel: they produce results instantaneously, are already part of ambulance equipment, and require minimal additional training to be applied in a sepsis context. Integrating lactate testing via capnography into the qSOFA criteria may thus be ideal for prehospital paramedic use. Some EMS centres have already adopted sepsis protocols measuring lactate via etCO2 readings. Sepsis Alert —an EMS protocol that has been introduced in Denver, Colorado— is nearly identical to qSOFA apart from the additional criterion of etCO2 levels less than or equal to 25 mmHg. When Sepsis Alert was initiated in Denver, the overall mortality for severe sepsis patients transported by EMS was nearly halved, from 26.7% to 13.6%.32

While LqSOFA tests may serve as a promising tool, it is essential that EMS centres reinforce training to improve sepsis detection rates.22 As EMS personnel treat patients in emergency situations, the identification of immediate injuries may be prioritized over the diagnosis of later-onset sepsis.33 Studies by Green et al. show that three-hour training sessions for EMS clinicians on identifying sepsis in patients increase early-diagnosis of sepsis in 40%–50% of emergency cases.32 However, the introduction of qSOFA and lactate technologies are more efficient to use and provide ambulatory clinicians with greater time and opportunity to identify sepsis. Hence, strengthening training on sepsis diagnosis, particularly the use of qSOFA and etCO2 technologies, may assist EMS personnel in improving the identification of sepsis. Though current studies suggest that LqSOFA criteria may significantly improve rates of patient diagnosis, there are limitations to this proposal. Few studies have clinically tested the effectiveness of qSOFA paired with etCO2 levels. Research by Guerra et al. demonstrated that the Sepsis Alert protocol could reduce mortality for sepsis patients arriving via EMS. These benefits are challenged by Daniel J. Lane, who suggested that this hybrid criteria yields no significant improvements in sensitivity or specificity compared to qSOFA alone.30,34 Green et al. explains that different clinical settings may benefit from different technologies to varying extents. In summary, additional research needs to be conducted to assess the validity of using etCO2 measurements to enhance qSOFA screening.34 CONCLUSION Of existing in-hospital sepsis screening tools, qSOFA demonstrates the greatest potential for practical usage in an EMS setting. While qSOFA’s simplicity impacts its accuracy, the addition of a novel lactate biomarker may significantly improve test sensitivity. Research presents capnography devices as a promising alternative for existing lactate laboratory tests that, when used in combination with qSOFA and effective training, may improve early diagnosis of sepsis by EMS providers. Further research is needed to assess the accuracy of an LqSOFA score in a pre-hospital setting.

TABLE 1: Criteria for SIRS, qSOFA, and SOFA sepsis screening tests.7 There is a

variety of screening tools used by healthcare professionals to identify septic patients in an inhospital setting. The criteria for SIRS, qSOFA, and SOFA are illustrated in the table below.

SIRS

qSOFA

21.

SOFA

Criteria for SIRS are met if at least two of four clinical findings are present.

Presence of at least two out of three clinical criteria.

Scores on a scale of zero to four are given for the following six systems based on the provided parameters.

Tachycardia: Heart rate >90 beats/min

Low blood pressure: SBP ≤100 mmHg

Respiratory: PO2/FiO2 mmHg

Tachypnea: Respiratory rate >20 breaths/min

High respiratory rate: ≥22 breaths/min

Coagulation: Platelets in 103/mm3

Fever/hypothermia: Temperature >38 or <36 ºC

Altered mentation: Glasgow coma scale <15

Liver: Bilirubin in mg/dL

Leukocytosis, leukopenia, bandemia: White blood cells >1,200/mm3, <4,000/mm3 or bandemia ≥10%

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Cardiovascular: Mean Arterial Pressure (MAP) in mmHg and doses of dopamine, epinephrine, norepinephrine given in mcg/kg/min Renal: Creatinine in mg/dL

22.

23.

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25.

26.

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Neurological: Glasgow coma score 28.

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30.

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PEER REVIEWED BY: DR. GEORGE FARJOU 33.

EDITED BY: SHADI SADEGHIAN & SHANZEY ALI

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Dr. George Farjou is an infectious disease physician at Fraser Health Authority and Assistant Clinical Professor of Medicine in the Faculty of Health Sciences at McMaster University. Aside from Farjou’s clinical work, his research has involved analytical surveys on evidence-based medical textbooks, as well as examining the role of community hospitals in trials of treatments for COVID-19.

introduction critical review

SIRS is an exaggerated immune response to external stressors that characterizes sepsis when combined with suspected infection.7 Although still in use clinically, the SIRS criteria has been criticized for its inability to predict organ dysfunction.7,8 SOFA has since repeatedly outperformed SIRS in predicting mortality rates and length of stay in the intensive care unit (ICU), but is significantly more time-consuming due to the weighted scoring system and the greater number of tests required.9-13 These concerns led to the creation of qSOFA— a quicker and more sensitive iteration of SOFA and SIRS. The qSOFA tool has been recommended in the Sepsis-3 criteria for its simplicity and increased predictive validity.9,14 Jiang et al. conclude that a qSOFA score of two or higher is more accurate in predicting mortality than a SIRS score of two or more.15 Similarly, Koch et al. found that qSOFA predicts negative patient outcomes in 97.8% of positive cases, while SOFA is accurate in 26.7% of those outcomes.6 Despite the simplicity of the qSOFA criteria, it consistently performs well in settings outside the ICU.16

Ruggieri AJ, Levy RJ, Deutschman CS. Mitochondrial dysfunction and resuscitation in sepsis. Crit Care Clin. 2010;26(3):567-75. Available from: doi:10.1016/j.ccc.2010.04.007. Liu S, He C, He W, Jiang T. Lactate-enhancedqSOFA (LqSOFA) score is superior to the other four rapid scoring tools in predicting in-hospital mortality rate of the sepsis patients. Ann Transl Med. 2020;8(16). Available from: doi: 10.21037/atm-20-5410. Zhou H, Lan T, Guo S. Prognostic prediction value of qSOFA, SOFA, and admission lactate in septic patients with community acquired pneumonia in emergency department. Emerg Med Int. 2020;2020. Available from: doi:10.1155/2020/7979353. Shetty A, MacDonald S, Williams J, Bockxmeer J, de Groot B, Cuevas L, et al. Lactate ≥2 mmol/L plus qSOFA improves utility over qSOFA alone in emergency department patients presenting with suspected sepsis. EMA. 2017;29(6):626-34. Available from: doi:10.1111/1742-6723.12894. Richardson M, Moulton K, Rabb D, Kindopp S, Pishe T, Yan C, Akpinar I, et al. Capnography for Monitoring End-Tidal CO2 in Hospital and Pre-hospital Settings: A Health Technology Assessment. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2016. Available from: https://www.ncbi.nlm.nih.gov/ books/NBK362376/ [cited 2021 Jan 21]. Adeva-Andany MM, Pérez-Felpete N, Fernández-Fernández C, Donapetry-García C, PazosGarcía C. Liver glucose metabolism in humans. Biosci Rep. 2016;36(6). Available from: doi:10.1042/BSR20160385. Safari E, Torabi M. Relationship between endtidal CO2 (ETCO2) and lactate and their role in predicting hospital mortality in critically ill trauma patients: A cohort study. Bull Emerg Trauma. 2020;8(2):83-8. Available from: doi:10.30476/BEAT.2020.46447. Hunter CL, Silvestri S, Dean M, Falk JL, Papa L. End-tidal carbon dioxide is associated with mortality and lactate in patients with suspected sepsis. Am J Emerg Med. 2013;31(1):6471. Available from: doi:10.1016/j. ajem.2012.05.034. Wiryana M, Sinardja K, Budiarta G, Widnyana I, Wayan A, Paramasari A. A correlation of end tidal CO2 (ETCO2) level with hyperlactatemia om patient with hemodynamic disturbance. J Clin Anesth. 2016;08(07). Available from: doi:10.4172/2155-6148.1000741. Sinto R, Suwarto S, Lie KC, Harimurti K, Widodo D, Pohan HT. Prognostic accuracy of the quick Sequential Organ Failure Assessment (qSOFA)lactate criteria for mortality in adults with suspected bacterial infection in the emergency department of a hospital with limited resources. Emerg Med J. 2020;37(6):363-9. Available from: doi:10.1136/emermed-2018-208361. Baumann BM, Greenwood JC, Lewis K, Nuckton TJ, Darger B, Shofer FS, et al. Combining qSOFA criteria with initial lactate levels: Improved screening of septic patients for critical illness. Am J Emerg Med. 2020;38(5):883-9. Available from: doi:10.1016/j.ajem.2019.07.003. Guerra WF, Mayfield TR, Meyers MS, Clouatre AE, Riccio JC. Early detection and treatment of patients with severe sepsis by prehospital personnel. J Emerg Med. 2013;44(6):111625. Available from: doi:10.1016/j.jemermed.2012.11.003. Green R, Travers A, Cain E, Campbell S, Jensen J, Petrie D, Erdogan M, et al. Recognition of sepsis in the prehospital setting: A prospective observational study. Emerg Med Int . 2016;2016. Available from: doi:10.1155/2016/6717261. Smyth MA, Brace-McDonnell SJ, Perkins GD. Identification of adults with sepsis in the prehospital environment: A systematic review. BMJ Open. 2016;6(8). Available from: doi: 10.1136/bmjopen-2016-011218. Lane DJ. The identification and management of sepsis in the prehospital setting. PhD thesis. Institute of Health Policy, Management and Evaluation University of Toronto; 2018. Available from: http://hdl.handle.net/1807/91963 [cited 2021 Jan 21].

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IN T E R V IE W SPOTLIGHT

table of contents

DR. C HE L S E A GABEL

E N G A GIN G IND I G E N O U S C O MMUNI T IE S IN RESEARCH HARGUN KAUR1 & MEERA CHOPRA1 1

Bachelor of Health Sciences, Class of 2023, McMaster University

Dr. Chelsea Gabel is the Canada Research Chair in Indigenous Well-being, Community Engagement, and Innovation, Director of the Indigenous Studies program at McMaster University, and former Director of the McMaster Indigenous Research Institute. As an Indigenous scholar, her work integrates community-based participatory and arts-based research methods in studying Indigenous health and well-being. Dr. Gabel’s interests include understanding how digital technology can be used for healing and empowerment of elders and youth. She also examines the pressures facing Arctic communities as they prepare for resource development. Dr. Gabel combines community- and arts-based research methods with academic rigour to create positive social change for Indigenous communities through public policy.

WHAT INSPIRED YOU TO GO INTO THE FIELD OF INDIGENOUS HEALTH? My background is Métis and I grew up in Manitoba. Being a Métis woman, it was really important for me to pursue research in Indigenous issues. Very early on in my career, I participated in the Federal Student Work Experience program. That was the turning point for me in my career. It basically allowed Indigenous students to work either in the federal government or within an Indigenous organization in the area of policy. [The program came] with the idea that [the government] wanted more Indigenous people in public policy, like working in government departments and in organizations. I started out as essentially an intern for an organization called the Assembly of First Nations [(AFN)], [where] I worked on the Indigenous Women’s Health File. [And it was during my internship that] I got a better sense of the bigger issues in our country that Indigenous peoples face. After I finished [my internship] at the AFN, I went over to the First Nations Indian Health branch of Health Canada. I think that’s where things really became clear to me because I was the only Indigenous person [in that department, even though I was only] a student. That was really horrifying because a lot of the people working on big policy for Indigenous peoples were non-Indigenous and many of them had stated that they had never even been

into an Indigenous community before. I thought, “How is this possible? How are these almost all non-Indigenous people working on policy and how does that impact communities on the ground?” And so I decided to pursue my PhD after that, and look more closely at the ways that federal, provincial, [and] territorial policies are impacting First Nations and Métis people specifically on the ground. The big turning point for me was the lack of Indigenous people in these kinds of positions. You get to really see why there are so many health disparities when these policies and programs aren’t being led by Indigenous people. WE READ ABOUT YOUR WORK IN USING DIGITAL TECHNOLOGY FOR HEALING AND EMPOWERMENT OF YOUTH AND ELDERS. CAN YOU TELL US MORE ABOUT THE POTENTIAL YOU SEE IN TECHNOLOGY AND POSSIBLE CHALLENGES YOU MAY HAVE FACED IN IMPLEMENTING THIS SPECIFICALLY IN INDIGENOUS COMMUNITIES?

I have an article in the Canadian Journal of Bioethics that talks about deficit-based research. We really don’t need more research telling us how bad it is in Indigenous communities. What we need is research that comes from a strength-based approach that talks about the importance of communities and all of the things that communities are doing that are so innovative and creative. That’s the type of work that I strive to do.

I don’t think as the director I necessarily [faced challenges], but I had to deal with a couple of other faculty members and their unethical approaches to research. A major challenge was understanding that Indigenous peoples, the most researched people in the world, have been weighed and they’ve given their blood and hair samples and they’ve shared their stories and academics have written about them and studied them and written dissertations. Historically, this has been done without their knowledge or consent. It’s maybe less of a problem now because we have more ethics guidelines in place, like the TriCouncil Policy Chapter 9, [in] which we have principles about who can own, control, and access Indigenous data. Certainly that has helped, but we still see poor research methods like helicopter researchers who fly in and out and then communities are like, “What did you do?” That’s one of the reasons why I think there’s a lot of mistrust in communities. It’s because of the way that research has been done historically, and even now, as the [COVID-19] vaccine is being rolled out and Indigenous communities are being given priority, a lot of communities have suspicion about why they’re being selected first. Because there has been poor vaccine research done in communities in the past. There’s a lot of fear and mistrust about the healthcare providers who are coming in and giving those vaccines. And is there cultural safety there? Do they understand some of the fears that are coming from communities? Even people who are going into the communities need cultural safety training, for example, around COVID[-19] and vaccines. That relationship-building and trust is so important because of the ways that research has been done historically [as a result of] all the colonial policies, like the residential school system and the Indian Act. For many people and communities still, colonialism is ongoing. We continue to see that with Brian Sinclair, the Indigenous man in Winnipeg who died waiting in the emergency room for 34 hours from a simple bladder infection, because he was discriminated against —that’s colonialism in the present day. People need to be aware of that. Building trust and forming those relationships, that’s why it’s so important. My colleague who’s doing her residency now has had some horror stories too. There’s just so many news stories about doctors and physicians being just completely inappropriate and racist.

M E D U CATO R | A P R I L 2015 M E D U CATO R | M A R C H 2 0 2 1

The article that Stacy Margerison and I wrote in the Canadian Medical Association Journal —if you go to [the issue in which it appeared], my photovoice project made the cover of the journal for that month. [The journal] also decided to do a featured podcast on our work. It was important to me for a number of reasons, but I think, first and foremost, it really validated to the medical community that Indigenous knowledge and arts-based research, and qualitative research or community-engaged research is valid. Indigenous knowledge is scientific knowledge, and so to profile our research for the Canadian Medical Association Journal was a signal about the importance of Indigenous research.

AS THE FORMER DIRECTOR OF THE MCMASTER INDIGENOUS RESEARCH INSTITUTE, WHAT CHALLENGES HAVE YOU FACED WITH ENGAGING AND BUILDING UP TRUST WITHIN INDIGENOUS COMMUNITIES?

introduction interview spotlight

I use a lot of arts-based research methods. First and foremost, I would say that I’m a community-engaged researcher or community-based participatory researcher. If you look [at] a lot of my projects, [you can see that] they[‘ve] shifted over the years. I would say I have a more eclectic program of research, but the one common denominator with all of my projects is that they are community-led and community-based. What that means is that I work with communities and it’s not me saying, “I want you to be like my research subjects, I’m going to study you,” because obviously there’s a long history of poor research [involving] Indigenous communities. There are still researchers doing unethical research with Indigenous peoples, who are the most researched group in the world. It’s so important for me to do community work. Communities will say, “We really want to do this. We want to use these methods, such as photovoice or focus groups.” These projects are really driven and led by communities. It’s my role as a researcher to support communities and to do research that is strength-based and will benefit communities.

I had a lot of rejections before [the photovoice project was] published, saying [my] population size [was] too small. Of course we’re going to work with a small number of people, because that’s what photovoice is —that’s what the arts-based research method is. We’re not doing a giant survey, which I’ve also done, and which also has value. Arts-based research works with smaller groups of people —and that’s the value of that approach.

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So much work has to be done around cultural safety —just even understanding basic history is so important, because those residential schools ended in 1996, but all their effects are intergenerational. All of those things that have happened have continued on into our communities today. So, it’s so important for health care professionals especially, to really understand and be aware of our history and how that impacts Indigenous peoples and communities today.

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interview spotlight table of contents

FOR THOSE WHO DO NOT IDENTIFY AS INDIGENOUS, WHAT WOULD YOU RECOMMEND IN UNDERSTANDING MORE ABOUT INDIGENOUS CULTURE AND BEING ABLE TO ENGAGE WITH OR INVOLVE INDIGENOUS COMMUNITIES IN RESEARCH IN A MEANINGFUL WAY?

I have some colleagues who will only work with Indigenous students, just because it’s too much to try and provide all that background. When I was the director of the McMaster Indigenous Research Institute, I got emails from faculty members about them needing an Indigenous person because they’re submitting a grant, since Indigenous research is obviously a big priority now. I have students who want to work with me who are non-Indigenous, who want to do a thesis or a major research project on Indigenous issues. For me it would be like, have you taken an Indigenous studies course? We have so many wonderful faculty members who teach great courses on Indigenous research methods, Indigenous theory, and even just first year Indigenous studies courses about the history and the impacts of the residential school system and the Indian Act and how that’s contributed to the poor health inequalities within our communities. I would absolutely say to students to make sure that [they] either take a course or get that background information before [they] even approach a community or an organization. Ask yourself, how can you give back to a community? What kind of expertise can you bring to the community? There’s often the expectation that we’re going to do the work for the students or for the faculty. I think we’re trying to flip that now for them to take our courses, do [their] own research, and read through the TRC’s recommendations to learn about the history of colonization and how that’s impacted communities. We have so many events about Indigenous studies and a speaker series to learn about our faculty and what they do. WHAT WAS THE MOST IMPORTANT/ MEMORABLE LESSON THAT YOU’VE LEARNED OVER THE COURSE OF YOUR CAREER? I was about to defend my PhD in political science, [which] has to always go out to an external examiner. My external examiner was a white [male] political scientist. The reviews came back and he said, “She

can’t defend this. This is not political science, not everybody supports community engagement, this isn’t part of the discipline. She needs to rework her whole dissertation so that it fits into the political science boxes.” It delayed my dissertation and I had to pay tuition again. It shook my confidence, but I remember that I wasn’t going to change my approach. [I had been working] with these communities for three years. I [couldn’t] change that. [I wasn’t] going to go back and do some discourse analysis or whatever political scientists do. I stood my ground and my supervisor was really awesome at the time too. That was also a really big turning point because I was just like, “I am going to continue to do this work. I’m going to get tenure and an academic job.” I was the first Indigenous scholar in the department to get a PhD and I went on to become a Canada Research Chair, which is one of the highest honours in the country. [It’s important to have] the confidence to stay true to yourself and your values. I was so proud of this work and it was so meaningful to me. I wasn’t about to change it for this white [male] political scientist. Passion for me is more important than talent, and having that drive is what got me through it. At [the] time, I was devastated and I thought I wasn’t going to get my PhD. But I didn’t want to change my whole dissertation to fit a political science disciplinary kind of approach. [In short,] confidence, patience, and passion are my takeaways.

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Issue 39

Articles inside

Implementing capnography for lactate- enhanced qSOFA scores: Sepsis diagnosis in the EMS setting

INTERVIEW SPOTLIGHT

Artificial intelligence in diagnosing lung

IWCH ABSTRACTS

through the sociopolitical and medical context Evaluating the local status of minority maternal health through institutionalized disparities in Hamilton

PATHOPROFILE

MEDPULSE

MEDBULLETINS

The implications of uterine transplants

INTRODUCTION