McMaster University Medical Journal, Vol. 18, Issue 1 by MUMJ

McMASTER UNIVERSITY MEDICAL JOURNAL VOLUME 18, ISSUE 1 2021

Case Report

A RARE PRESENTATION OF AUTOIMMUNE LIMBIC ENCEPHALITIS WITH ANTI-YO ANTIBODIES: A CASE REPORT

Reviews

COVID-19: A REVIEW ON THE INFLAMMATORY PROFILE OF SARS-COV-2 AND THE ASYMPTOMATIC STATE

Commentary

THE NEED FOR UNIVERSAL HEPATITIS C SCREENING IN INCARCERATED POPULATIONS

Family Physician Opportunities Brantford, Ontario

Live in a community large enough to build a leading edge hospital with colleagues who call you by your first name. Brant Community Healthcare System offers a 300-bed acute care facility boasting stable, state-of-the-art programs and specialists who support primary care in the community. There are a variety of family practice service models that appeal to new physicians including turn-key operations in family health organization models, group practices, hospitalist roles and a community healthcare centre. Take this outstanding opportunity to experience the exceptional quality of life that is unique to Brantford. Located in the picturesque Grand River Valley 20 minutes west of Hamilton, our community offers outstanding recreational opportunities including endless biking and hiking trails in an unmatched natural playground. In April 2018, Macleans listed Brantford, Ontario as the “best city in Canada to buy real estate.” (www.macleans.ca/economy/realestateeconomy/why-everyone-should-buy-real-estate-in-brantford)

In addition to local culture, arts and entertainment, you can easily access the diversity of large urban centres such as Toronto, Hamilton, London and Kitchener. Seven major universities are within commuting distance. For more information about practice opportunities, please contact Alice Preston, Medical Recruiter at 519 751-5544, ext. 2354 or e-mail alice.preston@bchsys.org.

__________________________________________________________ McMaster University Medical Journal Editorial Board 2020-21

__________________________________________________________ Editors-in-Chief AADIL BHARWANI AND LAURA LOCKAU Executive Editors ALI ZHANG AND LAUREN LIN Submission Editors MUNEEB AHMED SABRINA ALLARAKHIA JESSICA CHEE ANDREW CHEN ANNE-SOPHIE FORTIER CLARELLE GONSALVES

JASPER HO KEVIN KIM RYAN O’REILLY ARJUN PANDAY SHERIF RAMADAN DANIEL ROSENBERG

MURALIE VIGNARAJAH JIM XIE CAITLIN YEE JAMIE ZHEN

Reviewers SARAH BRASSARD CYNTHIA CHAN GIULIA COLETTA ALESSIA D’ELIA VANESSA DE RUBEIS JAPNIT DHAM TAHA ELGHAMUDI DEVANJITH GANEPOLA CLARELLE GONSALVES JESSICA GORMLEY KYLE JORDAN GOUVEIA

LAIBA JAMSHED SHAHZAIB KHATTAK KEVIN KIM LYNAEA KOROL-FILBEY NIRUSHI KUHATHASAN JAMES LAI SARAH MEDEIROS LEANNE MONTEIRO IBRAHIM NADEEM JANHAVI PATEL GENEVIEVE PERONO

NOAM RAITER SHERIF RAMADAN PAUNEEZ SADRI ZARWA SAQIB HANIAH SHAIKH ISABELLA STEFANOVA MEGAN VIERHOUT REBECCA WONG JAMIE ZHEN

Cover Art CORA MARINOFF

TABLE OF CONTENTS LETTER FROM THE EDITORS…………………………………………………………………v AADIL BHARWANI AND LAURA LOCKAU

CASE REPORTS PERI-OPERATIVE MANAGEMENT OF ACTH-SECRETING PANCREATIC NEUROENDOCRINE TUMOR AND MAJOR VESSEL RECONSTRUCTION…………........1 APRIL (YICHEN) LIU, SABARINATH BALACHANDRAN NAIR, AND SAEDA NAIR COEXISTENCE OF BANKART LESION AND ADHESIVE CAPSULITIS IN TWO SHOULDERS: A CASE REPORT……………………………………………………………….8 HETTIARACHCHIGE DILUKSHA PRASAD JAYAWARDANA A RARE PRESENTATION OF AUTOIMMUNE LIMBIC ENCEPHALITIS WITH ANTI-YO ANTIBODIES: CASE REPORT………………………………………………………………...15 EVA LIU, JANHAVI PATEL, ALICIA MATTIA, AND HAN-OH CHUNG HIGH-DOSE STEROIDS AND PENTOXIFYLLINE IN METHANOL-INDUCED OPTIC NEUROPATHY: A CASE REPORT AND REVIEW OF THE LITERATURE……………….22 KEEAN NANJI, ALEX POZDNVAKOV, TERESA SEMALULU, AND AMEEN PATEL

REVIEW ARTICLES COVID-19: A REVIEW ON THE INFLAMMATORY PROFILE OF SARS-COV-2 AND THE ASYMPTOMATIC STATE…………………………………………………………………..…28 DEVYANI BAKSHI, AMY MOOREHEAD, LOUBNA AKHABIR, DAVID PUTMAN, ALLISON KENNEDY, DAWN BOWDISH, AND JUDAH DENBURG SAFETY AND RISK FACTORS ASSOCIATED WITH ELECTRIC SCOOTER USE GLOBALLY: A LITERATURE REVIEW………………….…………………………………..48 MICHELLE SCHNEEWEISS, MOHAMMED HASSAN-ALI, AND APRIL KAM

iii

COMMENTARIES COVID-19 LOCKDOWN: NOT A ONE-SIZE-FITS-ALL SOLUTION………........................61 YASMINA GEBER AND PRISCILLA MATTHEWS TRIAGING OUT OF ELECTIVE SURGERIES DURING THE COVID-19 PANDEMIC: THE WRONG APPROACH?............................................................................………........................69 TAKHLIQ AMIR OPIOID TREATMENT AGREEMENTS IN CHRONIC NON-MALIGNANT PAIN: THE SOLUTION OR THE PROBLEM?……………...………………………………………………76 JASPER C HO AND YASOVINEETH BHOGADI THE NEED FOR UNIVERSAL HEPATITIS C SCREENING IN INCARCERATED POPULATIONS…………………………………………………………………........................84 JAMES ZHOU AND FIONA KOUYOUMDIJIAN

From the Editors

McMaster University Medical Journal, Volume 18 Aadil Bharwani, MD, PhD, and Laura Lockau, PhD, MD Candidate Editors-in-Chief Michael G. DeGroote School of Medicine The McMaster University Medical Journal is delighted to present its 18th annual issue, which continues to display the tireless endeavours in science and medicine driven by medical and graduate students across Canada. In a year marked by international communities rising to confront a devastating challenge through awe-inspiring scientific efforts, we strive to humbly provide a platform for works that span the breadth and depth of research. Akin to its predecessors, this 18th volume highlights the vanguard of scientific works through unique case reports, original research, and reviews and commentaries. Our authors describe a unique presentation of autoimmune limbic encephalitis, review the inflammatory and immunological underpinnings of SARS-CoV-2, and advocate for improved equity in healthcare through universal screening for Hepatitis C in incarcerated populations. In two independent and timely articles, they scrutinize the COVID-19 pandemic lockdown strategy and, relatedly, assess the policies concerning the cancellation of elective surgeries amidst a burdened healthcare system. As ever, we remain grateful to the tireless efforts of our editorial boards—the executive editors, submission editors, and reviewers—all of whom have generously contributed their valuable time and expertise to bring this issue to fruition. These efforts comprise a culture and tradition that have remained ever consistent across the history of this journal. We also thank the authors for the opportunity to showcase their work, which serves as a means to embrace that which we do not know, and to continually reflect upon new ideas and discovery. Finally: thank you, dear reader, for it is only with your support that this journal continues to strive and exist. Sincerely, Laura Lockau and Aadil Bharwani

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Case Report

Case Report: Peri-operative management of ACTHsecreting pancreatic neuroendocrine tumor and major vessel reconstruction April (YiChen) Liu1, Sabarinath Balachandran Nair2, and Saeda Nair3 Undergraduate Medicine, Michael G. DeGroote School of Medicine, Hamilton, Canada Department of Radiology, Hamilton Health Sciences, Hamilton, Canada 3 Department of Anesthesiology, Hamilton Health Sciences, Hamilton, Canada 1 2

Abstract Adrenocorticotrophic hormone (ACTH)-secreting pancreatic-neuroendocrine-tumors are extremely rare. They present a significant peri-operative management challenge because of the tumor’s extensive vascular involvement as well as excess hormone production resulting in electrolyte and metabolic disturbances. A 49-year-old male presented for resection of his ACTH-secreting pancreatic-neuroendocrinetumor involving the pancreatic head and many major vessels. Pre-operative assessments showed increased serum cortisol, low serum ACTH, negative 24-hour urine 5-hydroxyindoleacetic-acid, and no suppression with 1mg dexamethasone. Pre-operatively, he had ectopic Cushing’s syndrome, type II diabetes mellitus, hypokalemia and thrombocytopenia for which he was treated with insulin, intravenous potassium, and platelets. He was given octreotide at the beginning of surgery. The 10-hour procedure involved both general and vascular surgery. There was eight liters of blood loss and the patient required significant transfusions. At the end of surgery, he remained ventilated due to the duration of surgery and amount of blood loss. Postoperatively, he did well, but he developed adrenal insufficiency secondary to removal of his ACTH-secreting tumor and was discharged home on hydrocortisone. This case highlights the role of anesthesiologists as the peri-operative physician in maintaining homeostasis in these complex patients. It also shows the importance of pre-operative tumor characterization, carcinoid crisis prophylaxis, and a multi-disciplinary approach to the management of these rare tumors.

Keywords: Pancreatic neuroendocrine tumors, Multidisciplinary perioperative management, Ectopic Cushing syndrome Corresponding author: Dr. Saeda Nair, nairsaed@hhsc.ca 1

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Case presentation A 49-year-old male initially presented with a one-month history of generalized epigastric abdominal pain. He was investigated in the emergency department with an ultrasound which showed a vague abnormality in the pancreas region. Thus, a computed tomography scan of the abdomen was completed, showing a 9.5cm by 9.2cm pancreatic neck mass with multiple vascular involvements including the celiac artery, hepatic artery, left gastric artery, and splenic artery, as well as the superior mesenteric veins and splenic veins. Figure 1 displays a coronal view of the computed tomography scan completed. Based on the images and location, he was suspected to have a pancreatic neuroendocrine tumor. As such, he was referred to the hepatobiliary surgery service for pancreatoduodenectomy with vascular reconstruction.

Figure 1. Coronal view of the computed tomography scan completed with a red arrow indicating the pancreatic head mass visualized. Diagnosis Further workup showed increased serum cortisol, low serum ACTH, and no suppression with one milligram of dexamethasone. The 24-hour urine collection was negative for 5hydroxyindoleacetic-acid and the multiple endocrine neoplasia type I screen was negative. Upon 2

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further questioning, he endorsed face and arm swelling, easy bruising, hyperpigmentation in the upper part of his thorax, and weight gain. He also complained of decreased sexual function with no sex drive and some erectile dysfunction over the last two months even though he has had no fertility issues in the past. Based on the testing results and his signs and symptoms, he was diagnosed with ectopic Cushing syndrome. Management A couple of weeks prior to his scheduled surgery date, he presented to the emergency department with generalized weakness and peripheral edema. Subsequent bloodwork revealed hypokalemia with a serum potassium less than two as well as hyperglycemia. He was admitted. Endocrinology was consulted and this patient was started on both potassium replacement and insulin therapy. Hematology was also consulted for thrombocytopenia (platelet count of 52x 109/L). A thorough work-up was conducted and the thrombocytopenia was thought to be due to congestive splenomegaly secondary to splenic artery and vein involvement. One unit of platelets was transfused prior to surgery. In addition to standard pre-operative testing, he had an echocardiography completed which was normal. On the day of surgery, the patient had standard monitoring. Induction was completed using midazolam, sufentanil, propofol, and rocuronium and the patient was placed on desflurane for maintenance of anesthesia. Following induction, a right radial arterial line and right internal jugular central line were placed. A 16-guage peripheral intravenous access was established and connected to a Level 1® fluid warming device. 100mcg of octreotide was given subcutaneously at the start of the case. The surgery lasted 10 hours. It consisted of a pancreaticoduodenectomy with dissection and repair of many major vessels including the celiac artery, hepatic arteries (common, right, and left hepatic arteries), as well as the splenic artery and vein. The patient had an estimated eight liters of blood loss and received two units each of packed red blood cells, fresh frozen platelets, and cryoprecipitate. Throughout the case, glucose levels were monitored hourly and subcutaneous insulin was given to keep levels between eight to 10 mmol/L. Electrolytes were also monitored. Hypokalemia was treated with intravenous potassium. Outcome of the case At the end of the case, the decision was made to keep the patient ventilated and transfer him to the intensive care unit because of the massive transfusion and long duration of surgery. Postoperatively, he developed adrenal insufficiency secondary to removal of his ACTH-secreting tumor. The endocrinology team was consulted to initiate hydrocortisone therapy. He was discharged home on post-operative day 32 on a tapering dose of hydrocortisone.

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Review of the literature and discussion Background information Neuroendocrine tumors (NETs) arise from neuroendocrine cells that have properties of both nerve cells and hormone-producing cells. Thus, NETs are capable of releasing hormones into the blood. NETs can be classified as functional or non-functional depending on whether or not they produce these excess hormones (1). Pancreatic neuroendocrine tumors (PNETs) are a rare subset of NETs originating from hormone producing islet cells (2). PNETs have an estimated incidence of less than one per 100,000 individuals and represent 1.3% of all pancreatic neoplasms (3). Functional PNETs are even rarer, encompassing only approximately 10-30% of all PNETs (3). PNETs often occur sporadically, although they are associated with certain genetic conditions such as multiple endocrine neoplasia type I (1). Functional PNETs could be further classified by the type of hormone they secrete. Common hormones secreted by PNETs include insulin and gastrin, while adrenocorticotrophic hormone (ACTH)-secreting PNETs are extremely rare (3). Patients presenting for surgical resection of PNETs present a significant management challenge because of many reasons. The rich blood supply to the pancreas means that extensive vascular involvement is common with these tumors (4). This puts the patients at risk for significant blood loss and fluid shifts. Additionally, the production and release of excess hormones by PNETs result in peri-operative electrolyte imbalances and metabolic disturbances that need to be managed carefully. Because of the rarity of ACTH-secreting PNETs, consensus statements such as the “Consensus guidelines update for the management of functional p-NETs (F-p-NETs) and non-functional p-NETs (NF-p-NETs)” group all the rare functional PNETs, including other PNETs such as glucagon- and somatostatin- secreting tumors, into one category. Thus, this case report adds to the growing body of literature on the management of these patients (5). Discussion of the case This case report highlights many key principles in the peri-operative management of a rare ACTH-secreting PNET. Firstly, pre-operatively characterization of the type and hormone production of neuroendocrine tumors is important – this allows for proper management and treatment of hormone and electrolyte abnormalities. In the case of our patient, he had an ACTHsecreting PNET. ACTH is a releasing hormone normally secreted by the pituitary gland. Its primary function is to stimulate the release of glucocorticoid steroid hormones from the adrenal cortex. Ectopic ACTH secretion resulting in excessive glucocorticoid production is a very rare cause of Cushing syndrome (6). Patients with Cushing syndrome often present with glucose intolerance or type II diabetes mellitus, owing to glucocorticoids’ antagonistic effects to insulin (6). Excess glucocorticoids have mineralocorticoid activity in the kidneys. This promotes sodium reabsorption and potassium excretion and results in hypokalemia (6). Characterizing the hormone production of 4

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this patient’s tumour allowed for proper peri-operative management of our patient’s glucose levels and potassium levels. Another important management principle is the consideration of carcinoid syndrome. Carcinoid syndrome is a paraneoplastic syndrome that occurs in approximately 19% of patients with neuroendocrine tumors (7). While it is more frequently associated with carcinoid tumors of the gastrointestinal tract and pulmonary tract, it can also result from PNETs. Carcinoid syndromes are characterized by diarrhea, flushing, wheezing, and/or skin lesions; however, more severe manifestations include carcinoid heart disease which occurs in 40% of patients (7). Thus, there should be a low threshold for performing a pre-operative echocardiography in this patient population. Patients are also at risk for a carcinoid crisis. Carcinoid crisis could present with sudden changes in blood pressure – such as a hypertensive crisis from sudden release of catecholamines – excessive flushing, hyperthermia, and bronchospasm (7). Known triggers of carcinoid crises include the induction of anesthesia, minor and major procedures, and tumor manipulation during surgery. Thus, there is an increased risk of precipitating a crisis during the peri-operative period (7). Our patient was given a long-acting somatostatin analogue known as octreotide. Octreotide binds to somatostatin receptors on the PNET to control hormonal output and has been used as prophylaxis against carcinoid crisis (3). It has also been used peri-operatively to prevent the development of pancreatic fistula associated with pancreatic surgery (8). This case report also highlights the importance of a multi-disciplinary team approach to the perioperative management of these cases. Radiological studies are important for evaluation of tumor extent and relation to adjacent anatomical structures; regional and distant metastases; and vascular involvement (9). Consultation of the endocrinology and hematology teams were needed for pre-operative optimization. A vascular surgery team was involved due to the major vascular extensions. In summary, this case highlights the importance of pre-operative tumor characterization, carcinoid crisis prophylaxis, and a multi-disciplinary approach. It also demonstrates the significant role of the anesthesiologist in maintaining homeostasis in patients with complex metabolic derangements and significant blood loss. Consent This case report is published with written consent from the patient. Acknowledgements We would like to thank Toni Tidy in the Anesthesia Research department for facilitating patient consent.

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References 1.

Genetic and Rare Diseases Information Center: U.S. Department of Health & Human Sciences. Neuroendocrine tumor [Internet]. Gaithersburg, Maryland: Genetic and Rare Diseases Information Center; 2019. Available from: https://rarediseases.info.nih.gov/diseases/13445/neuroendocrine-tumor.

Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology. 2008;135:1469-1492.

Kaltsas G, Caplin M, Davies P, et al. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: Pre and Perioperative Therapy in Patients with Neuroendocrine Tumors. Neuroendocrinology. 2017;105: 245-254

Vinik A, Casellini C, Perry RR, et al. Pathophysiology and Treatment of Pancreatic Neuroendocrine Tumors (PNETs): New Developments. South Dartmouth: MDText.com; Inc, 2000.

Falconi M, Eriksson B, Kaltsas G, et al. EConsensus guidelines update for the management of functional p-NETs (F-p-NETs) and non-functional p-NETs (NF-p-NETs). Neuroendocrinology. 2016;103(2):153–171.

Davies M, Hardman J. Anaesthesia and adrenocortical disease. Brit J Anaesth. 2005;5:122126.

Ito T, Lee L, Jensen R. Carcinoid-syndrome: recent advances, current status and controversies. Curr Opin Endocrinol. 2018;25:22-35.

Alghamdi A, Jawas A, Hart R. Use of octreotide for the prevention of pancreatic fistula after elective pancreatic surgery: a systematic review and meta-analysis. Can J Surg. 2007;50:459-466.

Sundin A, Vullierme MP, Kaltsas G, Plöckinger U. ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors: radiological examinations. Neuroendocrinology. 2009;90:167-183.

Author biographies April Liu is a final year medical student at McMaster University with an interest in anesthesia. She completed her undergraduate degree in the Health Sciences program at McMaster University as well! Sabarinath Balachandran Nair is a staff interventional radiologist at Hamilton Health Sciences, mainly practicing at the Juravinski Hospital.

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Saeda Nair is a staff anesthesiologist at Hamilton Health Sciences, practicing at both the Hamilton General Hospital and Juravinski Hospital.

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Case Report

Coexistence of Bankart lesion and adhesive capsulitis in two shoulders: A Case Report Hettiarachchige Diluksha Prasad Jayawardana Faculty of Medicine – University of Colombo, Colombo, Sri Lanka

Abstract Bankart lesion is a critical anatomical lesion in patients with recurrent anterior shoulder dislocation. It is successfully managed arthroscopically with the aim of satisfactory clinical and functional outcomes. Whereas frozen shoulder is common among the female population with agonizing pain and functional disability which usually gets better over years. The treatment is mainly focused on controlling pain, restoration of range of movements and strengthening the joint by conservative treatment, failing which arthroscopy will be the last resort of management with favorable postoperative outcomes. A 45-year-old Asian male presented to the hospital with a 10-year history of recurrent right anterior shoulder dislocation and a 2-year history of left shoulder joint pain which was aggravated by movement of left shoulder. The special tests on right shoulder were suggestive of glenohumeral instability, whereas on left shoulder they showed supraspinatus injury with subacromial bursa or rotator cuff impingement. Recent Magnetic resonance imaging of right shoulder revealed evidence of Hill-Sachs lesion of the humeral head with soft tissue Bankart lesion of the labrum. An ultrasound scan of the left shoulder revealed evidence of a partial tear of supraspinatus tendon just proximal to its attachment. After conservative treatments failed, the patient received arthroscopic right shoulder joint stabilization and arthroscopic release of the left shoulder joint capsule. The patient was able to resume his daily activities as usual after completion of a 6-month long recovery program. A patient with simultaneous Bankart lesion and adhesive capsulitis in two shoulders is a rare presentation to clinical practice. Even though the outcomes were excellent following arthroscopic management, further studies are required to design standard treatment protocols for patients with coexistence of these two pathologies.

Keywords: Frozen shoulder, Bankart lesion, Hill-Sachs lesion, Arthroscopy, Physiotherapy, Shoulder joint

Corresponding author: dilukshaprasad@gmail.com

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Introduction The glenohumeral joint is an innately unstable ball-and-socket joint with complex anatomy and a large range of movements. Though its stability is maintained by an anatomical arrangement of soft tissue, muscle, and bone, it remains the most dislocated joint in the human body. Over 90% of glenohumeral dislocations are anteroinferior (1). Several key risk factors predispose to recurrent shoulder instability, including male sex, age <40 years at first presentation, joint hypermobility, and greater tuberosity fractures of the humeral head (2). The Bankart lesion is the most common sequelae of anteroinferior shoulder dislocation. There are two types of Bankart lesions: soft-tissue Bankart lesions are tears of the anteroinferior labrum and capsule, whereas bony Bankart lesions involve a fracture of the anteroinferior glenoid rim (3). Furthermore, compression fractures of the posterosuperior humeral head called Hill-Sachs lesions often arise from anterior shoulder dislocations. These lesions cause capsular laxity and decrease congruity between the humeral head and glenoid fossa, and may lead to recurrent shoulder dislocations. Arthroscopic stabilization is the most effective treatment for recurrent shoulder instability and is associated with low complication rates when performed under strict aseptic technique (4). On the other hand, adhesive capsulitis is a chronic inflammatory disease that presents with pain and stiffness of the shoulder (5). It mainly affects individuals between 40-70 years of age and is more common among females (6). Adhesive capsulitis can be classified as either idiopathic/primary, or secondary; most cases are idiopathic. Although frozen shoulder is often a self-limiting disease, various treatment options are available including physical therapy, nonsteroidal anti-inflammatory drugs, corticosteroids, electrical stimulation, shoulder manipulation, hydrodilation, and arthroscopic capsular release (7). I present the case of a 45-year-old male patient with a coexistence of Bankart lesion and adhesive capsulitis in two shoulders who underwent arthroscopic Bankart repair and capsular release. Case presentation A 45- year-old, Asian male presented to the hospital with a history of recurrent right anterior shoulder dislocation. Ten years ago, he had fallen on his outstretched right hand with the elbow extended and shoulder hyper-flexed above the head. He described immediate, intense pain and deformity of the right shoulder. However, his symptoms decreased after spontaneous reduction of the glenohumeral joint which occurred while lifting his right arm. He subsequently had several episodes of right shoulder dislocation even while sleeping, all of which spontaneously reduced. The patient also had a 2-year history of insidious onset dull left shoulder pain which radiated down the left arm and was aggravated by movement of the shoulder. There was no history of trauma or surgery to the left shoulder. He did not report any allergies or psychoactive substance use. The patient’s activities of daily living and social activities had been significantly disturbed due to fear of impending right shoulder joint dislocation and stiffness of the left 9

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shoulder joint. Conservative management with ayurvedic treatment had failed to improve his quality of life. Physical exam On inspection, the shoulders were symmetrical. There was restricted arm swinging on the left side and limited flexion and abduction on the right. The special tests on right shoulder were suggestive of glenohumeral instability, whereas on left shoulder they showed supraspinatus injury with subacromial bursa or rotator cuff impingement (Table 1). The neurovascular examination of the upper limbs and cervical spine was normal. Table 1. Summary of the results of special tests on shoulder joints examination.

Diagnosis Magnetic resonance imaging (MRI) of the right shoulder revealed a Hill-Sachs lesion of the humeral head with a soft tissue Bankart lesion of the labrum (Figure 1). Therefore, it was decided to perform arthroscopic Bankart repair with stabilization of the shoulder joint using three shuttling suture anchors. An ultrasound of the left shoulder revealed a partial tear of the supraspinatus tendon just proximal to its attachment without evidence of bursitis, tendinitis, or calcification of the joint. Therefore, supraspinatus tendinitis associated with adhesive capsulitis was diagnosed, and arthroscopic release of the capsule was scheduled to be performed after the conclusion of physical therapy for the right shoulder.

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Figure 1. Magnetic Resonance Imaging showing Hill-Sachs lesion (red arrow) and Bankart lesion (green arrow). Management After performing diagnostic arthroscopy, a Hill-Sachs deformity and soft tissue Bankart lesion of the right labrum were identified (Figure 2). Then, the arthroscope was placed through an anterior-superior portal to mobilize the anterior-inferior capsulolabral complex. Finally, shoulder stability was achieved with three shuttling suture anchors placed at the 5.30-6.00, 4.30, and 3.003.30 clock positions. The patient’s arm was placed in a sling postoperatively. He was instructed to wear a shoulder immobilizer for four weeks while beginning passive motion exercises. Supervised physical therapy was then initiated, with active and active-assisted range of motion. Strengthening exercises began eight weeks postoperatively. The patient was able to return to daily activities while maintaining strength, mobility, and stability of the right shoulder three months postoperatively.

Figure 2. Right shoulder in the beach chair position shows the arthroscopic view of soft tissue Bankart lesion of the labrum (blue arrow).

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Once the patient was able to perform daily tasks without limitation using the right shoulder (approximately four months postoperatively), he presented for left arthroscopic capsular release. During diagnostic arthroscopy, a tight calcified capsule with minor tears in the supraspinatus tendon was identified. A partial synovectomy over the long head of biceps, rotator cuff, anterior superior capsule, coracohumeral ligament, and superior glenohumeral ligament was performed to adequately release the capsule. Hypertrophic and calcified tissues were then removed using a shaver (Figure 3). Finally, manipulation under anesthesia was performed, and the upper limb was placed in a sling. The patient was discharged following an uncomplicated postoperative period. He participated in six weeks of physical therapy and his left shoulder pain and activities of daily living improved gradually. The patient was able to resume his daily activities as usual after completion of a 6-month long recovery program.

Figure 3. Left shoulder in the beach chair position shows shaving of the hypertrophic and calcified tissue (yellow arrow).

Discussion A patient with simultaneous Bankart lesion and adhesive capsulitis in two shoulders has not been reported in the literature to date (8). Because of this patient’s prolonged history of disability and combined pathology, he was offered arthroscopic treatment for both shoulders to minimize damage and maximize the chance of regaining full motion. The next challenge was determining which arthroscopic procedure to perform first. For that, we considered the possible sequelae of each pathology was as well as the duration of rehabilitation after each procedure: recovery is usually 12-22 weeks for arthroscopic Bankart repair, and 12-16 weeks for arthroscopic capsular release (9,10). Because of the risk of brachial plexus injury and rotator cuff tears following recurrent shoulder dislocations, it was decided to perform the arthroscopic Bankart repair first. The foremost limitation of this case report is our inability to make treatment recommendations based on a single patient’s experience. Staging this kind of treatment can vary from patient to patient according to their clinical picture. Although we identified patient age and 12

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level of motivation to return to work as key factors influencing the length of the rehabilitation program, further studies are needed to identify such factors to make better clinical judgments for this kind of situation. Conclusion In this particular case, the patient had a Bankart lesion in his right shoulder and adhesive capsulitis in the left. Both pathologies were treated by standard arthroscopic procedures with staged treatment. Even though the outcomes were excellent, further studies are required to design standard treatment protocols for patients with coexistence of these two pathologies.

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References 1.

Smith TO. Immobilisation following traumatic anterior glenohumeral joint dislocation: a literature review. Injury. 2006 Mar;37(3):228-37.

Olds M, Ellis R, Donaldson K, Parmar P, Kersten P. Risk factors which predispose first time traumatic anterior shoulder dislocations to recurrent instability in adults: a systematic review and meta-analysis. Br J Sports Med. 2015 Jul;49(14):913-22.

Kompel AJ, Li X, Guermazi A, Murakami AM. Radiographic Evaluation of Patients with Anterior Shoulder Instability. Curr Rev Musculoskelet Med. 2017 Dec;10(4):425-433.

Levy DM, Cole BJ, Bach BR Jr. History of surgical intervention of anterior shoulder instability. J Shoulder Elbow Surg. 2016 Jun;25(6):e139-50.

Tamai K, Akutsu M, Yano Y. Primary frozen shoulder: brief review of pathology and imaging abnormalities. J Orthop Sci. 2014 Jan;19(1):1-5.

Wong PLK, Tan HCA. A review on frozen shoulder. Singapore Med J 2010; 51(9): 694697.

Neviaser AS, Hannafin JA. Adhesive capsulitis: a review of current treatment. Am J Sports Med. 2010 Nov;38(11):2346-56.

Matsuki K, Sugaya H. Complications after arthroscopic labral repair for shoulder instability. Curr Rev Musculoskelet Med. 2015 Mar;8(1):83-58.

Carroll SPTD. Treatment of a Bankart Lesion Repair with Adhesive Capsulitis: A Modified Protocol. Capstone Project. Faculty of the Department of Physical Therapy, Sage Graduate School. 2009 May.

10.

Sharma S, Jacobs L. Management of frozen shoulder – conservative vs surgical?. Ann R Coll Surg Engl. 2011 Jul; 93(5):343-6.

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Case Report

A rare presentation of autoimmune limbic encephalitis with anti-Yo antibodies: Case report Eva Liu1, Janhavi Patel1, Alicia Mattia2, and Han-Oh Chung2 1 2

Undergraduate Medicine, Michael G. DeGroote School of Medicine, Hamilton, Canada McMaster University, Hamilton, Canada

Abstract Introduction: Paraneoplastic limbic encephalitis is a non-metastatic complication of malignant disease characterized by subacute neuropsychiatric symptoms and short-term memory deficits. Case: We present an atypical case of a 38-year-old, previously healthy female with recurrent seizures, severe persistent short-term memory loss, and emotional lability. The patient was diagnosed with autoimmune limbic encephalitis confirmed by magnetic resonance imaging findings and positive anti-Yo antibodies. She screened negative for occult malignancies. The patient responded to daily prednisone and intravenous immunoglobulins and her cognitive deficits were resolved. Conclusion: This is an unusual case of autoimmune encephalitis as anti-Yo antibodies are typically associated with cerebellar dysfunction. Our patient’s case adds to the one other published case showing induction of limbic encephalitis due to anti-Yo antibodies, and prompts consideration of paraneoplastic anti-Yo limbic encephalitis as a rare cause of symptoms in patients with limbic encephalitis-like symptoms and no known etiology. Keywords: Paraneoplastic syndrome, Encephalitis, Anti-Yo antibodies Corresponding author: hanoh.chung@mcmaster.ca

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Introduction Autoimmune encephalitis is a rare disease characterized by immune-mediated destruction of neurons in the central nervous system (CNS). Limbic encephalitis is one of the most common phenotypes of autoimmune encephalitis. Patients with limbic encephalitis typically present with subacute neuropsychiatric symptoms including mood and sleep disturbances, seizures, hallucinations, and short-term memory deficits that can progress into dementia (1,2). Paraneoplastic encephalitis is a subtype of autoimmune encephalitis secondary to an immune response as a non-metastatic complication of malignant disease. Paraneoplastic limbic encephalitis occurs in around 1 in 10,000 patients with cancer (3). In many patients, paraneoplastic encephalitis can precede the diagnosis of cancer. Therefore, it is important to screen for malignancy in all patients with autoimmune encephalitis to identify occult tumours. Treatment of underlying malignant disease may also improve the neuropsychiatric symptoms of autoimmune encephalitis (2). In younger patients with autoimmune encephalitis, misdiagnosis is unfortunately common, with symptoms often attributed to psychosis, drug abuse, or malingering (1). Here, we present the case of a previously healthy young adult with new-onset seizures. She was diagnosed with autoimmune limbic encephalitis confirmed by magnetic resonance imaging (MRI) findings. Her case was atypical as she tested positive for anti-Yo antibodies, typically associated with cerebellar degeneration rather than limbic encephalitis (2). Autoimmune encephalitis is an uncommon cause of neuropsychiatric symptoms. This case highlights a rarely seen variant with an atypical presentation of anti-Yo antibody syndrome presenting with a primary limbic encephalitis presentation. Case presentation A 38-year-old female presented to the hospital with acute generalized-onset seizure, confusion, and disorientation. The generalized-onset seizure episode was witnessed and described as lasting five minutes with tonic-clonic (stiffening with twitching or jerking) movements, facial flushing, diaphoresis (sweating), and dilated pupils with no incontinence or tongue biting. In the month leading up to this episode, the patient described episodes of flushing and sweating without any loss of consciousness or seizures. Her past medical history was significant only for anxiety and recreational cannabis use. She had normal development and no history of previous seizures. Her home medications included citalopram and lorazepam. On initial assessment, the patient had mild confusion, but otherwise her physical examination was unremarkable. She was afebrile. On initial neurological review she had appropriate affect, no obvious memory deficit, and normal pupillary function, visual fields, and eye movements. Power, tone, coordination, and gait were also normal. The patient had no symptoms of photophobia or headaches. The patient was discharged home with follow-up with outpatient neurology. 16

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Three months later, the patient returned to hospital with psychosis, seizure, and decreased level of consciousness. Toxicology screen was only positive for tetrahydrocannabinol (THC), the psychoactive substance in marijuana. The patient was admitted to the intensive care unit and continued to have severe persistent short-term memory and cognitive deficits, as well as emotional lability, for the next two weeks with no improvement. Diagnosis The patient presented with a constellation of seizures, severe persistent short-term memory loss, and emotional lability. Pheochromocytoma (a catecholamine-secreting adrenal gland tumour) and carcinoid syndrome (paraneoplastic syndrome secondary to a carcinoid tumour, which often presents as flushing and diarrhea) were suspected on initial presentation due to the patient’s episodes of flushed appearance and diaphoresis during the month leading up to the seizure as well as on presentation. However, the patient tested negative for 24-hour urine metanephrines and 5-hydroxyindolacetic acid. Pheochromocytoma and carcinoid syndrome also did not explain her subsequent short-term memory loss. Marijuana-induced toxicity was suspected based on the patient’s elevated liver enzymes, and positive toxicology screen for THC. There are reports of cannabis-induced transient global amnesia which might have explained her short-term memory loss (4). However, the patient had severe persistent short-term memory loss for over two weeks with no signs of improvement, whereas marijuana-induced amnesia usually does not cause loss of memory for over 48 hours (5). A CNS infection was considered due to elevated leukocytes (18×109/L); however, the patient was afebrile and had no other symptoms of infectious meningoencephalitis such as photophobia and headache. Cerebrospinal fluid (CSF) and serum were sent for Gram stains, cultures, and viral studies (including West Nile IgM, HIV p24 antigen, HIV 1/2 antibodies and HSV-1 and HSV-2), as well as Lyme disease IgM/IgG and VDRL antibody, which were all negative. Other autoimmune encephalitides and CNS vasculitides were also considered but the patient tested negative for anti-NMDA-R antibody (autoimmune encephalitis), non-specific markers of encephalitis including anticardiolipin, ANA, anti-DNA antibody, and markers of ANCA-associated vasculitis (c-ANCA and p-ANCA). Both non-invasive vascular imaging and inflammatory markers did not suggest a pattern of vasculitis. Finally, the MRI revealed hyperintensities in the medial temporal lobes (Figure 1). These findings, with new generalized-onset seizures and prolonged memory loss, prompted the consideration of limbic encephalitis. A lack of CSF pleocytosis and normal CSF protein level, along with a negative anti-NMDA-R antibody test, prompted a search for more unusual causes of limbic encephalitis. The patient’s paraneoplastic panel returned positive for anti-Yo antibodies confirmed with western blot analysis, with 100% sensitivity and 100% specificity as per the manufacturer-validated test characteristics (6).

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Figure 1. T2-weighted fluid-attenuated inversion recovery MRI showed hyperintensities (arrows) in the medial and posterior temporal lobes. This is a finding suggestive of limbic encephalitis. Since the patient tested positive for the anti-Yo paraneoplastic antibody, she was investigated for occult malignancies. Screening computerized tomography (CT) scan of her chest, abdomen, and pelvis, and an ultrasound of her abdomen and pelvis, showed no findings of malignancy. A screening tumour marker panel was negative, including carbohydrate antigen 199, carcinoembryonic antigen, and cancer antigen 125. A subsequent screening mammogram showed asymmetric densities in both breasts. Follow-up ultrasound testing revealed complex cysts in the right breast and hypoechoic nodules thought to be fibroadenoma. Management Following a clinical diagnosis of limbic encephalitis, the patient was treated using the BrainWorks Antibody-Mediated Inflammatory Brain Disease protocol which includes daily prednisone and intravenous immunoglobulin (IVIG) to suppress the autoimmune response (7). The patient was also started on antiepileptic therapy including lamotrigine, clonazepam, and clobazam. Lamotrigine is an anticonvulsant that selectively inhibits sodium channels. Clonazepam and clobazam are anticonvulsants that are part of the benzodiazepine class. The patient’s symptoms improved with treatment, and her cognitive deficits resolved. Outcome and follow-up The patient was discharged after 19 days in the hospital with outpatient neurology follow-up. Her Montreal Cognitive Assessment (MoCA) score was 29/30 two months post-discharge. A

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repeat MRI six months after treatment revealed almost complete resolution of the abnormalities. A repeat electroencephalogram (EEG) showed normal features. The patient’s memory deficits and mood disturbances improved, but she continues to have rare focal seizures. Repeat paraneoplastic antibodies were negative, including anti-Yo antibodies. Repeat anti-NMDA-R antibodies have been negative in the serum and CSF. Discussion Paraneoplastic limbic encephalitis is a rare non-metastatic complication of malignancy characterized by immune-mediated destruction of neurons. Patients typically present with subacute neuropsychiatric symptoms including mood and sleep disturbances, seizures, hallucinations, and short-term memory deficits that can progress into dementia (1,2). The diagnosis of paraneoplastic limbic encephalitis is based on a combination of clinical symptoms and paraneoplastic antibodies, as well as MRI and EEG findings. Fluid-attenuated inversion recovery (FLAIR) MRI will show hyperintense regions in the medial temporal lobe in 70–80% of patients with limbic encephalitis (2). EEG can show epileptic or generalized slow activity in the temporal lobes. There are a variety of autoimmune antibodies associated with limbic encephalitis, including those against extracellular antigens such as NMDA-R and LGI1 and intracellular antigens such as anti-Hu and anti-Ma2. It is worth noting that approximately 40– 50% of patients with clinical symptoms of limbic encephalitis will test negative for paraneoplastic antibodies (2). Limbic encephalitis is also rarely associated with anti-Yo antibodies (2). Our patient showed classic signs of limbic encephalitis including seizures, mood disturbances, and short-term memory deficits. This is correlated with MRI findings of hyperintense signals in the medial temporal lobes. She tested positive for anti-Yo antibodies, but not other antibodies commonly associated with limbic encephalitis such as anti-Hu and antiNMDA-R. Furthermore, our patient demonstrated positive response to immunosuppression with IVIG and corticosteroids. In approximately 70% of patients with paraneoplastic limbic encephalitis, neurological symptoms will be the first presentation of malignancy (2). Therefore, all patients diagnosed with paraneoplastic limbic encephalitis should be screened for occult tumours using chest and abdominal CT scans, and pelvic ultrasound repeated at increasing intervals to screen for occult tumours. Approximately 70–80% of patients with paraneoplastic neurological syndromes will screen positive for cancer upon imaging (2). Early detection and treatment of malignancy is important for patient recovery. From our literature search for anti-Yo antibodies and limbic encephalitis, we were able to find only one other case describing a 61-year-old patient presenting with limbic encephalitis, colon adenocarcinoma, and anti-Yo antibodies (8). The patient was not responsive to treatment and remained ventilator-dependent in a permanent vegetative state with no improvement in neurological status (8). The similarities between the two cases is that both patients presented with neurological disturbances, seizures, hyperglycemia, and metabolic acidosis. They also had findings suggestive of limbic encephalitis on MRI and tested positive for anti-Yo antibodies. The 19

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difference between the cases is that our patient is a younger individual, with no currently detectable occult cancers on imaging. Furthermore, our patient responded to corticosteroids and IVIG with improvement in short-term memory and cognition, while the other patient remained in a vegetative state. Nevertheless, these two cases indicate that anti-Yo antibodies may lead to limbic encephalitis in rare circumstances.

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References 1.

Dalmau J, Bataller L. Clinical and immunological diversity of limbic encephalitis: a model for paraneoplastic neurologic disorders. Hematol Oncol Clin North Am. 2006;20(6):131935.

Dalmau J, Rosenfeld MR. Paraneoplastic syndromes of the CNS. Lancet Neurol. 2008;7(4):327-40.

Darnell RB, Posner JB. Paraneoplastic syndromes involving the nervous system. N Engl J Med. 2003;349:1543–54.

Shukla P, Moore U. Marijuana-Induced Transient Global Amnesia. South Med J. 2004; 97(8):782-4.

Curran HV, Brignell C, Fletcher S, Middleton P, Henry J. Cognitive and subjective doseresponse effects of acute oral Delta 9- tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology (Berl). 2002;164(1):61–70.

EUROLINE Neuronal Antigens Profile 21 (IgG). EUROLINE DL 1111-1601-21 G; 6–7.

The International Inflammatory Brain Disease Outcome Study. Antibody-Mediated Inflammatory Brain Disease [Internet]. Toronto: 2015 [cited 2020 April 23]. Available from: http://www.sickkids.ca/PDFs/Research/BrainWorks/63976Antibody%20IBrainD.pdf

Adam VN, Budinčević H, Mršić V, Stojčić EG, Matolić M, Markić A. Paraneoplastic limbic encephalitis in a patient with adenocarcinoma of the colon: a case report. J Clin Anesth. 2013;25(6):491-5.

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Case Report

High-Dose Steroids and Pentoxifylline in MethanolInduced Optic Neuropathy: A Case Report and Review of the Literature Keean Nanji1 MD, Alex Pozdnyakov2 MD, Teresa Semalulu2 MD, Ameen Patel2 MB, FRCP(C), FACP 1 2

McMaster University, Department of Surgery, Division of Ophthalmology McMaster University, Department of Internal Medicine

Abstract Acute methanol poisoning is known to cause significant neurological and ophthalmological sequelae. There are case series and case reports documenting the improvement of visual impairment with high-dose intravenous steroids, pentoxifylline and supportive therapy; however, there currently lacks high-quality evidence for the treatment of methanol-induced visual impairment. This article summarizes a case of methanol poisoning, the attempt to salvage vision, and summarizes the available literature regarding the management of methanol optic neuropathy. Keywords: Methanol toxicity, Optic neuropathy, Pentoxifylline, Visual impairment Corresponding author: keean.nanji@medportal.ca

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Introduction Acute methanol poisoning treatment algorithms provide strategies to clear toxic levels of methanol metabolites and manage high anion gap metabolic acidosis to prevent neurological and ophthalmological sequelae. However, there are no evidence-based interventions aimed at restoring methanol-related impairment of visual function. Methanol toxicity is primarily attributed to the effects of its metabolite, formic acid. The accumulation of formic acid interferes with mitochondrial cytochrome oxidase and causes hypoxia, resulting in retinal and optic nerve toxicity (1). Case series and reports suggest potential benefits from the use of intravenous steroids and pentoxifylline for methanol-induced optic neuropathy (2-4). This case report describes a patient with methanol-related vision loss who was treated with high-dose intravenous steroids, pentoxifylline, and supportive therapy to salvage his vision. Case Presentation A 70-year-old male presented to his local hospital with a decreased level of consciousness and new-onset decreased visual acuity. Prior to his visit, he engaged in four days of binge drinking, during which he ingested approximately 150 mL of methanol. He started consuming methanol 72 hours prior to presentation and stopped 24 hours prior to arrival at his local emergency department (ED). The onset of visual changes occurred approximately 36 hours after he started to consume methanol. On presentation to his local hospital, he was afebrile, tachycardic and hypertensive. He was given 100 mEq of bicarbonate, 1 L of normal saline, 0.5 mg of midazolam and was transferred to our tertiary care center. His lab values on presentation to his local hospital and to our center can be found in Table 1. A CT head showed no evidence of acute intracranial abnormalities. An ECG demonstrated a prolonged QTc of 467 ms. The patient was given fomepizole, leucovorin, thiamine and started on hemodialysis. Table 1. Lab values of our patient on initial presentation and on presentation to our care center. On presentation to his local ED On presentation to our ED Sodium (mmol/L) 136 134 Chloride (mmol/L) 100 104 Bicarbonate (mmol/L) 5 5 Anion Gap (mmol/L) 31 25 Lactate (mmol/L) 11.6 2.5 pH 6.89 7.17 Osmolar Gap (mOsm/L) Not obtained 41.7 The patient’s initial bilateral best-corrected visual acuity (BCVA) was to hand motion bilaterally. Intraocular pressures were 26 and 19 mmHg in the right and left eyes respectively. Pupils were fixed and not reactive to light. Anterior segment examination revealed bilateral 2+ nuclear sclerotic cataracts. Posterior segment examination revealed a bilateral cup to disc ratio of 0.5. On day 1, his BCVA decreased to light perception bilaterally. 23

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By hospital day 5 he was systemically well but had experienced no improvement in visual acuity. After multiple discussions with the patient and his wife, and based on our literature review of reported benefits (2,3), he was treated with IV methylprednisolone 1g daily for 3 days followed by 40mg of oral prednisone as well as a 6-week course of 400 mg of pentoxifylline, 1000 mg of vitamin B12, 2000 U of Vitamin D and 1250 mg of calcium carbonate. By hospital day 11, six days post initiation of steroids, his BCVA remained to light perception bilaterally, his pupils remained unreactive to light. and posterior segment examination revealed a bilateral cup-to-disc ratio of 0.1 with no pallor. Optical coherence tomography (OCT) through the retinal nerve fiber layer (RNFL) showed an average thickness of 129 microns in the right and 140 microns in the left. There was no improvement in visual acuity 37 days following hospital admission and 32 days after starting the steroids. His pupils were persistently nonreactive to light and examination revealed bilateral cup-to-disc ratios of 0.5 without nerve pallor. OCT through the RNFL revealed a thickness of 89 and 100 microns in the right and left eyes respectively. The initial thickening of the RNFL followed by subsequent thinning is characteristic of acute swelling followed by progressive atrophy seen in methanol optic neuropathy (5). Discussion We describe a case of methanol toxicity with severe visual impairment that did not improve following hemodialysis and treatment with high-dose steroids, pentoxifylline, and supportive therapy. The patient presented to the emergency department in severe metabolic acidosis with a pH of 6.89. Our patient’s course was consistent with the clinical course of methanol poisoning reported in the literature which correlates the severity of ocular changes to the degree of acidosis (6) and which suggests an initial pH of less than 7.2 is associated with a poor visual prognosis (7). The role of early initiation of steroids remains controversial. As the toxicity from methanol optic neuropathy is mostly inflammatory, it has been hypothesized that high-dose steroids may help prevent blindness by inhibiting the demyelinating process (4). Table 2 summarizes pertinent findings from the current literature exploring steroids and supportive management as potential treatments. In a previous case series, six patients treated within three days of methanol ingestion with 1 gram intravenous methylprednisolone daily for four days followed by 10 days of oral prednisone all experienced significant improvements in BCVA (4). Of note, this report did not comment on the subjects’ presenting pH. In a review evaluating 19 patients with pH levels varying from 6.47-7.30, Liu et al. found that patients who experienced a complete recovery had shorter durations of acidosis (8). In contrast, a review of 97 patients with pH levels between 6.82 and 7.37 concluded that early presentation did not seem to significantly alter the course of visual recovery (7). A case series published by Shukla et al. likewise found no significant relationship between time of treatment following poisoning and visual outcome among 17 patients presenting between 6 and 45 days following methanol ingestion (2). Notably, in addition to 1g methylprednisolone for 3 days followed by oral prednisone, these patients received one week of hydroxycobalamine as well as 6 weeks of cyclandelate and pentoxifylline, 24

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suggesting a potential benefit to supportive therapy as a supplement to steroid treatment. Pentoxifylline is a phosphodiesterase inhibitor with rheologic action. It decreases the viscosity of the blood and improves microcirculation. It is hypothesized that pentoxifylline may augment axon regeneration following injury (9). In addition to the findings of the aforementioned case series published by Shukla et al. (2), there exists a modest body of evidence supporting a potential therapeutic role for pentoxifylline therapy in treating a variety of optic nerve pathologies. For instance, in a small randomized control trial by Khan et al., treatment with pentoxifylline resulted in improved BCVA in cases of optic atrophy (9) Additionally, Chahal et al. described a case reporting on potential benefits of pentoxifylline in radiation-induced optic neuropathy (10). While pentoxifylline in combination with steroids and supportive therapy was not beneficial in our case, further investigation is warranted. In contrast to previous reports which demonstrate a potential benefit from the use of intravenous steroids, pentoxifylline and supportive therapy for methanol-induced optic neuropathy, the results of our case suggest limited benefit in patients with severe acidosis who do not present in a timely manner to a health care setting. Ultimately, the risks and benefits of these treatments must be evaluated on a case-by-case basis to decide what is best for each patient.

Declaration of interests The authors have no potential conflicts of interests to disclose.

Patient consent Consent for this case report was given by the patient on July 24th, 2019.

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Table 2: Summary of studies incorporating the use of corticosteroids in the management of acute alcohol toxic ingestion Study

Design

Intervention

Shukla M et al. (2006)2

Case series

•

• • •

Abrish ami M et al. (2011)4

Case series

•

1 gram IV methylprednisolone in 500 ml ringers lactate over 2 hours on days 1-3, then 40 mg of oral prednisolone for 14 day followed by a 4-6 week taper. Oral cyclenelate (400 mg) once daily for 6 weeks. IM hyroxycobalamine (1.5 ml) once daily for 1 week. oral pentoxyphylline (400 mg) once daily for 6 weeks. 250 mg IV methyl prednisolone every 6 h for 4 days, then 1 mg/kg of oral prednisolone for 10 days.

Inclusion Criteria (sample size) Sudden onset of blurred vision after alcohol intake, followed by severe loss of vision with semi- dilated or dilated pupil in most.

Chahal HS et al (2013)9

Doubleblind RCT

Case report

Treatment group: oral pentoxifylline ≥ 6 weeks (16-18 mg/kg body weight given in two equal doses). • Control group: placebo for same duration. Anti-glaucoma medications were given to all patients with glaucomatous optic atrophy • 6 mg of dexamethasone, 400 mg of pentoxifylline and 400 IU of vitamin E, each given 3 times per day for 14 days, then dexamethasone tapered over 6 weeks. Pentoxifylline and vitamin E given for a total of 6 months. •

Comments

Baseline: • Mean BCVA of 0.86±0.08 in the right eye and 0.93±0.1 in the left eye (using the logMAR scale). • Mean macular thickness (225.2 – 24.83 in the RE and 229.1 – 19.56 in the LE). • Optic disc swelling in 5 patients. • Nerve fiber layer edema in 4 patients. Following treatment: • Mean BCVA of 0.33±0.18 in the RE and 0.29±0.2 in LE. • Difference between baseline and after treatment BCVA (p=0.008 and p=0.003, respectively). Mean macular thickness and cup-to-disc ratio unchanged. • Treatment group: BCVA at baseline and 6 months were 1.35 ± 0.44 and 0.75 ± 0.45 (p=0.002). • Control group: BCVA at baseline and 6 months were 1.32 ± 0.42 and 1.31 ± 0.42 (p=0.157). • Treatment has no effect on RAPD and fundus pictures.

All males, mean age 26.34±2.7 years.

(n = 17)

History of sudden visual loss following ingestion of homemade alcoholic beverages. (n = 6)

Khan P et al. (2013)8

Vision Related Select Results Outcomes VA • 1 Week: 10/17 patients showed improvement in VA by one Snellen’s line. • 1 Month: 5 cases that did not show any visual recovery at 1 week showed gain in VA by one or more Snellen’s lines. • 3 Months: 16/17 patients showed good visual recovery (1 previously improved case showed deterioration of VA).

Diagnosis of optic atrophy (from any cause) of less than one year duration.

BCVA, optical coherent tomography of macula and optic nerve head, fundus photo, complete ophthalmolo gic exam of the patients.

BCVA, pupillary reaction, RAPD, fundus pictures.

(n = 15 patients; 30 eyes) Patient with radiation optic neuropathy following gamma knife therapy for partially resected pituitary tumour.

• •

•

Baseline: counting fingers in the right eye, 20/20 in the left eye, RAPD. 2 weeks: VA was 20/40 in the right eye, with marked improvement in the right visual field. 6 weeks: 20/40 in the right eye, with further improvement in the visual field. 18 weeks: 20/25 in the right eye.

• (n = 1) Abbreviations: BCVA, Best Corrected Visual Acuity; NA, Not Applicable; RAPD, Relative Afferent Pupillary Defect; VA, Visual Acuity

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References 1.

Liesivuori J, Savolainen H. Methanol and formic acid toxicity: biochemical mechanisms. Pharmacol Toxicol. 1991 Sep;69(3):157-63.

Shukla M, Shikoh I, Saleem A. Intravenous methylprednisolone could salvage vision in methyl alcohol poisoning. Indian J Ophthalmol. 2006 Mar;54(1):68-9.

Sodhi PK, Goyal JL, Mehta DK. Methanol-induced optic neuropathy: treatment with intravenous high dose steroids. Int J Clin Pract. 2001 Nov;55(9):599-602.

Abrishami M, Khalifeh M, Shoayb M, Abrishami M. Therapeutic effects of high-dose intravenous prednisolone in methanol-induced toxic optic neuropathy. J Ocul Pharmacol Ther. 2011 Jun;27(3):261-3.

Nurieva O, Diblik P, Kuthan P, Sklenka P, Meliska M, Bydzovsky J, et al. Progressive Chronic Retinal Axonal Loss Following Acute Methanol-induced Optic Neuropathy: FourYear Prospective Cohort Study. Am J Ophthalmol. 2018 Jul;191:100-115. doi: 10.1016/j.ajo.2018.04.015.

Shah S, Pandey V, Thakore N, Mehta I. Study of 63 cases of methyl alcohol poisoning (hooch tragedy in Ahmedabad). J Assoc Physicians India. 2012 May;60:34-6.

Desai T, Sudhalkar A, Vyas U, Khamar B. Methanol poisoning: predictors of visual outcomes. JAMA Ophthalmol. 2013 Mar;131(3):358-64.

Liu JJ, Daya MR, Carrasquillo O, Kales SN. Prognostic factors in patients with methanol poisoning. J Toxicol Clin Toxicol. 1998;36(3):175-81.

Khan P, Khan L, Awasthi U, Khan A, Siddique Z, Chand R. Pentoxifylline: A Therapeutic Remedy For Optic Neuropathies. J Evol Med Dent Sci 2013;20(2):3516–22.

10.

Chahal HS, Lam A, Khaderi SK. Is pentoxifylline plus vitamin E an effective treatment for radiation-induced optic neuropathy? J Neuroophthalmol. 2013 Mar;33(1):91-3.

Author Biographies 1. Keean Nanji is an ophthalmology resident at McMaster University 2. Alex Pozdnyakov is a graduate of McMaster University’s school of medicine. 3. Dr. Teresa Semalulu is an internal medicine resident at McMaster University. 4. Dr. Ameen Patel is a general internal medicine staff physician at the Juravinski Hospital.

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Review Article

COVID-19: A review on the inflammatory profile of SARS-CoV-2 and the asymptomatic state Devyani Bakshi, Amy Moorehead, Loubna Akhabir, David Putman, Allison Kennedy, Dawn Bowdish, Judah Denburg McMaster University

Abstract The COVID-19 pandemic caused by the novel coronavirus, SARS-CoV-2, has resulted in significant death, disease burden, and panic worldwide. Several studies have determined that COVID-19 is associated with an exaggerated cytokine storm. SARS-CoV-2 induces the proliferation of pro-inflammatory cytokines that results in vascular damage, hypercoagulation, and ultimately respiratory distress. This review presents a detailed and comprehensive look into the inflammatory profile of SARS-CoV-2 on the pulmonary epithelium and discusses immune regulation in the asymptomatic and mildly symptomatic state. In addition, this review highlights possible risk factors that have been correlated with severe COVID-19 disease. Understanding the immunological profile of SARS-CoV-2 is vital to early detection and diagnosis of infected patients. A comprehensive understanding of the SARS-CoV-2 host response may also assist in the development and discovery of therapeutic and preventative agents in the near future. Keywords: COVID-19, Cytokine storm, Immune cell dysfunction, Asymptomatic, Inflammatory pathways, SARS-CoV-2 Corresponding author: devyani.bakshi@medportal.ca

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Introduction Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel RNA enveloped betacoronavirus (1). Outbreaks of COVID-19 began in December 2019 in Wuhan, China (2). SARS-CoV-2 is responsible for the current global Coronavirus Disease 2019 (COVID-19) pandemic. Since then, SARS-CoV-2 has spread aggressively with over 100 million confirmed COVID-19 cases and over 2.5 million deaths globally (3). COVID-19 clinical outcomes are heterogeneous, with some people presenting asymptomatically and others requiring intensive care and external ventilation. While the exact reason for this heterogeneity in disease outcome remains unknown, it is likely due to the interaction between SARS-CoV-2 and the individual host immune response. Human coronaviruses can be categorized as low or high pathogenic subtypes. Low pathogenic coronaviruses infect the upper respiratory tract and cause cold-like symptoms, while highly pathogenic variants predominantly infect lower airways and can cause fatal pneumonia and acute respiratory distress syndrome (ARDS) (1). Most infected patients present with fever, cough, fatigue, and chest tightness. Severe disease is associated with dyspnea, hypoxia, more than 50% lung involvement (as demonstrated on imaging studies), pneumonia (with a bilateral ground-glass appearance on imaging), respiratory failure, and systemic shock (4). Disease progression is associated with an exaggerated host inflammatory response leading to a cytokine storm (1). To further complicate matters, upon infection, the median incubation period is two to seven days, making testing and immediate detection more difficult (5). SARS-CoV-2 has similar characteristics to other highly pathogenic coronaviruses which can also cause ARDS and cytokine storm production. These include SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). SARS-CoV-2 shares over 79% genetic similarity with SARS-CoV and shares some similarity with MERS-CoV; therefore, we can look towards these coronaviruses to learn more about SARS-CoV-2 (6,7). Despite its similarity to SARS-CoV and MERS-CoV, the morbidity and mortality associated with SARS-CoV-2 far surpass those of SARS-CoV and MERS-CoV. With over 34 million global confirmed cases and over one million confirmed global deaths, further investigation into the inflammatory profile and pathophysiology of SARS-CoV-2 remains of utmost importance to understand potential pharmaceutical targets, disease progression, and populations at risk (8). This review comprehensively summarizes the pathophysiology of SARS-CoV-2 and how it interacts with the host immune system to elicit an inflammatory profile and cytokine storm associated with severe COVID-19. In addition, this review explores the possible immunophenotypes of asymptomatic, mildly symptomatic, and presymptomatic SARS-CoV-2 infection to highlight the role of a dysregulated immune system in COVID-19.

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Pathophysiology and cytokine storm Viral entry into cells Similar to SARS-CoV, SARS-CoV-2 employs angiotensin-converting enzyme (ACE) 2 as a receptor for cellular entry (Figure 1) (9). ACE2 is a cell membrane enzyme that plays a role in lowering blood pressure. Hydrolysis of ACE by ACE2 results in reduced production of angiotensin II, a vasoconstrictor peptide, thereby lowering blood pressure. ACE2 is highly expressed in cells of the lungs, arteries, heart, kidney, and intestine(9). Viral entry is contingent on the binding of the surface unit (S1) of the viral spike (S) glycoprotein to ACE2 (10). Viral S glycoprotein binding to ACE2 results in S protein cleavage which facilitates viral entry (10). The binding affinity of the viral SARS-CoV-2 S protein to the ACE2 enzyme is higher than in SARSCoV (9,10). This higher affinity of SARS-CoV-2 could explain the increased pathogenicity, disease severity, and viral replication rate as compared to SARS-CoV (9-11). SARS-CoV-2 cellular entry is also dependent on transmembrane serine protease 2 (TMPRSS2). TMPRSS2 is a serine protease that activates the viral S glycoproteins on SARSCoV-2 through proteolytic cleavage(10). Proteolysis permits refolding of the cell membrane and the energy release required to create stable virus-cell linkages and subsequent viral and host cell membrane fusion(11). TMPRSS2 also facilitates SARS-CoV-2 uptake through ACE2 cleavage (Figure 1) (11). A kinetic study of SARS-CoV-2 inoculation into human intestinal cells resulted in ACE2 downregulation 4-6 days after infection(12). ACE2 downregulation is likely due to TMPRSS2 cleavage and the production of interleukin (IL)-4 and interferon (IFN) 𝛾 (12). TMPRSS2 has also been implicated in the spread of other pathogenic viruses, such as influenza A and MERS-CoV (10). Co-expression of both ACE2 and TMPRSS2 are required for successful SARS-CoV-2 viral entry. ACE2 is thought to be the limiting factor in viral entry as its expression is limited to a transient secretory cell type (13). Both ACE2 and TMPRSS2 are highly expressed on cells of the respiratory tree, particularly nasal and bronchiolar epithelial cells, alveolar epithelial cells type II, goblet, and club cells (9-11,13). This is why SARS-CoV-2 predominantly causes nasopulmonary damage, pneumonia, and eventually ARDS in severe cases and also why disease does not initially affect multiple organ systems. Other cells that also highly express both ACE2 and TMPRSS2 include cells from the cornea, esophagus, ileum, colon, gallbladder, and common bile duct (9). SARS-CoV-2 activity and function have not been extensively studied in these cell sites and structural damage to these cells is not as extensive as cells of the respiratory tree (9). The recruitment of monocytes and APCs Following infection of host nasal epithelial cells, viral replication rate increases as the epithelialendothelial barrier integrity breaks down (14). Infected host cells release damage-associated molecular patterns (DAMPs). Examples of DAMPs include adenosine triphosphate (ATP), 30

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nucleic acids, and oligomers (15). Resident monocytes, neutrophils, and antigen-presenting cells recognize these DAMPs and are recruited to the area of initial infection using chemokines such as CCL3, CXCL10, and monocyte chemoattractant protein 1 (MCP1) (16).

Figure 1. Possible mechanisms contributing to the exaggerated cytokine storm and cellular damage in COVID-19. (A) The SARS-CoV-2 virus enters alveolar epithelial cells through binding of the viral structural spike (S) glycoprotein to angiotensin-converting enzyme 2 (ACE2) receptor. Transmembrane serine protease 2 (TMPRSS2) facilitates viral entry by cleaving ACE2 and activating the SARS-CoV-2 S protein. (B) Infected type I and type II pneumocytes release viral progeny, causing viral titers to rapidly increase. Infected cells also release inflammatory signalling cytokines, such as interleukin (IL)-6, tumour necrosis factor (TNF)-ɑ, IL-1, and interferon (IFN)-Ɣ, which promote the activation of nearby monocytes and lymphocytes. Chemoattractants released by infected cells facilitate the recruitment of macrophages and T-cells to the site of infection. (C) In the late stage of COVID-19 infection, excessive inflammatory cytokine production leads to epithelial and pneumocyte apoptosis. The loss of barrier integrity can lead to alveolar airspace edema and hyaline membrane formation due to fibrotic damage, which may progress to acute respiratory distress syndrome (ARDS).

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Monocyte activation and initial cytokine production Activation of the monocytes triggers the release of pro-inflammatory cytokines (1,16). IL-6, macrophage inflammatory protein 1𝛼 (MIP-1𝛼), tumour necrosis factor (TNF)-𝛼, IFN- 𝛼 and 𝛽, IL-1𝛽, IL-6, and IL-12 have been associated with pulmonary inflammation in COVID-19 (Figure 1) (2,15,17,18). In particular, IL-6 appears to be implicated in the disease progression and cellular damage present in SARS-CoV-2 infection. Plasma IL-6 levels are indicators of disease severity and morbidity in COVID-19 (19). In patients with severe disease, IL-6 is upregulated for 5 to 10 days following infection before tapering down (17). The sustained upregulation of IL-6 is thought to increase endothelial and interstitial nasopulmonary damage, contributing to more severe disease (16,20). IL-6 expression is also significantly correlated with increased expression of other inflammatory markers and acute-phase proteins such as C-reactive protein (CRP), serum amyloid A (SAA), antitrypsin, hepcidin, fibrinogen, and complement proteins (20). Upregulation of these acute phase proteins contributes to thickening of alveolar walls, infiltration of airspaces, and endothelialitis (14). IL-6 may also play a role in increased mucus production because it stimulates mucin gene (MUC5AC and MUC5B) expression in tracheobronchial epithelial cells (9). The release of these inflammatory chemokines and cytokines results in significant airway infiltration and inflammation which manifest as symptoms of COVID-19 (Figure 1). IFN cytokines promote alveolar cell apoptosis through Fas/Fas ligand (FasL) signalling (1). This contributes to a compromised lung epithelial cell barrier causing microvascular leakage and alveolar edema. Interstitial monocyte infiltration and pulmonary edema result in hypoxia and eventually ARDS (14). The accumulation of inflammatory cells and cytokines causes the diffuse the thickening of alveolar walls and leads to impaired diffusion capacity. Eventually, the cytokine storm can circulate systematically to cause multi-organ dysfunction (21). Adaptive T-cell response In addition to the innate immune response, changes in adaptive immune cells have also been implicated in SARS-CoV-2 pathophysiology. Involvement of the adaptive immune response is unique when compared to other respiratory viruses, such as Influenza A and SARS-CoV, which elicit mainly innate immune responses (22). The cytokines expressed in response to SARS-CoV infection, such as IL-1𝛽, IFN-𝛾, IP-10, and MCP1 promote a type 1 helper T-cell (Th1) response (18,21). High titers of IL-6 may be responsible for T helper 17 cell (Th17) differentiation in COVID-19 animal models (21). The involvement of the adaptive immune response is critical in defining outcomes of SARS-CoV-2 disease. T cells react to the spike protein to initiate an adaptive antiviral immune response which functions to upregulate cytotoxic T cells which recognize and eliminate virus-infected cells (3). This robust T-cell mediated immune response prevents viral titers from rising uncontrollably. 32

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Despite T-cell activation in animal and in vitro models, patients with COVID-19 present with marked leukopenia (19). In patients with more severe COVID-19, significant leukopenia was evident as early as 3 days post-infection and persisted thereafter (17). Levels of helper Tcells (cluster of differentiation (CD)3+ and CD4+), cytotoxic T-cells (CD3+ and CD8+), and regulatory T-cells (Tregs) remain low in patients with severe disease (19). Altered APC function and impaired DC migration during infection may result in insufficient T-cell priming and decreased virus-specific T-cell recruitment in the lungs thereby minimizing detection of SARSCoV-2 virions and promoting an unchecked cytokine storm synonymous with severe disease (23). Another possible explanation for the marked leukopenia in COVID-19 includes T-cell exhaustion. In highly inflammatory viral infections like COVID-19, recent immunohistology studies have demonstrated that CD8+ T-cells are unable to sustain long-term activation and enter an ‘exhaustive stage’ (24,25). Exhausted T-cells (Tex) are prone to apoptosis and express apoptotic-specific cell markers such as program cell death marker (PD-1) and T-cell immunoglobulin and mucin domain-3 (Tim-3)(24). Tex demonstrate a decrease in effector function and proliferative capacity which may contribute to the unchecked cytokine storm in COVID-19 (26). Lymphopenia and T-cell exhaustion could contribute to poor prognostic outcomes of COVID-19 as excessive cell death and upregulation of PD-1 contribute to fibrotic and inflammatory changes in the lung parenchyma (3). Dysfunction of coagulation pathways The inflammatory cytokines released during APC activation also activate coagulation pathways, which can lead to disseminated intravascular coagulation (DIC). DIC is a condition associated with microvascular and macrovascular thrombosis that leads to poor blood flow, thereby contributing to multiple organ dysfunction (MODs). Consumption of clotting factors and platelets can lead to hemorrhaging. Although the exact mechanism of this coagulation upregulation remains unknown, it is likely due to upregulation of tissue factor (TF) by activated mononuclear and vascular endothelial factors (2). TF promotes the coagulation cascade which in turn converts the soluble acute phase protein fibrinogen into fibrin, a key concluding step in the coagulation cascade. Furthermore, activated monocytes and dendritic cells also express oxidized phospholipids (OxPLs) which contribute oxidative stress, thereby promoting TF upregulation and thrombosis (14). Therefore, a positive feedback cycle is created in which host cell damage and recruited APCs contribute to peripheral thrombi formation. As such, patients with COVID19 are at high risk for thromboembolic complications such as deep venous thrombosis, pulmonary embolism, and thrombotic arterial complications (27).

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The battle between virus and the immune system Both viral mechanisms and the host response are thought to play a role in the overamplification of the host immune response. SARS-CoV-2 encodes viral proteins, such as non-structural protein (NSP)1, NSP3, and open reading frame 3B (ORF3B). These viral proteins play a role in evading and antagonizing anti-viral IFN responses by inhibiting the activity of IFN regulatory factor 3 (IRF3) and IFN-I(28, 29). Inhibition of early IFN signalling from activated monocytes and host epithelial cells contribute to the evasion of early viral infection and allow viral titer to rise rapidly. To further complicate matters, SARS-CoV-2 possesses a rapid virus replication rate which accelerates pulmonary epithelial damage (1). This push and pull between the virus and host immune response causes endothelial barrier disruption, dysfunctional capillary oxygen transmission, and impaired oxygen transmission which can lead to ARDS (21). SARS-CoV-2 in the asymptomatic, presymptomatic, or mildly symptomatic state Understanding and quantifying the asymptomatic state Despite the ability of SARS-CoV-2 to elicit a cytokine storm and lead to respiratory distress, a percentage of individuals who are infected remain asymptomatic or mildly symptomatic (30). Studies have suggested asymptomatic infection rates between 2% to 41%, but the true value remains elusive because it inevitably includes a portion of presymptomatic individuals (31-33). The exact quantification of the asymptomatic population is further complicated because viral cultures are generally negative for SARS-CoV-2 eight days post-symptom onset, thus limiting the time frame for testing (34). Asymptomatic carriers are classified based on the absence of overt symptoms, such as fever, cough, sneezing, and shortness of breath, at the time of testing or during the preceding 14 days despite the presence of detectable viral load (30). The viral load detected in both asymptomatic or minimally symptomatic patients is not significantly different from symptomatic patients (35,36). Consequently, asymptomatic patients likely have the ability to transmit the virus to uninfected individuals (37,38). Viral load in the upper respiratory tract appears to peak at symptom onset and viral shedding begins 2 or 3 days before symptom onset (38). Since the latent period is shorter than the incubation period (2 to 7 days) for SARS-CoV-2, there is a period of time in which the patient is presymptomatic but infectious (36,39). During the first week following infection, although symptoms may remain minimal or mild, pharyngeal shedding is high so individuals can be infectious before they realize they have COVID-19 (40). This viral transmission pattern is similar to seasonal influenza. Therefore, further investigation into the similarity between influenza and SARS-CoV-2 viral life cycles may shed more light on the infection pattern of SARS-CoV-2. 34

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In addition to the lack of overt symptoms, upon testing, asymptomatic SARS-CoV-2 carriers also have normal or slightly low lymphocytic levels and normal acute-phase inflammatory protein markers, such as CRP levels, indicating no or minimal signs of immune upregulation (41,42). While a portion of these patients are pre-symptomatic and will, in the future, go on to develop overt symptoms and disease, some continue to remain asymptomatic. The asymptomatic and presymptomatic population is difficult to study and quantify. However, this population provides crucial information about the interplay between the host immune system and SARS-CoV-2 infection. Possible mechanisms of asymptomaticity and implications for treatment development The exact mechanism behind the immune regulation of the asymptomatic state remains elusive. It is possible that asymptomatic patients have a high titer of SARS-CoV-2-specific immunoglobulin (Ig)G neutralizing antibodies during the latent period of viral infection. These neutralizing antibodies are primed by asymptomatic primary infection and may protect against future infection. For example, asymptomatic Zika patients had expression of Zika-specific neutralizing IgG2a and IgG2b antibodies in maternal serum which prevented an overexaggerated type I IFN response and minimized viral load upon initial asymptomatic infection (43). Serologic testing in patients with asymptomatic or previously infected patients may shed further insight into this area (44). Current treatments being investigated for COVID-19 include polyclonal antibodies isolated from SARS-CoV-2-infected patients. SARS-CoV cross-reactive antibodies are being explored due to the genetic similarity between the S-proteins of the two coronaviruses (45). Recombinant human monoclonal neutralizing antibodies which bind cells expressing fulllength S proteins of SARS-CoV and SARS-CoV-2 were recently isolated (46-48). This particular antibody targets the S1B receptor-binding domain (RBD) of SARS-CoV and SARS-CoV-2 and may shed more insight into the immunology of SARS-CoV-2 asymptomatic infections or may provide the basis for an effective pharmaceutical treatment (46,48). In SARS-CoV-2 mouse models, these S-protein monoclonal antibodies synergistically protected mice from weight loss, reduced viral load, and decreased pulmonary inflammation (48). Asymptomatic patients provide a unique insight into the interaction of SARS-CoV-2 with the ‘ideal’ immune response and should be investigated. COVID-19 in children Incidences of symptomatic COVID-19 in children have been minimal. Between 2% to 5% confirmed COVID-19 cases are in individuals under 18 years (49). More recent studies have highlighted that risk of infection in pediatric groups is similar to adults but infection is asymptomatic in nature (50,51). Mildly symptomatic profiles in children include nasal congestion, sore throat, sneezing and rhinorrhea, and cough (50). Most of these cases (over 75%) 35

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resolved within 48 hours of hospitalization without intensive care or mechanical ventilation (50). Since ACE2 expression is similar in children and adults, the discrepancy between disease severity in the two age groups is likely due to the pediatric immune system (52). The immature immune system in children may delay or dampen kinetic upregulation of type I IFN responses in children leading to a more mildly symptomatic disease course (52,53). As children are more susceptible to infection by other respiratory viruses, including 𝛽-CoV, they possess a high-titer of multiple neutralizing antibodies which may offer cross-protection against SARS-CoV-2 infection. Further investigation into the immunological profile of SARS-CoV-2 in pediatric cases is necessary to understand the asymptomatic state and may also shed light on protective factors against SARS-CoV-2 infection. An uncommon multi-inflammatory syndrome (MIS) has been described in children with SARS-CoV-2 infection (54). This illness has features of Kawasaki’s disease, toxic shock syndrome, acute abdominal conditions and encephalopathy (55). Children diagnosed with this syndrome are often older (median age of 8 years), have cardiac involvement (up to 80% of patients) and evidence of a cytokine storm (in 92%) (54,56). MIC remains endemic to the pediatric age group although the reason for this remains elusive. MIC is a serious condition; children with MIS require intensive care and mechanical ventilation (56). Factors associated with increased disease severity Although a large number of patients infected with SARS-CoV-2 often recover or are asymptomatic, others experience severe respiratory distress and death. One of the questions that needs to be addressed is whether there are predisposing or presenting factors associated with increased disease severity. Initial studies of COVID-19 patients in Wuhan, China revealed that patients with severe disease often present with signs of respiratory distress upon 2-3 days of hospitalization (20,57). These patients often experience shortness of breath with a respiratory rate (RR) greater than 30 times per minute and oxygen saturation levels of less than 95% in resting state which are all initial signs of ARDS (20). Comparative cytokine kinetic studies in the severe disease group revealed higher levels of CRP, IL-6, IL-10, neutrophil-to-lymphocyte ratio (NLR), fibrinogen, and IFN-𝛾 when compared to the milder group; these differences were sustained for over 10 days of hospitalization before tapering off (20,58). However, these patients were not longitudinally followed up and therefore, disease presentation before hospitalization was not observed and infection kinetics are difficult to pinpoint. Metabolic comorbidities and COVID-19 A significant portion of the patients who experience severe disease (over 25%) often have comorbid diseases, and this percentage is even higher in hospitalized patients (60% to 90%) (59). Examples of common comorbid diseases include hypertension (present in up to 57% of patients), type II diabetes mellitus (up to 34%), cardiovascular disease (up to 30%), chronic kidney disease 36

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(up to 13%), chronic hepatitis B viral infection (up to 5%), and multiple myeloma (up to 3%) (59-62). Not only do these co-morbid chronic pathologies strain the immune system and impair its ability to timely respond to SARS-CoV-2 virus, but some of them also result in basal inflammatory states that may predispose these patients to higher titers of inflammatory cytokines. Chronic metabolic comorbidities may also dampen the immune system by decreasing macrophage and lymphocytic function (60). Older individuals (65 years and older) often have many comorbid conditions, making them disproportionately affected by COVID-19. Mortality from COVID-19 is highest in people 65 years and older (63). Hospitalized COVID-19 patients can also present with atypical symptoms, such as gastrointestinal symptoms, olfactory dysfunction, anosmia, or ageusia (64). Patients with COVID-19 and comorbidities have longer hospitalizations, a higher likelihood of progressing to severe disease (37.6% versus 20.5%), and a higher mortality rate (8.2% versus 5.2%) compared to patients without comorbidities (58,65). Smoking and COVID-19 In addition to metabolic comorbidities, many studies have also highlighted a link between smoking and severe COVID disease (66,67). Studies have reported that between 19% to 25% of patients admitted with COVID are smokers (65,66). ICU admissions and mortality are also higher in COVID patients who are smokers (68). However, data on smoking history (in terms of packs per year and frequency) remains limited and the findings may not be generalizable to the public (67). This link in part may be due to the link between smoking, hypertension, dyslipidemia, and respiratory disorders; therefore, smokers often possess comorbid diseases that increase vulnerability to COVID-19. Smoking also increases ACE2 expression on alveolar epithelial cells, thereby increasing the point of entry receptor necessary for SARS-CoV-2 infection (68 69). In addition, tobacco smoke exposure predisposes individuals to higher levels of nitric oxide (NO) consumption (68), which have been associated with an increase in angiotensin I conversion to angiotensin II through ACE upregulation. Increased angiotensin II levels in turn contribute to higher ACE2 expression (68). Nicotine promotes an increase in inflammasome activity and higher levels of basal IL-2, TNF-𝛼, IL-6, MCP-1, and IL-1 𝛽 levels (68,70). In addition to the inflammatory responses in the lungs, smoking also impairs the tight barrier junction of the lungs, increases oxidative stress, and impairs mucociliary clearance. These alterations in the pulmonary structure and function create an environment ideal for viral replication and infection (70). The lung damage and increase in the basal inflammatory state associated with smoking may likely promote a higher local tissue viral load and development of the cytokine storm seen in SARS-CoV-2 infection. While there have been studies investigating the link between smoking and COVID-19 severity, the effects of vaping and electronic cigarettes on COVID-19 severity remain elusive and must be more extensively researched. This is especially important considering alarmingly increasing rates of vaping amongst youth and young adults.

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Chronic respiratory pathologies in patients with COVID-19 In contrast to the recognizable link between metabolic disorders or smoking and increased COVID-19 severity, chronic respiratory problems, such as COPD and asthma, have been minimally reported as comorbidities in patients with SARS-CoV-2 infections (66,71). Only 10% of people with chronic respiratory problems have tested COVID positive (66). This paradox could be due to underdiagnosis or poor recognition of chronic respiratory disease in patients with COVID-19. Alternatively, a different type of immune response elicited by the chronic disease could promote early detection of the SARS-CoV-2 virus. For example, perhaps in patients with chronic asthma, an early and controlled type I IFN response promotes viral detection and prevents the cytokine storm. However, mortality of patients with comorbid COPD is increased compared to those without it, suggesting against early viral protection (71). A more likely explanation could be that the therapies used by patients with chronic respiratory diseases may prevent an exaggerated immune response and thereby limit disease severity or symptomatic initial infection (71). Inhaled corticosteroids are a mainstay treatment for asthma with up to 75% of asthmatics using inhaled corticosteroid therapeutics. In China, initial management of SARSCoV-2 infection involves the administration of inhaled corticosteroids (71). In vitro murine studies have demonstrated that inhaled corticosteroids and bronchodilators can diminish SARSCoV-2 replication and prevent disease progression (71-73). Early administration of inhaled corticosteroids may prevent viral proliferation and exaggerated cytokine production. Further investigation into the immunology of chronic respiratory disease and SARS-CoV-2 infection may provide more insight into the paradoxical lack of relationship between COVID-19 cases and chronic respiratory conditions. It may also highlight protective immunological therapies against SARS-CoV-2 infection. Conclusion Although there has been a surge of data investigating the inflammatory profile and immune interactions in patients with COVID-19, it is evident that an exaggerated inflammatory response contributes to disease severity. SARS-CoV-2 interactions with immune cells will need to be explored, which is necessary for the effective development of novel therapies and effective clinical therapies. While the majority of the research appears to focus on cytokines and the adaptive immune response, the role of other elements of the innate immune system, such as hemopoietic stem cells and innate lymphoid cells, remains largely unexplored. This review has attempted to categorize the SARS-CoV-2-induced immune response into either a “pro” and “anti” inflammatory nature, however, it is recognized that many cytokines and chemokines are contextual and may elicit varied responses in different environments. More research into longitudinal immune responses pre- and post- SARS-CoV-2 infection could further shed light on the role of these contextual immune modulators.

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In addition to refining our understanding of the immunology of COVID-19, greater investigation into predisposing factors for increased disease severity is required to better understand populations at risk. Asymptomatic and mildly symptomatic patients remain an important reservoir for learning the intricacies between the host immune system and SARS-CoV2. The interactions of SARS-CoV-2 with the immune system have implications for future therapies and treatments. Multiple therapies targeting either the host or virus are currently being investigated and are in clinical trials. SARS-CoV-2 targeting therapies focus on interrupting the viral replication cycle of SARS-CoV-2 (74,75). RNA-dependent RNA polymerase inhibitors, remdesivir and favipiravir, are antiviral drugs currently being used in phase III clinical trials (NCT04252664 and NCT04257656)(76, 77). Anti-inflammatory agents, such as dexamethasone and methylprednisolone, are also being explored and have been shown to reduce rates of mechanical ventilation and mortality in patients with COVID-19 (78-80). The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial (NCT04381936) demonstrated that dexamethasone reduced 28-day mortality in COVID-19 patients (81). However, considering the toxicity of glucocorticoids, the dosage and precise guidelines on their use are not yet established (79). IL-6 is a critical cytokine in the SARS-CoV-2 immune response and has been correlated to disease severity. As such, over a dozen clinical trials are currently exploring monoclonal antibodies against IL-6, tocilizumab and sarilumab, as a treatment for COVID-19 patients (82). Initial results suggest that tocilizumab is effective in symptomatic relief for patients with severe COVID-19 when given in repetitive doses; however, many trials are still ongoing (83). These therapies highlight the importance of understanding the nuances of the host immune response in SARS-CoV-2 pathophysiology to elicit possible pharmacological defences. The information and data collected on SARS-CoV-2 are fragmented and many areas of research need to be pursued to provide a comprehensive picture of this virus. Although it is difficult to conduct research in the midst of a pandemic, the data available from infected patients is invaluable not only for infected patients but also for the general public as a whole. Declaration of competing Interests The authors do not have any competing interests. Acknowledgements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Figure created with BioRender.com.

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Review Article

Safety and risk factors associated with electric scooter use globally: A literature review Michelle Schneeweiss, Mohammed Hassan-Ali, April Kam McMaster University

Abstract Electric kick scooters (e-scooters) are a form of micro-mobility devices that have been implemented in city streets worldwide as a viable travel solution. E-scooter companies have launched in over 100 U.S cities and various international countries, including Europe, Australia and New Zealand. On January 1st, 2020, Ontario launched its pilot program to permit e-scooters onto provincial roads. Due to the implementation and recent growth of this new technology, it is important to evaluate what is already known about e-scooter use and what remains to be discovered. We conducted a literature review to understand the general prevalence of e-scooter usage, common injury patterns, demographics of patients commonly involved in e-scooter injuries, and risk factors associated with injuries. We also sought to understand the current legislation surrounding e-scooter use in Ontario, other provinces across Canada, and other countries. Common injuries included: extremity fractures, facial fractures, lacerations and head injuries (including concussions and intracranial hemorrhages). Most commonly injured riders were men between 20- 40 years old, and our findings indicate that limited helmet use and acute alcohol intoxication may contribute to e-scooter injuries. These findings can help to direct future research questions and prepare primary care and emergency room physicians for the potential surge in e-scooter use here in Ontario, Canada.

Keywords: Electric scooter, E-scooter, Rideshare, Scooter share, Safety, Legislation, Canada, Pediatrics, Pediatric health

Corresponding author: Michelle.schneeweiss@medportal.ca

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Introduction Dockless electric scooters (e-scooters) are battery-powered two- or three-wheel motorized vehicles which can be dropped off and picked up from arbitrary locations in a service area (1). In 2017, Bird launched as the first dockless e-scooter rideshare company. It was promoted as an environmentally friendly form of micro-mobility, and a solution to traffic congestion and the ‘last-minute mile’ problem (2). Today, ride-share companies that provide e-scooters make use of mobile applications that allow users to rent scooters by the minute similar to services like Uber, Lyft, and other taxi companies (1). There are many advantages to e-scooter travel that makes their use attractive. E-scooters are considered convenient. As a form of ‘first-mile/last-mile travel’, they can connect urban users to a transit hub, and allow users to easily cross short distances that are too long to walk but too short for a drive (2). Initiation of e-scooter rental is easy and simply requires riders to engage with the ride-sharing company’s mobile phone app. Users can find a scooter, open their corresponding app, and scan the scooter’s QR code to ‘unlock’ the scooters. After arriving at their destination, users then lock the scooter and end their trip by taking a picture of the QR code. Users can drop off e-scooters ‘almost anywhere’ as long as users follow the parking guidelines set out by the city officials (2). The relatively low cost of e-scooters also makes them an attractive form of transportation (3). Furthermore, e-scooters have been touted as an environmentally friendly mode of transportation, as they run on electric batteries instead of fossil fuels (3). Compared to e-bikes, e-scooters appear to be easier to operate and reportedly feel safer to users (3). According to a study conducted in 2018, 70% of those surveyed across the US view e-scooters positively (4). In another study, 22% of people who had spent time in an area where they saw e-scooters available for rent said they had tried to use one at least once, despite the fact that many riders (27%) said they were uncertain of which traffic laws to follow (5). Over the years, the use of e-scooters has grown in popularity across North America and worldwide (6). However, there are many disadvantages associated with e-scooter use that makes their implementation controversial (3). Reports have shown that e-scooters are often left in unauthorized places, which leads to issues such as blocked pedestrian pathways (3). E-scooters tend to have relatively short battery life (3), require good weather conditions to function properly and are susceptible to damage from bad terrain (3). Moreover, the claim that e-scooters are ecofriendly has also been contested, as the lithium battery needs to be replaced every 300-1000 charges, and many cities are not currently able to process/recycle these batteries appropriately (3). The most troubling drawback of e-scooters is the safety issues surrounding this vehicle. Since the Fall of 2018, at least 1500 injuries have been reported in the United States while using a rentable e-scooter (7), and at least eight resulted in deaths. With these concerns in mind, many Canadians wonder how the introduction of e-scooters will impact the safety of our general and pediatric populations. As the Ontario government recently enacted a pilot project in January 2020 to legalize e-scooters (8), it is critical to evaluate what is already known about this technology. To prepare healthcare providers for the potential surge in this technology, it is important to determine which populations use e-scooters and what 49

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kinds of injuries are associated with their use. Not only will emergency room physicians likely be treating patients that present with these injuries, but there may be a role for primary care physicians to counsel their patients on how to engage with this technology in a safe way. This review will summarize data collected on e-scooter use including prevalence, common injuries, demographics of injured patients and potential risk factors for injuries. Using these results, we will propose areas for future research. Methods First, a comprehensive search of peer-reviewed journals was completed based on a wide range of key terms, including: Power scooter, e-scooter/escooter/electric scooter, mobilized scooter, and scooter share, Canada, safety, legislation, and current use. These terms were combined in various ways, with “AND”, “OR”, and “WITH” commands in between terms to obtain the most narrowly defined and appropriate articles. This process was completed initially through the McMaster University Library search database. Six databases were searched, including Google Scholar, Pubmed, Web of Science, MEDLINE, Embase and CINAHL. Second, a comprehensive search of grey literature was completed to identify publications including annual reports, research reports, working papers, newspaper articles, editorials/commentaries, and government documents. The key terms used to complete the search were the same as those listed above in the search amongst peer-reviewed journals. The search engine used for this process was primarily Google. Finally, the ‘Snowball Method’ was used to identify relevant articles, where the works cited section for each article found was reviewed in order to find additional articles. The reliability and credibility of all articles were considered and evaluated by authors. This evaluation was based on the quality of content, the relevance to the topic, the published year, and the citation frequency (if applicable). In investigations of the identified articles, general themes were identified. Through an iterative process, the authors grouped these themes into four important dimensions using our clinical experience and/or role as educators to guide the analysis. Results Our search process ultimately found 33 articles written from 2018 – 2020. The findings from these articles revealed three major sub-topics: i) expected use and legislation in Ontario and previous use in Canada, ii) previous injuries reported in the literature, and iii) potential risk factors for e-scooter related injuries.

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Expected use and legislation in Ontario and previous use in Canada On January 1st, 2020, Ontario launched its pilot project to permit e-scooters onto provincial roads (8). The pilot project was enacted as a way to “expand business opportunities and help cut down congestion on provincial roads” (8). The goal was to evaluate the use of e-scooters in Ontario over a five-year ‘trial’ period, during which lawmakers will have the ability to examine the general safety of e-scooters and their ability to integrate with local traffic and other vehicles (9). Ultimately, lawmakers will decide at the end of the five-year project if the existing legislation is adequate to appropriately regulate e-scooter use (9). The province has established broad rules and requirements for e-scooters but has left it up to individual municipalities to create and pass bylaws tailored to the local regulation of escooters (9). Province-wide rules indicate that riders must be at least 16 years old and must wear a helmet while driving the vehicles if under 18 years of age (8). The law states that an e-scooter helmet must be made to the standard of a bicycle helmet, rather than one designed to withstand the impact of a collision of a motorcycle (10). E-scooter vehicles must weigh under 45 kilograms (8), must be equipped with a horn or bell, have one white light in the front, one red light in the back, and reflective material on the sides (11). E-scooters are permitted to travel up to a maximum speed of 24km/hr but are not allowed on controlled-access highways (9). Given each municipality’s discretion over which bylaws to enact into regulation, the rules governing the use of e-scooters may vary from municipality to municipality. Therefore, municipalities have the ability to limit and/or ban the use of e-scooters altogether (11). Municipalities that permit e-scooters will be responsible for designating areas where e-scooter use is permitted such as municipal roads including parks and trails, the location of parking spaces, and how e-scooters will be managed in each municipality. Although a best practices document was developed by the ministry to guide individual municipalities in their adoption of e-scooters (9), the sudden proliferation of scooters in city roads has prompted fears that the technology is outpacing regulation (10). The Ministry of Transportation expects that this pilot project will yield enough meaningful evidence on the safety and feasibility of e-scooter use to determine if a permanent framework should be established (8). E-scooters have previously been made available under pilot projects in other provinces, including Quebec and Alberta (12). In September of 2018, a notice of motion was approved in Calgary to implement a two-year dockless bicycle share pilot project, which included the ability to add other shared transportation options (13). In addition to piloting the dockless bicycle share services, the City of Calgary concluded their 16-month pilot program to test the viability of escooters in the city in November 2020 (13). For this pilot project, the city allowed third-party operators with a set number of shared e-scooters, to access city sidewalks, exclusive bicycle lanes and parks and pathways (14). Montreal also introduced e-scooters in June 2019, with the intention to offer more environmentally friendly modes of transportation. Two dockless ridesharing companies, Lime and Bird, were allowed to operate, before the pilot project came to what was expected to be a brief pause for the winter in November 2019 (15). However, in 51

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February 2020, the city of Montreal decided to ultimately ban Lime and Bird e-scooters from the roads after riders kept violating the rules associated with their use (15). The city claimed the scooters were often left abandoned in the middle of high traffic streets, and often left right outside metro stations (15). It was ultimately reported by ministry officials that just 20% of the vehicles were parked in their designated spaces and that the city didn’t want to ‘police escooters’ (15). Sociodemographics and clinical trends of injuries reported in the literature Several case reports and case series completed across the world have characterized the types of injuries, patient demographics and the clinical outcomes commonly associated with e-scooter use. The first scientific study in the United States to assess the types of injuries associated with escooter use was conducted by Trivedi et al. (16). By characterizing the injuries of patients presenting to emergency departments in Southern California over the course of one year, they found that injuries associated with standing electric scooter use were mostly minor but could be severe and costly (16). They noted similar patterns of injury as Segways but pointed out that standing electric scooters were more economic and more accessible to the general public than Segway transporters, and therefore could have a substantially greater impact on public health given their popularity. Trivedi et. al found that riders themselves were most injured, suffering from fractures, head injuries, and soft tissue injuries (32%, 40% and 28%, respectively). These results agreed with the findings of Nellamattathil and Amber, who found that musculoskeletal injuries (with a predilection to the upper extremity) were the most common injury pattern noted (6). On the other hand, Kobayashi et al. found that one-third of patients presenting to level 1 trauma centers in California required operative intervention, (the majority of which were open extremity and/or facial fractures (17). Schlaff et al. found that through the 15-month dockless pilot period in Washington, DC, 13 patients suffered injuries serious enough to merit neurosurgical consultation. Specific injuries included skull fractures, central cord syndromes, and vertebral compression fractures. One patient showed symptoms that required procedural intervention by a neuro-interventional radiologist and one patient was pronounced dead soon after arrival to the hospital (18). A report from Austin Public Health found that though the majority of patients (70%) suffered injuries to the upper limbs (hands/wrist/arm/shoulder), half of identified riders (48%) had injuries (fractures, lacerations, abrasions) to the head, and fifteen percent of riders had evidence suggestive of traumatic brain injury (19). Kobayashi et al. found that extremity fractures were again the most frequent injury (42%), followed by facial fractures (26%) and intracranial hemorrhage (18%) (17). Trivedi et al. (16) noted that though riders of electric scooters were required to be at least 16 years old by state law (and 18 by company rental agreements), there was a small proportion (10.8%) of patients that presented with e-scooter injuries who were younger than 18 years old. One of the conclusions from this study was that it “suggests that self-enforced regulations 52

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imposed by private electric scooter companies may be inadequate.” This finding was similar to that of Ishmael et al., who looked at operative orthopaedic injuries associated with electrical scooter incidents in California. They found that though mean patient age was found to be 35 years old, 4 of the patients they analyzed were paediatric patients. Many results point to increased injuries over time following the introduction of ride-share programs. Kobayashi et al. found that during their study period, monthly admissions of patients with e-scooter related injuries increased significantly over time (17). Officials at Austin Public Health saw two injuries occurred per day on average throughout the period they conducted their study (19). E-scooter injuries dramatically increased in Auckland following the launch of escooter systems in October 2018 (20), with the rate of injuries increasing from two injuries per week before their introduction to an average of 35 per week post-introduction of ride-sharing programs (20). In Dunedin, New Zealand, there had been no e-scooter related emergency department (ED) presentations the year before the e-scooter sharing service was introduced. Post-introduction, 56 e-scooter related ED presentations from 54 separate events were identified in 2019, one year after the e-scooter sharing service was introduced (21). Many studies revealed a specific pattern in the type of rider that is most commonly injured in e-scooter accidents. An epidemiological study conducted by Public Health officials, in Austin, Texas from September to the end of November 2018, found that the majority of patients were riders themselves, and the majority of patients identified as male (19). Riders ranged from 9-79 years old, with nearly half (48%) aged between 18-29 years old. Similarly, Kobayashi et al. found that the majority of patients were between the ages of 20-40 years old, with a mean of 37.1 years (17). The majority (65%) were also male. Blomberg et al. conducted a study evaluating patients injured in e-scooter rides in Copenhagen and similarly found that the majority of patients, themselves riders, were between 18-25 years old. Non-riding patients were mostly elderly people who had tripped over scooters, causing them to sustain moderate to severe injuries (22). No obvious trends in terms of ethnicity or cultural background of injured patients have been noted thus far. Potential risk factors associated with e-scooter use Among various studies, lack of helmet use was found in almost all riders; Dimaggio et al. found that less than 1% of injured riders wore a helmet (23), while Trivedi et al. found that just 4% of all patients were wearing a helmet, despite California laws making helmet use mandatory at the time the study was conducted (16). Jay Doucet, M.D., chief of the trauma division at the University of California San Diego Health Hospital, says that his facility ‘has admitted more than 150 e-scooter-related major trauma victims since Jan. 1st, 2019, and just 2% of victims he treated were wearing helmets when they crashed’ (5). During a public observation component of their study, Badeau et al. reported that lack of helmet use was observed in 94.3% of riders (24).

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In addition to lack of helmet use, Kobayashi et al. also found that almost half (48%) of escooter riders were alcohol-impaired at the time of presentation to the emergency department (with a blood alcohol level >8 mg/dL) (17). Blomberg et al. conducted a study evaluating patients injured in e-scooter rides in Copenhagen and also found that many patients were under the influence of alcohol or other drugs (22). Alcohol consumption while riding e-scooters has also been identified as a significant risk factor in e-scooter accidents in several studies (17,20,22,24,25). Bekhit et al. found that alcohol consumption was found to be a contributing factor in 29% of all e-scooter related injuries (20), while Badeau et al. found that 16% of injured patients reported alcohol intoxication (24). Discussion Given the infancy of ride-sharing programs for e-scooters, research is still in its early stages. With the sudden rise, popularity and accessibility of these scooters in major metropolitan areas, healthcare workers need to be educated and prepared for the expected increase in the use and abuse of e-scooters in the coming years. It is important to compare the incidence and types of e-scooter related injuries in paediatric and adult riders to injuries sustained by riders utilizing other forms of ‘last-minute mile’ transportation. For example, previous studies have shown that manual scooters, (sometimes referred to as ‘kick scooters’) are ‘relatively safe’, with a small number of accidents overall (26). Some studies have demonstrated that manual scooter injuries tend to be ‘minor to moderate’ (26) in nature, and typically include fractures and contusions in various areas (26). To the authors’ knowledge, there are currently no studies that directly compare e-scooter use/injuries to that of manual scooter use/injuries. Future studies should focus on directly comparing e-scooter injuries to that of manual scooter injuries such that their absolute risk can be properly assessed and understood. On the other hand, electric bikes (e-bikes) are another popular form of micro-mobility for youth and adults, whose injuries have become a major health concern in recent years (27). Previous studies have also shown that the locations (often face and head) and types of injuries (often fractures) are similar between regular/non-e-bikes and e-bikes; however, often e-bike related trauma is more severe in nature (28). Specifically, e-bike injuries tend to result in higher injury severity scores (ISS), longer patient stays in hospital, and higher percentages of patient admission to ICU (28, 29). Previous studies have also indicated that when it comes to e-bikes, children are more likely to suffer from head and face injuries more often than their adult counterparts (28). However, various personal blogs, consumer reviews, and online newsletters have compared e-scooters and e-bikes and have touted e-bikes as the ‘obvious choice for safety’ (30, 31). The lack of studies comparing e-scooters to other forms of micro-mobility and various forms of motorized vehicles limits users and physicians from understanding the risk of this technology in a greater societal context. A nuanced understanding of this risk is essential in enabling physicians to have open conversations with their patients and answer questions related 54

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to this technology. As such, future studies should therefore directly compare e-scooter related injuries to e-bikes, as well as other forms of transportation, including Segways, and Hoverboards. This will help to understand the implications of this technology in a broader context. As well, major organizations like the Canadian Pediatric Society (CPS), the Canadian Academy of Sport and Exercise Medicine (CASEM), and other organizations could use this information to issue position statements regarding appropriate use guidelines for consumers, as well as counselling guidelines for primary care practitioners. As it stands today, much remains unknown about the current risk factors associated with e-scooter injuries. Our review has identified three areas that should be the focus of future research: (i) the role of alcohol use, (ii) lack of helmet use, and (iii) specific usage patterns and common injuries in Canadian paediatric and adult populations. It is of utmost importance that future studies characterize the risks that alcohol and lack of helmet use pose to e-scooter riders. Currently, the reason for the profound lack of helmet use is unclear. It has been suggested that perhaps many riders do not want exposure to lice or germs that could be found in shared helmets provided by the ride-sharing program. As well, many make a spontaneous decision to ride while they’re already out and do not have access to a helmet (23). Kobayashi et al. found that 98% of the patients in their study were not wearing a helmet and attributed this high proportion in part to the lack of legislation in the USA requiring helmet use with e-scooter devices (17). Allem and Majmundar found that posts to Bird’s official Instagram page rarely showed e-scooter being used with protective gear (32), and only 1.54% of posts mentioned protective gear in the comment box (32). The authors argue that even though Bird offers free helmets to all active riders, ‘reposting its customers’ photos without wearing protective gear signals that Bird approves of its customers riding without a helmet (32). Future studies can further explore how social media use influences rider behaviour and the clinical implications of marketing decisions. Lack of helmets could potentially be a problem for paediatric populations. A 2017 survey conducted but the American Academy of Paediatrics (AAP) found that parents were less likely to make their child or adolescent wear a helmet while riding a scooter when compared to riding a bike (33). While many cities have placed age restrictions on those who can legally ride escooters, these vehicles remain easily accessible to minors (33). Most ride-sharing programs do not have a way to verify the user’s age, so children and teenagers have the ability to sign up and rent e-scooters without parental consent so long as they have access to a mobile app and a credit card (33). We also call for the initiation of future research analyzing the common injuries that paediatric and adult populations present with. These studies will help better prepare primary care physicians for patient counselling when it comes to engaging with this technology. In the past, Canadian paediatricians have counselled and warned against the use of backyard trampolines (34) and have provided evidence-based guidance around the healthy and meaningful use of ‘screen time’ and social media (35). Family doctors have taken on a similar role, previously warning their patients about the health implications of various new forms of technology, from genetically modified food (36) to ‘Black Henna Tattoos’ (37). We believe that counselling 55

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around e-scooter is not only warranted, but necessary should future studies continue to show that this technology poses a significant health risk to paediatric and adult populations. Finally, future research can be used to assist emergency room physicians navigate the potential increase in e-scooter use. Ultimately, treatment algorithms can be created for primary care and emergency department physicians to follow when treating patients presenting with escooter related injuries (for example, if patients present with a head injury, order non-contrast head CT; if patients do not present with a head injury, begin by…). Additionally, future research will also hopefully help in the development of legislation and policies that need to be implemented to hopefully prevent the frequency and severity of emergency room cases and guide public health and transportation ministries as to best practices. This legislation could take the form of mandatory helmet use laws, minimum requirements for riders, and so on. Physician advocates may encourage lawmakers to create marketing guidelines for this technology to help keep vulnerable patients safe since some e-scooter companies are advertising the use of escooters without protective equipment (32). In conclusion, e-scooter technology is a new form of micro-mobility that has the potential to cause serious harm to Canadians, both from paediatric and adult populations. While there are news reports, as well as individual case studies and case series reports documenting patient demographics and injuries associated with this technology, there currently exist no formal systematic reviews or meta-analysis. While narrative reviews are useful in quickly and efficiently summarizing the evidence on this technology, a systematic review would help to summarize the state of evidence on e-scooters in a more comprehensive and objective way. Specifically, these reports are needed to help formally summarize the data that exists on specific injury types, prevalence, and severity. Furthermore, future studies should investigate the roles of alcohol use and lack of helmet use can make on injury prevention and mitigation. As e-scooter use increases throughout Ontario, this data will be paramount in keeping Canadians informed and safe.

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Smith A. Electric scooters remain prohibited in Toronto until proper regulations developed [Internet]. DailyHive. 2019 [cited 2020 Nov 9]. Available from: https://dailyhive.com/toronto/toronto-e-scooter-update-october?auto=true

Jogi O. Are Electric Scooters Awesome or Terrible? A Look at the Pros and Cons. [Internet]. Entrepreneur. 2018 [cited 2020 Nov 10]. Available from: https://www.entrepreneur.com/article/318486

Electric Scooters Market Size, Share & Trends Analysis Report By Product (Retro, Standing/Self-Balancing, Folding), By Battery (Sealed Lead Acid, NiMH, Li-Ion), By Voltage, And Segment Forecasts, 2020 - 2030 [Internet]. Grand View Research; 2020 Feb [cited 2020 Nov 10] p. 1–164. Available from: https://www.grandviewresearch.com/industry-analysis/electric-scooters-market

Felton R. 8 Deaths Now Tied to E-Scooters [Internet]. Consumer Reports. 2019 [cited 2020 Nov 10]. Available from: https://www.consumerreports.org/product-safety/deathstied-to-e-scooters/

Nellamattathil M., Amber I. An evaluation of scooter injury and injury patterns following widespread adoption of E-scooters in a major metropolitan area. Clin Imaging. 2020;60(2):200–3.

Jeffords S. 5-year electric scooter pilot begins New Year’s Day in Ontario [Internet]. CityNews. 2019 [cited 2020 Nov 10]. Available from: https://toronto.citynews.ca/2019/12/31/electric-scooter-pilot-ontario/

Electric Kick-Style Scooters (e-scooters) [Internet]. Ministry of Transportation; 2019 Nov [cited 2020 Nov 10]. Available from: http://www.mto.gov.on.ca/english/vehicles/electric/electric-scooters.shtml

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Moore J. Watch: Toronto’s surge in e-bike ownership creates concerns over safety [Internet]. NewsTalk 1010. 2018 [cited 2020 Nov 10]. Available from: https://www.iheartradio.ca/newstalk-1010/news/watch-toronto-s-surge-in-e-bikeownership-creates-concerns-over-safety-1.3726810 57

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11.

Ontario Announces E-Scooter Pilot to Help Grow Ontario’s Economy [Internet]. Province of Ontario; 2019 Nov [cited 2020 Nov 10]. Available from: https://news.ontario.ca/mto/en/2019/11/ontario-announces-e-scooter-pilot-to-help-growontarios-economy.html?amp;amp

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Daigle T. Here's why e-scooters are rolling out so slowly in Canada [Internet]. CBC News. 2019 Sept [cited 2020 Nov 10]. Available from: https://www.cbc.ca/news/technology/escooters-canada-analysis-1.5273793

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Shared electric scooter pilot [Internet]. City of Calgary; 2020 Oct [cited 2020 Nov 10]. Available from: https://www.calgary.ca/transportation/tp/cycling/cycling-strategy/sharedelectric-scooter-pilot.html

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Chan K. Lime officially launches in Calgary with 1,000 electric scooters [Internet]. DailyHive. 2019 [cited 2020 Nov 10]. Available from: https://dailyhive.com/calgary/limeelectric-scooters-calgary-launched-july-2019

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Laframboise K. Montreal to ban shared, dockless e-scooters [Internet]. Global News. 2020 [cited 2020 Nov 10]. Available from: https://globalnews.ca/news/6568241/montrealelectric-scooters/

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Trivedi TK, Liu C, Antonio ALM, Wheaton N, Kreger V, Yap A, et al. Injuries Associated With Standing Electric Scooter Use. JAMA Netw Open. 2019 04;2(1):e187381.

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Kobayashi LM, Williams E, Brown CV, Emigh BJ, Bansal V, Badiee J, et al. The emerging e-pidemic of e-scooters. Trauma Surg Acute Care Open. 2019;4(1):e000337.

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Schlaff CD, Sack KD, Elliott R-J, Rosner MK. Early Experience with Electric Scooter Injuries Requiring Neurosurgical Evaluation in District of Columbia: A Case Series. World Neurosurgery. 2019 Dec;132:202–7.

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Dockless Electric Scooter-Related Injuries Study [Internet]. Epidemiology and disease surveillance unit. Epidemiology and public health preparedness division: Austin Public Health; 2018 Nov [cited 2020 Nov 10] p. 1–15. Available from: https://www.austintexas.gov/sites/default/files/files/Health/Epidemiology/APH_Dockless_ Electric_Scooter_Study_5-2-19.pdf

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Bekhit MNZ, Le Fevre J, Bergin CJ. Regional healthcare costs and burden of injury associated with electric scooters. Injury. 2019;(0226040, gon).

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22.

Blomberg S.N.F., Rosenkrantz O.C.M., Lippert F., Collatz Christensen H. Injury from electric scooters in Copenhagen: A retrospective cohort study. BMJ Open. 2019;9(12):e033988.

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DiMaggio C.J., Bukur M., Wall S.P., Frangos S.G., Wen A.Y. Injuries associated with electric-powered bikes and scooters: analysis of US consumer product data. Inj Prev. 2019;((DiMaggio, Bukur, Frangos) Department of Surgery, NYU Langone Health, NYU School of Medicine, New York City, NY, United States).

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Badeau A., Carman C., Newman M., Steenblik J., Carlson M., Madsen T. Emergency department visits for electric scooter-related injuries after introduction of an urban rental program. Am J Emerg Med. 2019;37(8):1531–3.

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Haworth N.L., Schramm A. Illegal and risky riding of electric scooters in Brisbane. Med J Aust. 2019;211(9):412–3

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Gross I, Weiss DJ, Eliasi E, Bala M, Hashavya S. E-Bike–Related Trauma in Children and Adults. J Emerg Med. 2018;54(6):793–8. doi:10.1016/j.jemermed.2017.12.012.

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Dimaggio CJ, Bukur M, Wall SP, Frangos SG, Wen AY. Injuries associated with electricpowered bikes and scooters: analysis of US consumer product data. Inj Prev. 2019;26:524– 8. doi:10.1136/injuryprev-2019-043418.

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Lopez N. E-bike or electric scooter: Which is right for you? The Next Web 2020. https://thenextweb.com/plugged/2020/07/08/e-bike-or-electric-scooter-which-is-right-foryou/ (accessed April 2, 2021).

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Morgan A. E-Scooters Aren’t for Kids: AAP Urges Safety Rules [Internet]. Healthy Children. 2019 [cited 2020 Nov 10]. Available from: https://www.healthychildren.org/English/safety-prevention/on-the-go/Pages/EScooters.aspx

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Commentary

COVID-19 lockdown: Not a one-size-fits-all solution Yasmina Geber and Priscilla Matthews Schulich School of Medicine & Dentistry – Western University, London, Canada

Keywords: COVID-19, Lockdown, Public Health

Corresponding author: ygaber@uwo.ca

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Introduction The rapid spread of the novel coronavirus (COVID-19) has caused many health bodies to implement policies in an attempt to curb viral transmission (1). Due to a lack of vaccines and pharmacological treatments for COVID-19 early in the pandemic, governments were compelled to utilize strategies to mitigate spread such as social distancing and lockdowns (1). The term "lockdown" has no precise definition in the literature, however we will use it below to refer to government measures implemented to decrease community mobilisation in order to reduce the spread of COVID-19. A recent review of observational data from 27 countries demonstrated that the growth rate of daily case counts declined after 15 days of lockdown (1). This deceleration in disease transmission demonstrated a success of lockdown measures, however the growth rate continued to be positive with no decline in the absolute number of new daily cases. Given that the number of daily cases continued to grow, albeit at a slower rate, these results appear to indicate that lockdowns alone were not sufficient to halt the pandemic (1). The concern this raises is that although lockdowns appear to have some impact on disease transmission, they also have the potential to have unintended negative impacts on the social and mental health of global communities (1). In certain circumstances, the costs of lockdown may be considered too high for specific communities to bear, risking long-term, detrimental impacts (1). This paper will explore the potential drawbacks of lockdown measures implemented in the global North and South on social and mental wellbeing. Countries from each continent that had sufficient data for analysis at the time of writing were selected for further analysis. The countries chosen were the United States of America (USA) and the United Kingdom (UK) from the global North, and India and Kenya from the global South. Impacts on food insecurity and income Implementing lockdown measures had a number of unintended impacts on local populations in terms of worsening existing disparities and disproportionately affecting vulnerable populations. A particularly concerning issue has been the inability of individuals to fulfill food security needs in certain regions (2-5). Prior to the onset of the pandemic, a considerable portion of the population in the UK (7.6%) and US (11%) were already experiencing food insecurity (5,6). Food insecurity is defined as limited, irregular access to sufficient, nutritious foods to lead an active, healthy lifestyle (6). Food insecurity induces feelings of anxiety due to the uncertainty of securing one’s next meal, fear of food running out, or inability to maintain a balanced diet due to financial constraints (7). Since the introduction of COVID-19-related lockdowns, the prevalence of food-insecure households has increased in both the UK (16.2%) and USA (38%) (7). This rise is greater than what was seen in the USA during the Great Depression and has fostered increasing concerns about the unintended consequences of lockdowns (5).

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The announcement of border shutdowns and quarantine enforcements in the USA and UK sparked fear of an impending economic crisis, driving people to panic and overstock on supplies and resulting in shortages in food stores (2,5,6). As seen in the 2007-2008 economic recession, food shortages led to price crises, with imported foods becoming more expensive (7). Therefore, the implementation of lockdown measures and panic purchasing may have further contributed to the challenges facing vulnerable populations and food-insecure households (6). It is worth noting that the pandemic has exacerbated food insecurity disproportionately in communities of colour (2). In addition, among low-income populations in the USA, individuals who were already experiencing food-insecurity had higher rates of job loss or reductions of work hours when compared to low-income individuals who were not experiencing food insecurity, further exacerbating existing disparities (5,6). These findings are concerning as they demonstrate that COVID-19 lockdown measures have the potential to widen existing racial and socioeconomic disparities in many global North settings. The impact on food insecurity has been even greater in the global South. One study reported that 95% of Kenyan participants had experienced reduced income as a result of the lockdown (8). Consequently, 88% of participants were unable to purchase sufficient food for their households. Kenyan health practitioners also highlighted the challenges faced by local populations in abiding by physical distancing measures. A specific challenge stemmed from small, overcrowded and shared spaces within the slums that act as a transmission ground for the virus (8). With 56% of Nairobi’s population living in slums, Kenya’s capital quickly became the country’s COVID-19 epicenter (8). Circumstances in India have been similar. The Indian government was praised by the World Health Organization (WHO) for their timely and quick response to the pandemic; however, India’s response has put vulnerable populations at a major disadvantage (9). For instance, India has high intranational migration, but their food ration cards are not portable; migrants from one state cannot utilize their ration cards in another (10). Recent data pointed towards an imminent starvation crisis, with 72% of migrants reporting that their existing food stores were running out (9,10). Furthermore, recent reports have suggested that the government’s efforts to remedy food insecurity would not be sufficient (9). According to estimates by Sumner et al., COVID-19 may be undoing three decades of global efforts to decrease international poverty levels, potentially translating into an increase of 420 to 580 million people living in poverty (7). Impacts on mental health and domestic violence In addition to the socioeconomic impacts, lockdown measures have been associated with a wide range of psychological consequences in the global North and South. Previous studies have shown that feelings of depression, anxiety, and uncertainty about the future heighten with social isolation (11). Isolation may also lead to physical and mental health consequences such as poor sleep quality, increased thoughts of suicide, increased substance abuse, and decreased lifespan 63

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(11). Results from the Kaiser Family Foundation (KFF) Tracking Poll show that Americans sheltering in place during the COVID-19 pandemic were more likely to report negative mental health impacts compared to those who were not sheltering in place (11). Similarly in the UK, a survey by the Office of National Statistics indicated that as the lockdown started, around 50% of the British population experienced high levels of anxiety (12). Additionally, psychiatrists in the UK have observed an increased number of patients with suicidal or self-harm ideations (13). Projections have estimated that social isolation could partially contribute to excess mortality from suicide and alcohol abuse in the near future (11). Cases of domestic violence have also unfortunately increased as lockdowns began (14). As families isolate within themselves, it becomes increasingly challenging for victims to avoid abuse. Rises in domestic violence have been evidenced by significant increases in the number of people seeking help. For example, 549 people in Chicago called domestic violence hotlines the week after the lockdown began in April 2020, which was a substantial increase from the 383 people who used the hotlines during the first week of March 2020 (14). Likewise in the UK, calls to the National Domestic Abuse helpline rose by 25% and 49% in the second and third weeks respectively after lockdown began (15). In contrast, in some cities across the USA, police have observed a drop in calls, which authorities believe may be attributed to the victims’ proximity to their abusers and inability to make calls without detection (14). Although the number of studies is limited, similar psychological trends have been observed in the global South. The loss of jobs and businesses brought on by the lockdown, combined with limited access to mental health resources, has resulted in a 20% spike in mental health cases in India (16). The Indian Psychiatry Society reported that distress calls and suicidal tendencies were alarmingly high as a result of regional lockdowns (16). In Kenya, the mental health climate has also become worrisome. The lockdown has changed social relationships, triggering fear, loneliness, and stress from both financial loss and a lack of resources to meet basic needs (17). Furthering the negative mental health impacts are intensive media, which creates feelings of helplessness and anxiety (17). Indian and Kenyan leaders must work to address the worsening mental health impacts in their respective countries in sustainable, innovative ways that acknowledge the resource limitations in these settings. Reports of domestic violence have also increased in India and Kenya. Due to lockdown protocols, many Indian women and girls are stuck at home with an abusive partner, resulting in a steep rise of 94% in domestic violence cases (18). Similarly, children’s helplines in India have received increasing numbers of calls (18). To make matters worse, there is a loss of support from the outside world. Victims of abuse are unable to escape or congregate with friends or relatives in different homes due to physical distancing protocols. In Kenya, there was a 34% rise in domestic violence calls within the first three weeks of lockdown; this increased violence can result in psychological harm and unplanned pregnancies (19). This tragic surge of domestic violence during COVID-19 has been referred to as the “shadow pandemic,” begging for immediate, comprehensive action.

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Impacts on society and education Social structures have been impacted by the pandemic, with worsening inequities across the global North and South. Education is one of the main pillars that drives social mobility, however COVID-19-related lockdown measures and school closures have limited educational opportunities, with negative impacts estimated to affect about 900 million learners (2). Furthermore, given that food insecurity has been shown to have a detrimental effect on children’s academic performance, the growing prevalence of food insecurity from ongoing lockdown measures is likely to worsen this crisis (20). Previous studies have shown that children from low socioeconomic backgrounds lose about a month of academic achievement during summer vacation, an observation that was not apparent in their higher socioeconomic counterparts (20). With school closures during COVID-19, negative impacts of even greater magnitude may be observed (20). Moreover, the complete shift to digital educational platforms at home has amplified existing barriers for low-income children, such as turbulent family structures and limited internet access. All together, it is clear that pre-existing conditions of poverty combined with changes during the pandemic have impeded children’s wellbeing and could worsen existing disparities in learning outcomes (20). School closures brought about by the 2009 H1N1 outbreak restricted 27% of Taiwanese individuals from going to work due to parental duties, resulting in job losses for 18% of those families (2). Similarly, school closures have resulted in a reduction of healthcare workers’ hours by 6-19% (2). The similarity of policies and outcomes implemented during both the H1N1 and COVID-19 outbreaks illustrates that lessons on mitigating negative consequences were not learned from the past. When faced with a potential outbreak in the future, it is critical to use past learnings to shape future guidelines. From a societal lens, COVID-19 also introduced struggles for power, with police brutality and corruption rates rising in the global South. In Kenya, obedience to lockdown measures is demanded with force, and sometimes resulting in unlawful killings (21). Unfortunately, this produces counterintuitive results as people are forced into crowded cells, further catalyzing the spread of the virus (21). Unfortunately, documentation of similar situations has been surfacing for other countries, including Chile, Lebanon, and Hong Kong (3). Conclusion Overall, although lockdown measures have been taken to curb the spread of COVID-19 in the global North and South, concerns about the unintended consequences of such measures on physical, mental and social inequities remains worrying. Implementing lockdowns was one of the few evidence-based approaches that leaders could lean on at the beginning of the pandemic; however, global infrastructures may not have been sufficiently prepared for such measures (1). It is evident that although such strategies are intended to protect people from COVID-19, they may also yield unintended harms in other ways. In fact, there is a fear that if lockdowns are 65

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prolonged, affected populations may suffer more from the social and economic consequences as opposed to the virus itself (3,12,20). If future lockdowns are imposed, better supports and preparedness must be developed to ensure that people can comply in ways that preserve their physical, mental, and social well-being.

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References 1.

Meo SA, Abukhalaf AA, Alomar AA, AlMutairi FJ, Usmani AM, Klonoff DC. Impact of Lockdown on COVID-19 Prevalence and Mortality During 2020 Pandemic: Observational Analysis of 27 Countries. European Journal of Medical Research. 2020 Dec;25(1):1-7

Nicola M, Alsafi Z, Sohrabi C, et al. The Scio-Economic Implications of the Coronavirus Pandemic (COVID-19): A review. International Journal of Surgery. 2020;78:185-193. doi:10.1016/j.ijsu.2020.04.018

Pleyers G. The Pandemic is a battlefield. Social movements in the COVID-19 lockdown. Journal of Civil Society. 2020;16(4):295–312.

Mboera LEG, Akipede GO, Banerjee A, Cuevas LE, Czypionka T, Khan M, et al. Mitigating lockdown challenges in response to COVID-19 in Sub-Saharan Africa. International Journal of Infectious Diseases. 2020;96:308–10.

Wolfson JA, Leung CW. Food Insecurity and COVID-19: Disparities in Early Effects for US Adults. Nutrients. 2020;12(6):1648. doi:10.3390/nu12061648

Loopstra, R. Vulnerability to Food Insecurity Since the COVID-19 Lockdown (2020). Imperial College of London.

Sumner A, Hoy C, Ortiz-Juarez E. Estimates of the Impact of COVID-19 on Global Poverty. WIDER Working Paper. April 2020. doi:10.35188/unu-wider/2020/800-9

Shupler M, Mwitari J, Gohole A, et al. COVID-19 Lockdown in a Kenyan Informal Settlement: Impacts on Household Energy and Food Security. 2020. doi:10.1101/2020.05.27.20115113

The Lancet. India Under COVID-19 Lockdown. The Lancet. 2020;395(10233):1315. doi:10.1016/s0140-6736(20)30938-7

10.

Choudhury P, Koo W, Li X, Kishore N, Balsari S, Khanna T. Food Security and Human Mobility During the COVID-19 Lockdown. SSRN Electronic Journal. May 2020. doi:10.2139/ssrn.3600376

11.

Panchal N, RK, Kamal R, Orgera K, et al. The Implications of COVID-19 for Mental Health and Substance Use [Internet]. KFF. https://www.kff.org/coronavirus-covid19/issue-brief/the-implications-of-covid-19-for-mental-health-and-substance-use/. Published April 21, 2020. Accessed June 26, 2020.

12.

Torjesen I. Covid-19: Mental Health Services Must be Boosted to Deal with “Tsunami” of Cases After Lockdown. BMJ. 2020:m1994. doi:10.1136/bmj.m1994.

13.

Wan W. The Coronavirus Pandemic is Pushing America into a Mental Health Crisis [Internet]. The Washington Post. https://www.washingtonpost.com/health/2020/05/04/mental-health-coronavirus/. Published May 4, 2020. Accessed June 26, 2020. 67

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14.

Bosman J. Domestic Violence Calls Mount as Restrictions Linger: 'No One Can Leave' [Internet]. The New York Times. https://www.nytimes.com/2020/05/15/us/domesticviolence-coronavirus.html. Published May 15, 2020. Accessed June 26, 2020.

15.

UK lockdown: Calls to Domestic Abuse Helpline Jump by Half [Internet]. BBC News. https://www.bbc.com/news/uk-52433520. Published April 27, 2020. Accessed June 26, 2020.

16.

Krishnan M. Mental Illness, Suicides Rise in India During Covid-19 crisis [Internet]. RFI. http://www.rfi.fr/en/international/20200514-mental-illness-suicides-on-the-rise-in-indiaduring-covid-19-lockdown. Published May 14, 2020. Accessed June 26, 2020.

17.

Community Mental Health: Experiences from Nairobi's COVID-19 Response [Internet]. Mental Health Innovation Network. https://www.mhinnovation.net/blog/2020/apr/15/community-mental-health-experiencesnairobi%E2%80%99s-covid-19-response. Published April 15, 2020. Accessed June 26, 2020.

18.

Nigam S. Covid-19: India’s Response To Domestic Violence Needs Rethinking. Social Science Research Network. May 2020. doi:10.31234/osf.io/4bpny.

19.

Shimanyula J. Activists Appeal to AU as Abuse Against Women, Girls Soars Under Covid-19 [Internet]. RFI. http://www.rfi.fr/en/africa/20200427-activists-appeal-to-au-asabuse-against-women-girls-soars-under-covid-19. Published April 27, 2020. Accessed June 26, 2020.

20.

Van Lancker, W., & Parolin, Z. (2020). COVID-19, School Closures, And Child Poverty: a Social Crisis in the Making. The Lancet Public Health, 5(5), e243-e244.

21.

'Never again': Protesters March Against Kenyan Police Brutality [Internet]. Al Jazeera. https://www.aljazeera.com/news/2020/06/protesters-march-kenyan-police-brutality200608162743597.html. Published June 8, 2020. Accessed June 25, 2020.

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Commentary

Triaging out of elective surgeries during the COVID-19 pandemic: The wrong approach? Takhliq Amir Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON

Abstract The devastating burden of COVID-19 on the health of individuals and capacities of health systems has led to blanket cancellations of elective surgeries globally. In response, surgery and anesthesia societies worldwide have published perioperative guidelines to inform the continuation of elective surgical procedures during the pandemic and the resumption of services in the intra- and post-pandemic phase. The effects of these widespread cancellations on the health of patients or the overall cost to the health systems are unclear but emerging anecdotal evidence is painting a grim picture. This commentary aims to review the current literature on the cancellation of elective surgeries in response to the COVID-19 pandemic, summarize broad recommendations from recently developed perioperative guidelines, and discuss key considerations for the resumption of elective surgeries in the intra- and post-pandemic world.

Keywords: Elective surgery, Triage, COVID-19 Corresponding author: takhliq.amir@medportal.ca

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Introduction The COVID-19 pandemic and its resultant toll on individuals of all ages have severely overwhelmed the capacities of healthcare systems worldwide. In the midst of managing an ongoing and rapidly evolving pandemic—and ensuring capacity for anticipated surges—the past year has seen blanket cancellations of elective surgeries globally (1). In comparison to emergency surgeries, elective surgeries are procedures that are scheduled in advance for conditions that are not acutely life- or limb-threatening. However, ‘elective’ does not equate to optional. Rather, the line between urgent and non-urgent for many elective procedures is blurry, with many procedures potentially a life-changing option for patients. For instance, while vascular surgeries may be scheduled as elective, cases of limb ischemia or aneurysmal disease are still urgent and require immediate treatment (1,2). The protracted delay of elective operations, such as tumour resections or hip replacements, runs the risk of increased morbidity, decreased quality of life, and increased costs for individual patients due to increased disability and time off from work (3). Some arguments in favour of the cancellation of elective surgeries include protecting patients and healthcare providers from risks of in-hospital COVID-19 transmission, increasing availability of ICU beds for COVID patients, preserving PPE, and redirecting surgeons and perioperative teams to provide support in other areas, such as critical care (4). A retrospective cohort study from China on asymptomatic patients undergoing major surgery during the incubation period of the COVID-19 infection found that intensive care was required by 44% of the patients due to COVID-19 disease progression postoperatively, with a 20% mortality rate post-ICU admission (5). However, the evidence was considered low quality and the sample size was small. Despite limited evidence, the fear of COVID-19 transmission led to blanket cancellations of elective surgeries worldwide in the initial peak of the pandemic without knowledge of short- or long-term impacts on individual patient health and health systems. The issue has since become a matter of policymaking by individual institutions and regional healthcare bodies—balancing the risk of harm due to delay of elective procedures against the possibility of increased exposure to COVID-19 in hospitals. A study in Ontario estimated the surgical backlog between mid-March to mid-June 2020 to be over 148,000 surgeries, with an estimated time of 84 weeks needed for clearance (6). Results from the study demonstrated a drop in surgical volume by 38% for cancer, 42% for cardiac, 73% for vascular, 81% for transplant, 94% for pediatric surgeries, and 96% for other adult surgeries in April 2020 compared to April 2019. For many of these patients, at best, cancellations equate to a prolonged wait to healing. At worst, they equate to progressively debilitating pain/complications and the potential for irreversible disease progression.

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Development of surgical triage guidelines Back in March 2020, when Italy’s health system became incapacitated by the pandemic, the Italian College of Anesthesia, Analgesia, Resuscitation, and Intensive Care released guidelines for triaging care. These guidelines included factors such as age, comorbidities, and pre-existing functional status in the algorithm for decision-making regarding ICU admissions (7). Since then, several surgery and anesthesia societies have published guidelines regarding the provision of surgical care during the COVID-19 pandemic, many of which balance broad public health safety considerations and resource availability with individual acuity of need. The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) and The European Association for Endoscopic Surgeons (EAES) released recommendations regarding surgical response during the pandemic (8). Their guidelines suggested postponing elective surgical and endoscopic procedures based on the burden of COVID-19 locally, general recommendations for procedural considerations (i.e., dedicated ORs, minimizing OR staff numbers, etc.), and practical measures for laparoscopic, endoscopic, and other surgical procedures. The American College of Surgeons (ACS) statement focused on emphasizing regional cooperation to ensure capacity and resources for surgical procedures, principles for prioritization strategies (i.e., phased re-opening of ORs, specialties’ prioritization, etc.), and discussed considerations for surgical care from the preoperative phase to post-discharge care planning (9). The ACS further published individualized guidelines for various types of surgeries (i.e., vascular surgery, pediatrics, etc.) aimed at facilitating local decision-making (10). Others, such as the Federation of Surgical Specialty Associations (U.K.), have published regularly updated guidelines that define appropriate timelines based on the type of condition and procedure (11). For example, an aortic dissection or empyema with sepsis should be treated with emergency surgery within 24 hours, while surgery for aortic stenosis can be performed within 1 month. In Ontario, Ontario Health released a report titled A Measured Approach to Planning for Surgeries and Procedures During the COVID-19 Pandemic, which included thresholds for acute care capacity, protective equipment, and personnel availability before elective surgeries could be resumed (12). While many of these guidelines likely provide some much-needed direction to individual institutions, the limited research evidence to support their recommendations continues to present a challenge. In a scoping review on the short- and long-term effects of the pandemic on the delivery of surgical services, it was found that many of these newly developed perioperative guidelines only offer anecdotal data based on individual care provider expertise (13). Upon review of the guidelines, it also becomes clear that beyond general safety and resource availability recommendations, they offer no consensus on the process of prioritizing certain procedures, surgical specialties, or defined plans for the restart of surgical care in the postpandemic phase. While the value of individual expertise should not be undermined, this has inadvertently left the door open for considerable uncertainty in best practices and likely increases

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the moral and ethical dilemma faced by surgeons, anesthesiologists, and perioperative teams involved in healthcare. Considerations for elective surgeries in the intra- & post-pandemic phase Given the extraordinary nature of the pandemic and the massive scale-back of elective surgeries globally, it remains a challenge to identify the best method to manage the backlog of elective procedures after the pandemic. One study, led by the COVIDSurg Collaborative, projected an estimated 28 million elective procedures to be cancelled or postponed during the 12-week peak of the pandemic (4). They also estimated that a median of 45 weeks would be required to clear the backlog with a 20% increase in surgical volume in the post-pandemic setting. Arguably, the burden of COVID-19 on those facing delays in care may have just as devastating of an impact on the health of individuals as that caused by the virus itself. Articles in mainstream media are rife with examples of people suffering from health consequences due to cancelled surgeries (i.e., heart disease or cancer care) (1). Cancellation of elective surgeries also present substantial—and potentially catastrophic—consequences for health systems globally. A study published in August 2020 calculated the potential cost of postponing elective procedures for at least 3 months in the United Kingdom (U.K.) (2). With the possibility of 40,000 elective procedures cancelled, the authors estimated that the cost of clearing the resultant backlog would be over £2 billion, or ~$3.5 billion CAD. This cost is likely to be significantly higher if patient morbidity caused by delays in healthcare was taken into account. While the solution to this problem remains to be identified, it has become clear that complete cancellations of elective surgeries do not take into account the nuances of individual patient needs, operative indications, and the spectrum of disease that is involved. A starting point in resuming elective surgical care, then, should be a more granular approach that slowly triages surgical patients back into care based on the urgency of their condition. Engelman et al.’s proposed principles for adult cardiac surgical programs is one example to guide the re-initiation of surgical care: 1) collaboration to achieve increased case volumes based on local resources available within the healthcare system; 2) prioritization of patients based on factors suggesting that they are at a high-risk; and 3) constant re-evaluation of local conditions to monitor the rise in hospital admissions, availability of resources, and risk of transmission to healthcare providers and patients (14). Another approach places the emphasis on lifesaving operations unless resource scarcity necessitates a shift to prioritization based on quality of life years saved (15). With this approach, considerations for surgical care can be divided into two different phases—before and after the peak of the pandemic—with a staggered approach aiming to ensure gradual recovery of surgical volumes. To guide prioritization of individual patients, the MeNTS (medically necessary, timesensitive procedures) scoring system can be utilized (16). It includes 21 factors related to the procedure (i.e., length of hospital stay, duration of operation, etc.), disease (i.e., risk of delay on

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the outcome, alternative non-surgical therapeutic options, etc.), and the patient (i.e., age, preexisting comorbidities, etc.). The total scores are then used to estimate the level of surgical risk, risk to personnel, and resource utilization. The use of such a tool can help to identify patients most in need of surgeries and reduce moral and ethical burdens placed on healthcare providers who have to make challenging decisions that measure individual patient needs against broader public health risks. Other recommendations can be more practical in nature and warrant consideration for future pandemic planning. Ensuring adequate PPE for healthcare workers, having protocols for designated ORs, ICUs and wards, maintaining constant public health communication, and ensuring that hospital leadership secure enough supply of resources to provide support for patients are all imperative to maintaining a functioning healthcare system (17,18). Where procedures are cancelled, providing simple reassurance to patients through telemedicine can go a long way towards ensuring that they are not falling through the cracks (19). Conclusion While the COVID-19 pandemic has posed significant risks to individuals worldwide, the need to allocate resources and care safely and equitably is crucial. Blanket cancellation of elective surgeries is dangerous for the health of countless individuals and communities, likely made worse by the inability to measure the full impact on patients’ health outcomes at this time. It is likely that in the aftermath of this pandemic, epidemiological and clinical data will emerge regarding the perioperative factors and postoperative outcomes that are most significant when prioritizing surgical services. Research to evaluate the effects of elective surgery cancellations on ‘collateral damage’—both the health costs to patients and the economic costs to healthcare systems as a result of declining quality of life and worsened conditions owing to a delay in care—is greatly needed. In the post-pandemic world, then, it would be crucial for health systems to develop a disaster plan that includes policies and processes for the continuation or delivery of surgical services during public health crises. Until then, all healthcare bodies and institutions should deeply reconsider the potentially catastrophic impacts of the cancellation of elective surgeries on the health of those unable to receive timely care during this pandemic.

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References 1.

Rosenbaum L. The untold toll—the pandemic’s effects on patients without Covid-19. N Engl J Med. 2020 Jun;382:2368-2371.

Ding A, Onida S, Davies AH. The painful cost of cancelling surgery due to COVID‐19‐can we do anything about it? Br J Surg. 2020 Aug;107(9):e336.

Fu SJ, George EL, Maggio PM, Hawn M, Nazerali R. The Consequences of Delaying Elective Surgery: Surgical Perspective. Ann Surg. 2020 Aug;272(2):e79–e80.

Negopdiev D, Collaborative C, Hoste E. Elective surgery cancellations due to the COVID19 pandemic: global predictive modelling to inform surgical recovery plans. Br J Surg. 2020 Jul;107(11):1440-9.

Lei S, Jiang F, Su W, Chen C, Chen J, Mei W, et al. Clinical characteristics and outcomes of patients undergoing surgeries during the incubation period of COVID-19 infection. EClinicalMedicine. 2020 Apr;21:100331.

Wang J, Vahid S, Eberg M, Milroy S, Milkovich J, Wright FC, et al. Clearing the surgical backlog caused by COVID-19 in Ontario: a time series modelling study. CMAJ. 2020 Nov;192(44):E1347-56.

Craxì L, Vergano M, Savulescu J, Wilkinson D. Rationing in a pandemic: lessons from Italy. Asian Bioeth Rev. 2020 Sept;12(3):325-30.

Francis N, Dort J, Cho E, Feldman L, Keller D, Lim R, et al. SAGES and EAES recommendations for minimally invasive surgery during COVID-19 pandemic. Surg Endosc. 2020 Jun;34(6):2327-31.

Jou J, Waterman R, Rhodes L, Haworth J, Moberg A, Schaefer R, McHale M. Essential surgery during the covid 19 pandemic: The implementation of a pre-operative universal covid testing program. The American Journal of Surgery. 2021 Apr 1;221(4):770-1.

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American College of Surgeons [Internet]. Joint Statement: Roadmap for Maintaining Essential Surgery during COVID-19 Pandemic; 2020 [updated 2020 Aug 10; cited 2020 Nov 23]. Available from: https://www.facs.org/covid-19/clinical-guidance/nov2020roadmap

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American College of Surgeons [Internet]. COVID-19: Elective Case Triage Guidelines for Surgical Care; 2020 [updated 2020 Mar 27; cited 2020 Nov 23]. Available from: https://www.facs.org/covid-19/clinical-guidance/elective-case

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The Federation of Surgical Specialty Associations [Internet]. COVID-19 documents; [updated 2021 May 13; cited 2020 Nov 23]. Available from: https://fssa.org.uk/covid-

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19_documents.aspx 13.

Ontario Health [Internet]. A Measured Approach to Planning for Surgeries and Procedures During the COVID-19 Pandemic; 2020 [updated 2020 May 7; cited 2020 Nov 23]. Available from: https://www.ontariohealth.ca/sites/ontariohealth/files/202006/A%20Measured%20Approach%20to%20Planning%20for%20Surgeries%20and%20Pr ocedures%20During%20the%20COVID-19%20Pandemic.pdf

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Søreide K, Hallet J, Matthews JB, Schnitzbauer AA, Line PD, Lai PB, et al. Immediate and long‐term impact of the COVID‐19 pandemic on delivery of surgical services. Br J Surg. 2020 Sep;107(10):1250–1261.

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Engelman DT, Lother S, George I, Ailawadi G, Atluri P, Grant MC, et al. Ramping up Delivery of Cardiac Surgery During the COVID-19 Pandemic: A Guidance Statement from The Society of Thoracic Surgeons COVID-19 Task Force. Ann Thorac Surg. 2020 Aug;110(2): 712–717.

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Brindle ME, Doherty G, Lillemoe K, Gawande A. Approaching surgical triage during the COVID-19 pandemic. Annal Surg. 2020 Aug;272(2):e40.

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Prachand VN, Milner R, Angelos P, Posner MC, Fung JJ, Agrawal N, et al. Medicallynecessary, time-sensitive procedures: a scoring system to ethically and efficiently manage resource scarcity and provider risk during the COVID-19 pandemic. J Am Coll Surg. 2020 Aug;231(2):281-288.

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Cavallo JJ, Donoho DA, Forman HP. Hospital capacity and operations in the coronavirus disease 2019 (covid-19) pandemic—planning for the nth patient. JAMA Health Forum. 2020 Mar;1(3):e200345-e200345.

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Mayol J, Pérez CF. Elective surgery after the pandemic: waves beyond the horizon. Br J Surg. 2020 Aug;107(9):1091-1093.

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Ives J, Huxtable R. Surgical ethics during a pandemic: moving into the unknown? Br J Surg. 2020 Aug;107(9);1089-1090.

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Commentary

Opioid treatment agreements in chronic nonmalignant pain: The solution or the problem? Jasper C Ho and Yasovineeth Bhogadi Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Canada

Abstract Opioid treatment agreements (OTAs) are routinely used in the primary care setting for patients initiating chronic opioid therapy for non-malignant pain despite limited empirical evidence supporting their use. In this commentary, we contextualize current practices in Ontario with regard to OTAs. We highlight the lack of high-quality evidence showing that utilizing OTAs leads to beneficial outcomes for patients or prescribing physicians, and explore the ethical quagmire they create in clinical practice. Physicians utilizing OTAs need to be aware of the limitations of OTAs and sensitive to their potential impact on the physician-patient relationship. We advocate for a return to a collaborative, patient-centered approach with physicians encouraged to involve patients in a shared decision-making process to set mutually agreeable goals for treatment with opioids, to obtain informed consent from patients, and to better tailor these agreements to reflect the interests of all parties involved. Further research and debate are required to improve the effectiveness and ethical justification for using OTAs in clinical practice.

Keywords: opioids, ethics, primary care, opioid treatment agreement, contract. Corresponding author: vineeth.bhogadi@medportal.ca

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Introduction Opioid treatment agreements (OTAs) are a ubiquitous part of managing chronic opioid use in the primary care setting. First introduced in a 1994 abstract by Kirkpatrick et al. and formalized in 1995 by Burchman and Pagel (1,2), the original opioid “protocol-contract” (Figure 1) for nonmalignant chronic pain has faded from the literature, and current clinical practice has diverged from its roots. Original formulations of OTAs began with a statement of the lack of evidence of opioids for the treatment of chronic non-malignant pain. Patients were clearly warned about the risks of constipation, sedation, cognitive impairment, respiratory arrest, physical and psychological dependence, tolerance, and neonatal abstinence syndrome (2). Further iterations focused on patient expectations: analgesia as an approach to maintaining function and not to completely eliminate pain; opioids as bridging measures while developing pain management behaviours; and frequently scheduled re-evaluations of opioid requirements and response (1). In contrast, modern OTAs delineate strict limits on behaviours, doses, refills, and firmly defend the right of the physician to terminate the prescription or relationship (3). Although today’s iterations seem more proscriptive and less informative, OTAs used in major United States academic pain centres even in the late 1990s had consistent themes of disallowed behaviour and termination procedures (4). In this article, we aim to provide commentary on OTAs in the current local context given the shift in the opioid-related landscape over the past few decades. We narratively summarize pertinent evidence supporting utilization of OTAs in practice, potential ethical concerns associated with their use, and advocate for a transition away from OTAs to a more collaborative, patient-centered approach towards chronic pain.

I understand that I am receiving opioid medication from Dr ______ to treat my pain condition. I agree to the following conditions under which this medication is prescribed: 1. I will not seek opioid medication from another physician. Only Dr ______ will prescribe opioids for me. 2. I will not take opioid medication in larger amounts or more frequently than is prescribed by Dr ______. 3. I will not give or sell my medication to anyone else, including family members; nor will I accept any opioid medication from anyone else. 4. I will not use over-the-counter opioid medications. 5. I will only fill my prescriptions at one pharmacy, which is: _____________ 6. I understand that if my prescription runs out early for any reason, I will have to wait until the next prescription is due. I understand that if I break these conditions, Dr ______ may choose to cease writing opiate prescriptions for me, and this will be noted in my medical record. Figure 1. Example opioid treatment agreement, adapted from Kahan 2006 (3). 77

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Current utilization of opioid treatment agreements in Canadian practice There are no specific Canadian federal or provincial legislative requirements for clinicians to use OTAs when prescribing opioids. However, national regulatory and medico-legal bodies have made recommendations in this context (5). The official stance of the College of Physicians and Surgeons of Ontario (CPSO) is that OTAs may be considered, but not required when prescribing opioids (5). The Canadian Medical Protective Association has recommended the use of OTAs based on now-outdated guidelines (6). These recommendations have made their way into provincial standards and metrics for primary care as well: Ontario’s Family Health Teams (FHTs) may require OTAs for every patient on chronic opioid therapy regardless of individual risk for misuse or diversion, and Health Quality Ontario’s Primary Care Reports delivered biannually to FHTs specifically suggest OTA uptake (7). Rationalizing opioid treatment agreement use If not strict legal or professional requirements, what drives this practice? The indoctrination of OTAs as standard management of patients on chronic opioids in the primary care setting may originate from physician unease with opioids. In their paper, Arnold and colleagues theorize that physicians cling to OTAs due to “opiophobia” originating from hyper-awareness of the negative effects of opioids on individuals and society—thereby ensuring legal and moral defensibility of their prescribing practices—as well as a need to control the perceived inherent uncertainties associated with patients on chronic opioid therapy (8). Concordantly, medical residents demonstrate increased use of OTAs compared to more experienced clinicians, suggesting that they may be more malleable to expectations of “good clinical practice” given their relative inexperience (9). Furthermore, the use of OTAs increases residents’ comfort and sense of reward with managing chronic opioids, which tend to be low at baseline (10,11). Symbolic control codified as OTAs may justify overly rigid limits, unilaterally modifying treatment plans, or limited individualization of treatment plans. Evidence for opioid treatment agreements is limited A 2010 systematic review showed a 7–23% absolute risk reduction in opioid misuse with OTAs in four cohort studies (12). However, the overall evidence was of poor quality and high heterogeneity, limited by considerable variation in the definition of opioid misuse in the identified studies (12). Additionally, most studies included were conducted in specialty pain clinics or primary care practices with complex management strategies not representative of the outpatient settings where most patients are prescribed long-term opioids for chronic nonmalignant pain (12). Most recently, the 2017 Canadian Guidelines for Opioids for Chronic NonCancer Pain did not recommend OTAs based on a meta-analysis of four studies, which concluded that formal structured treatment agreements did not lead to a significant difference in opioid misuse rates in patients with chronic non-cancer pain and resulted in a small trend towards harm (13). Most analyses and guidelines discuss the effects of agreements on opioid misuse or diversion: these are real and pressing public health and safety concerns that happen to directly 78

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challenge the ego of physician authority. Yet, beyond misuse, there was an astonishing lack of evidence in the literature for whether OTAs decrease inappropriate opioid prescribing; decrease the duration of such therapy; increase patient satisfaction, pain control, or functional status; or reduce the adverse effects of chronic opioid therapy. One nonrandomized study conducted in Arizona showed that OTAs are negatively associated with opioid discontinuation and have no impact on decreasing opioid dosage (14). These individualized patient-centered outcomes should be more important in our clinical practice than determining misuse or diversion and should be more thoroughly explored. OTAs damage the physician-patient relationship and are ethically questionable OTAs significantly conflict with our basic duty: primum non nocere or first, do no harm. When OTAs are used to alleviate physician discomfort, the measured balance between benefits and harms to individual patients is disrupted with paternalistic considerations that constrain the freedoms and rights of patients (8). The potential for harm resulting from “best practice” opioid management cannot be ignored. Physicians who tend to use urine drug tests (UDTs), OTAs, and other “opioid best practice” tools tend to be more likely to discontinue opioids for patients with aberrant opioidrelated behaviours; paradoxically, they are more likely to confidently prescribe opioids in the first place (15). These same practices may exacerbate bias and discrimination in pain management. For example, Black primary care patients are less likely to have their pain documented or to be seen by a pain specialist, but more likely to have higher numbers of UDTs and to be referred for substance abuse assessments (16). OTAs provide prior justification for this nonrandom screening. Results of these UDTs are inconsistently interpreted: when positive for heroin or cocaine, opioid renewal rates are significantly lower than if nonprescribed marijuana, opioids, or benzodiazepines are found (17). Yet, logically, concomitant use of so-called illicit drugs does not necessarily negate valid indications for opioids. Requiring patients to sign OTAs can be construed as coercive, particularly when presented as a mandatory condition to treatment. Coercion prevents informed consent in all circumstances (18). Patients, especially those with chronic pain, are by design placed into a situation where they have no choice but to sign an agreement that is physician-centric in order to obtain controlled medications, or risk being under-treated (19,20). One ethically concerning study forced patients already on chronic opioids into choosing to comply with OTAs and UDT, wean opioids, or leave the practice (21). No consideration in the analysis was given to factors in their decisions. Unsurprisingly, patients who sign OTAs worry more about having their opioids discontinued and feel less trusted by their doctor (22). As with other aspects of healthcare, the true meaning of OTAs remains inaccessible to the layperson. Only half of patients with OTAs are aware of them (23). The language used is typically eight grade levels above the recommended reading level for healthcare documents (24). It is reasonable to question whether patients can justifiably be threatened with penalties, when a significant portion of them cannot understand or acknowledge the very nature of their agreement, limiting true informed consent. Given that adequate pain control is a fundamental human right as well as a core obligation of physicians, we should be more vigilant about reducing these barriers to better treatment of chronic pain (25).

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Moving past treatment agreements OTAs were initially devised with positive intentions in the wake of increasing recognition of the harms of opioids, leading to uptake and inclusion of recommendations by regulatory and medicolegal bodies such as the CPSO to prevent opioid misuse and diversion. However, we need to openly acknowledge the limited high-quality evidence to date supporting their effectiveness and impact on patient-centered health outcomes (12,26,27). Recommendations for their use should be based on proven benefits and harms in practice. It is therefore difficult to draw meaningful conclusions on the effectiveness of OTAs or necessarily advocate for their exclusion from clinical practice. Physicians should utilize caution and reflect on their personal rationale for utilizing OTAs and the specific contents therein. In lieu of continuing to promote the use of OTAs via medical dogma and organizational standards, this defensive contractual approach to patient care should be modified into a less rigid, more individualized patient-centered approach. This will be an enormous challenge given their integration into many facets of medicine. Yet, their lack of certain benefits counterbalancing significant potential ethical issues calls for change at all levels. We encourage physicians to engage patients in a shared decision-making process where both parties can negotiate, settle on mutually agreeable goals for treatment, and carefully document informed consent for that plan (28). In a return to original intentions, more emphasis should be placed on communicating the potential benefits and harms of opioids, and frequent reevaluation of response and requirement for chronic opioid therapy should be strongly considered. Foreseeable challenges are that shared decision-making models of chronic opioid therapy and monitoring likely require more time, attention, and careful consideration in day-to-day practice. Many physicians may require additional support and education from their institutions, regulatory bodies, and government health authorities to effectively navigate such conversations with patients. At the minimum, health-care practitioners should be aware of the scope and limitations of the available evidence supporting OTAs in current clinical use. As a whole, we should advocate for more research and clinical integration of patient-centered outcomes and collaborative opioid treatment in primary care.

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Kirkpatrick AF, Derasari M, Kovacs PL, Lamb BD, Miller R, Reading A. A protocolcontract for opioid use in patients with chronic pain not due to malignancy. J Clin Anesth. 1998;10(5):435–43.

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Kahan M, Srivastava A, Wilson L, Mailis-Gagnon A, Midmer D. Opioids for managing chronic non-malignant pain: safe and effective prescribing. Can Fam Physician. 2006 Sep;52(9):1091–6.

Fishman SM, Bandman TB, Edwards A, Borsook D. The opioid contract in the management of chronic pain. J Pain Symptom Manage. 1999 Jul;18(1):27–37.

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Canadian Medical Protective Association. Opioids: We can do better [Internet]. 2016 [cited 2020 Nov 15]. Available from: https://www.cmpa-acpm.ca/static-assets/pdf/about/annualmeeting/com_16_opioid_We_can_do_better-e.pdf

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Arnold RM, Han PKJ, Seltzer D. Opioid contracts in chronic nonmalignant pain management: objectives and uncertainties. Am J Med. 2006 Apr;119(4):292–6.

Touchet BK, Yates WR, Coon KA. Opioid contract use is associated with physician training level and practice specialty. J Opioid Manag. 2005;1(4):195–200.

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Patchett D, Grover M, Kresin M, Bryan M, Nordrum J, Buras M, et al. The benefits of a standardized approach to opioid prescribing. J Fam Pract. 2019;68(6):E1–7.

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Hosain F, Lee J, Ata A, Bhullar RK, Chang AK. Physician Renewal of Chronically Prescribed Controlled Substances Based on Urine Drug Test Results. J Prim Care Community Health. 2019;10(101518419):2150132719883632.

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McCann KS, Barker S, Cousins R, Franks A, McDaniel C, Petrany S, et al. Structured Management of Chronic Nonmalignant Pain with Opioids in a Rural Primary Care Office. J Am Board Fam Med JABFM. 2018;31(1):57–63.

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Sherman KJ, Walker RL, Saunders K, Shortreed SM, Parchman M, Hansen RN, et al. Doctor-Patient Trust Among Chronic Pain Patients on Chronic Opioid Therapy after Opioid Risk Reduction Initiatives: A Survey. J Am Board Fam Med JABFM. 2018;31(4):578–87.

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Penko J, Mattson J, Miaskowski C, Kushel M. Do patients know they are on pain medication agreements? Results from a sample of high-risk patients on chronic opioid therapy. Pain Med Malden Mass. 2012;13(9):1174–80.

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Staehler TMM, Palombi LC. Beneficial opioid management strategies: A review of the evidence for the use of opioid treatment agreements. Subst Abuse. 2020 Apr 2;41(2):208– 15.

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Payne R, Anderson E, Arnold R, Duensing L, Gilson A, Green C, et al. A rose by any other name: pain contracts/agreements. Am J Bioeth AJOB. 2010;10(11):5–12.

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Commentary

The need for universal hepatitis C screening in incarcerated populations James Zhou1 and Fiona Kouyoumdijian2 1 2

Michael G. DeGroote School of Medicine, McMaster University Department of Family Medicine, McMaster University

Abstract Hepatitis C carries a large burden of disease in Canada. Barriers to care, especially in the incarcerated population, may impede effective treatment and the achievement of targets for disease eradication. Access to universal screening in incarcerated populations could support engagement in the care cascade, and local studies around prevalence and screening efficacy could be used to justify and inform screening programs. A focus on incarcerated populations is an important step toward HCV eradication and ensuring equitable healthcare for all. This article will discuss the HCV care cascade, the unique burden of HCV in correctional facilities, and provide an argument in support of universal screening in incarcerated populations.

Keywords: HCV, Hepatitis C, Universal screening, Prison(er) health, Incarcerated populations Corresponding author: james.zhou@medportal.ca

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Health burden of Hepatitis C Hepatitis C virus (HCV) is a bloodborne RNA flavivirus known to cause chronic liver disease (1). HCV can be transmitted vertically through childbirth, or horizontally through percutaneous blood exposure such as injection drug use. Following an acute, mostly asymptomatic infection, most patients will eventually develop chronic HCV, leading to cirrhosis and hepatocellular carcinoma. Globally, 71 million people currently live with chronic HCV, including 194 500 Canadians as of 2017 (2). Acknowledging the global health burden of HCV, the World Health Organization (WHO) has set a goal to eliminate the disease by 2030. The WHO intends to enhance the link between screening and treatment as the central pillar of their strategy (3). However, Canada is currently not on track to accomplish this target (4). In the context of national and international efforts to eliminate HCV, there is a need to define HCV epidemiology and engage people in the HCV care cascade, especially within subpopulations that experience a disproportionate burden of disease and barriers to care. The Hepatitis C care cascade Since the discovery of HCV in the late 1980s by Alter, Houghton, and Rice (5), substantial advances have been made in the diagnosis and treatment of this disease. The steps from diagnosis to treatment are collectively known as the HCV care cascade (Figure 1). Today, laboratory testing for the HCV antibody is the mainstay of screening, followed by RNA testing to confirm the active disease. Patients who test positive for HCV through screening or assessment are usually referred to a health care provider with expertise in HCV treatment. Treatment can then be initiated with direct-acting antivirals (DAA) over eight weeks or more, depending on the viral genotype (6). DAAs have a very high efficacy as they were seen to induce a sustained virologic response in 96.6% of cases and significant decreases in rates of cirrhosis and hepatocellular carcinoma (7). Therefore, early screening, diagnosis, and treatment of HCV in asymptomatic individuals can prevent these largely irreversible complications. Despite effective treatment options, care cascade engagement remains a common barrier to treatment. We define ‘engagement with the care cascade’ as ensuring that individuals at risk of HCV are offered appropriate screening, with subsequent linkage to diagnostic tests and treatment if indicated. Given bloodborne transmission of HCV, high-risk populations include those who share needles (e.g. related to injection drug use, tattooing), recipients of blood products (before 1992), and those who use drugs intranasally (8). In 2011, Trubnikov et al. estimated that 44% of Canadians with chronic HCV remain undiagnosed (9). O’Neill et al. found that only one-third of newly diagnosed HCV cases in Alberta were successfully referred to a specialist, and just 11% of new cases were prescribed treatment within two years (10). Untreated chronic HCV carries substantial societal costs, and in 2012, it was reported that HCV had the greatest burden of disease of any infectious pathogen in Ontario (12). In a 2014 study, Myers et al. estimated that by 2032, HCV will cost the Canadian healthcare system an estimated $260 million per year. 85

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Most of this amount is attributed to the medical and social costs of chronic disease management (12). Within the context of available treatment, the burden of undiagnosed HCV is enormous. In addition to the risk of preventable long-term complications, the undiagnosed and untreated population also represents a reservoir for further disease spread. Therefore, it is essential for high-risk populations to be screened and engaged in the care cascade as quickly and effectively as possible.

Figure 1. The HCV care cascade: screening, diagnosis, and treatment of hepatitis C virus (HCV) infection. Barriers exist in each step that prevent patients from progressing through the care cascade and accessing full treatment. Hepatitis C in Canadian incarcerated populations The prevalence of HCV is exceptionally high in the Canadian incarcerated population. In 2011, a study found that 25% of people in Quebec provincial correctional facilities were antibody positive – a prevalence rate 40 times higher than the general population (13). The high prevalence is a consequence of the high rates of injection drug use and needle sharing occurring within communities and during incarceration, in the context of the criminalization of drug use. Furthermore, a disproportionate percentage of people who experience incarceration are Indigenous, suffer from substance use disorders, or experience unstable housing situations. All these attributes are independently associated with a decreased likelihood of achieving milestones in the care cascade, adding an element of intersectionality within the incarcerated population (10). For the purposes of this paper, it is necessary to explain the difference between Canadian federal and provincial correctional facilities, as they are governed by different policies. People sentenced to 24 months or more are incarcerated in federal correctional facilities administered by the Correctional Service of Canada. Those serving less than 24 months and those who are detained while awaiting trial are held in provincial and territorial correctional facilities, administered by provincial/territorial governments (14). 86

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The time in correctional facilities provides an important opportunity to identify HCV infection through screening and to initiate engagement along the HCV care cascade (15). The Canadian Task Force on Preventive Health Care, the Canadian Association for the Study of the Liver, and the World Health Organization have all recommended universal HCV screening for people who experience imprisonment (7,16,17). There is currently routine screening in place at the time of admission to federal correctional facilities. However, in provincial and territorial correctional facilities, routine screening may not occur. Many common barriers to HCV care cascade engagement exist for people in these facilities (Table 1) including a short median length of stay and uncertainty regarding many people's release dates (18). Additional research and quality improvement are needed to address barriers to the HCV care cascade for those incarcerated in provincial correctional facilities. Table 1. Potential barriers to HCV care cascade engagement in provincial correctional facilities. Logistical barriers Short median length of stay Uncertainty around length of stay/date of release Interpersonal barriers Lack of trust between patients and healthcare providers Institutional barriers No universal screening policy Challenges in access to health care Focus on acute medical issues rather than preventive care Competing priorities Stress of incarceration Acute medical issues (e.g. withdrawal, lack of continuity of care) Legal issues Logistical, interpersonal, and institutional barriers to engagement with the HCV care cascade during incarceration in provincial correctional facilities. Universal opt-out screening is currently not implemented in Ontario provincial facilities (18). Universal screening Universal screening for HCV for people within provincial correctional facilities represents one way to support engagement in the care cascade. Universal screening involves consensual laboratory testing for all people admitted to correctional facilities, regardless of known risk factors for HCV. Integrating screening into the admission process would remove some barriers to the first step of the care cascade (Figure 1) since it would support access to testing for people with shorter imprisonment lengths. Thus, this policy change could increase the likelihood of people receiving their diagnostic results prior to release. Several trials have assessed the impact and cost-effectiveness of universal screening for HCV in prisons (19,20,21). A US modelling study identified voluntary opt-out screening in prisons as highly cost-effective while also reducing HCV transmission rates in the community. 87

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The researchers found estimated incremental cost-effectiveness ratios between $19 600 to $29 200 per quality-adjusted life-year (15). A UK trial found universal screening to be cost-effective if at least 40% of detected cases were linked with community treatment upon prison release (22). A separate trial demonstrated high cost-effectiveness if screening was followed up with an eightto-twelve-week DAA treatment in the community (23). Nevertheless, various limitations exist in implementing universal screening programs in Canadian provincial correctional facilities. While pilot trials have been promising, knowledge gaps regarding the widespread implementation of screening persist. For instance, a 2018 systematic review of HCV screening in prisons found no research assessing how enhanced screening measures impacted treatment uptake (24). It is still unknown if universal screening would lead to improved outcomes, such as lower incidence of cirrhosis and hepatocellular carcinoma. As screening represents only a portion of the care cascade, additional barriers exist for other stages which need to be addressed in tandem to generate meaningful health outcome improvements. For example, transportation to a specialist clinic for treatment was a major barrier in an Australian study of HCV in prisons (25). Connections to appropriate services for follow-up in the community upon release were also difficult to establish and maintain. Shorter incarceration times for those in provincial prisons may be insufficient to complete the DAA treatment course. These limitations identify potential areas for further research around HCV screening in incarcerated populations. Next steps To address gaps in knowledge regarding HCV epidemiology and its care cascade, we are conducting a study at a local provincial detention centre, with the goal of better understanding limitations in screening access for this population. At this facility, HCV screening is currently ordered by a physician. Given scarce healthcare resources, several weeks often pass between admission and initial physician consultation. In the context of short lengths of stay, many people may not see a physician or receive their screening results before discharge. Universal screening on admission could therefore remove this barrier to the HCV care cascade. However, it is necessary to first obtain objective data regarding the efficacy of the current physician-ordered, opt-in model. We will review patient charts to identify HCV risk factors and information on HCV status, HCV testing, referral for HCV care, and HCV treatment. We plan to link provincial public health laboratory data to ascertain data on positive tests in the community and correctional facilities. Finding low rates of screening and testing for people who experience incarceration, especially for people with multiple risk factors for HCV, will support the case for implementing universal opt-out screening in provincial correctional facilities in Ontario. Conclusion Hepatitis C carries a large burden of disease in Canada. Barriers to care, especially in the incarcerated population, may prevent effective treatment and the achievement of targets for 88

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eradication. Universal screening in this population could support engagement in the care cascade, and local studies around prevalence and screening efficacy could be used to justify and inform screening programs. A focus on incarcerated populations is an important step toward the goal of HCV eradication and to ensure equitable care for all.

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Surveillance of hepatitis C [Internet]. Government of Canada. 2020 [cited 21 December 2020]. Available from: https://www.canada.ca/en/public-health/services/diseases/hepatitisc/surveillance-hepatitis-c.html

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Kronfli N, Buxton J, Jennings L, Kouyoumdjian F, Wong A. Hepatitis C virus (HCV) care in Canadian correctional facilities: Where are we and where do we need to be?. Can Liver J. 2019 Jun;2(4):171-183.

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antiviral therapy cost‐effective in UK prisons? A prevention benefit analysis. Hepatol. 2016 Jun;63(6):1796-1808. 24.

Kronfli N, Linthwaite B, Kouyoumdjian F, Klein M, Lebouché B, Sebastiani G et al. Interventions to increase testing, linkage to care and treatment of hepatitis C virus (HCV) infection among people in prisons: A systematic review. Int J Drug Pol. 2018 Jul;57:95103.

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McMaster University Medical Journal, Vol. 18, Issue 1

Articles inside

THE NEED FOR UNIVERSAL HEPATITIS C SCREENING IN INCARCERATED POPULATIONS

TRIAGING OUT OF ELECTIVE SURGERIES DURING THE COVID-19 PANDEMIC: THE WRONG APPROACH?

SAFETY AND RISK FACTORS ASSOCIATED WITH ELECTRIC SCOOTER USE GLOBALLY: A LITERATURE REVIEW

COVID-19 LOCKDOWN: NOT A ONE-SIZE-FITS-ALL SOLUTION

HIGH-DOSE STEROIDS AND PENTOXIFYLLINE IN METHANOL-INDUCED OPTIC NEUROPATHY: A CASE REPORT AND REVIEW OF THE LITERATURE

PERI-OPERATIVE MANAGEMENT OF ACTH-SECRETING PANCREATIC NEUROENDOCRINE TUMOR AND MAJOR VESSEL RECONSTRUCTION

A RARE PRESENTATION OF AUTOIMMUNE LIMBIC ENCEPHALITIS WITH ANTI-YO ANTIBODIES: CASE REPORT

COEXISTENCE OF BANKART LESION AND ADHESIVE CAPSULITIS IN TWO SHOULDERS: A CASE REPORT