Inside: In search of an HIV vaccination Volume 13: Number 1. 2020 ISSN 2009-0838 smj

Royal College of Surgeons in Ireland RCSI Student Medical Journal

The story of narrative medicine RCSI DEVELOPING HEALTHCARE LEADERS WHO MAKE A DIFFERENCE WORLDWIDE

Acknowledgements

Thank you to the RCSI Alumni for their continued support of us as students – providing career advice, acting as mentors, enabling electives and research, and supporting the publication of the RCSIsmj since its inception in 2008.

As today’s generation of students and tomorrow’s generation of alumni, we are very grateful for this ongoing support.

A warm and special thanks to Prof. David Smith for the time and encouragement he has given to the RCSIsmj Ethics Challenge, and for his support of the annual debate.

We would also like to thank the Dean, Prof. Hannah McGee, for her sponsorship, and Margaret McCarthy in the Dean’s office for her constant endorsement and assistance.

The RCSIsmj was extremely privileged to have a number of professors and clinicians involved in this year’s journal clubs. We would very much like to thank the following individuals for their support of and participation in the journal club, and to express our appreciation of their time, knowledge, and expertise:

Prof. Arnold Hill Dr Mark Murphy Dr Jennifer Clarke RCSIsmj contents

4 Editorial Royal College of Surgeons in Ireland Student Medical Journal 4 Director’s welcome

Executive Committee Director Rachel Adilman RCSI Ethics Challenge Editor-in-Chief Alyssa Conti Peer Review Director Magar Ghazarian 5 RCSIsmj Ethics Challenge 2020/2021 Senior Editor Brian Li 6 RCSIsmj Ethics Challenge winner 2019/2020 Assistant Peer Review Director Alison Hunt Executive Secretary Audrey Potts Research spotlight Webmaster Tiffany Yeretsian 10 Biological differences matter Senior Peer Reviewer 12 AMG 510: the kryptonite of mutant KRASG12C Alexandr (Sacha) Magder

Peer Reviewers Interview Samantha Tso Savvy Benipal 14 Prof. Catherine Godson Michelle Gyenes Nikki Cliffe David Seligman Case reports Kassandra Gressmann 17 A case of spontaneous pneumomediastinum in an asthmatic young adult Jake McDonnell Jeremy Lau 22 Morvan syndrome: rare or underdiagnosed? Claire Gallibois Lori Israelian Alexa Higginbotham Original article Ananya Pentaparthy 26 Patient perception of health status in the setting of multimorbidity and polypharmacy: a Sean Coll Angela Joannou preliminary analysis of baseline SPPiRE trial data Blaire Beers-Mulroy Ashka Shah Jessica Iyer Review articles Flavia Dumitrascu 34 Have you tried zapping it? Neuromodulatory treatments for drug-resistant epilepsy Lisle Blackburn Eva Stolz 39 Blue light blocking glasses: should we all be wearing them? 45 The applications and limitations of the Tei index Senior Staff Writer Katie Nolan

Staff Writers Staff reviews Hannah Suchy 50 In search of a HIV vaccination: failures, successes, and innovations in eliciting humoral Deena Shah Christine Okeefe and cellular immunity against HIV Carol Rizkalla 56 Supercentenarians: a look into the lives of the world’s oldest old Aidan McKee 62 Living in lead: the evolution of interventional radiology Director of Education 69 3D models lead a revolution Sannihita Vatturi 75 Precision psychiatry: made-to-measure medicine Education Secretary Tayler Declan Ross 82 Marijuana in medicine: wonder drug or ‘I wonder if it really works’ drug?

Education Officers Matthew Patel Perspectives Harleen Jhinger 90 Remembering the Great War: figures of the First World War Fraser Jang-Milligan 95 Breaking the cycle of condescension: the medical hierarchy Public Relations Komal Marwaha 99 The story of narrative medicine Yavani Kulasingham 107 Gender identity and stigma

Abstracts JOURNALISM CONTENT DESIGN

112 3D in vitro collagen-based scaffold platform to study neuroblastoma growth and The Malthouse, 537 NCR, Dublin 1. migration T: 01-856 1166 F: 01-856 1169 www.thinkmedia.ie Design: Tony Byrne, Tom Cullen and Niamh Short Book review Editorial: Ann-Marie Hardiman, Paul O’Grady and Colm Quinn 114 The Soul of a Doctor

Please email comments to [email protected], join our Facebook page, or follow us on Twitter @RCSIsmj to discuss journal articles. Submissions to [email protected]. See www.rcsismj.com to find out more, see past editions, and to follow our blog.

Volume 13: Number 1. 2020 | Page 3 RCSIsmj editorial and director’s welcome

Looking back to see the future of healthcare

As 2020 marks the beginning of a new decade, we reawaken with how we as physicians can improve the lives of the transgender advancements in the field of medicine. However, in order to clearly see community. where we can go, we must take a step back and remember where we It is important to remember that medicine is as much an art as it is a have come from. In Volume 13 of the RCSIsmj we take a look at how science. As Hippocrates said: “Wherever the art of medicine is loved, medicine has transformed into what it is today, from Anirudh Gautam’s there is also a love of humanity”. perspective detailing the impact of the First World War, to Staff Writer It is an incredible honour to share RCSIsmj Volume 13 with you. I am Hannah Suchy’s and Senior Staff Writer Katie Nolan’s depictions of the continually inspired that the dedication and hard work of my peers evolution of specialties such as interventional radiology and precision manifests so eloquently in this journal. I hope you enjoy reading it as psychiatry. Medicine is about having the hindsight to learn from the much as we enjoyed creating it. lives of supercentenarians, portrayed by Staff Writer Christine Okeefe, while simultaneously advancing the field. This volume of the RCSIsmj pays special tribute to where the field of medicine has evolved from, while igniting excitement for where it can go. We recognise that the development of a HIV vaccine, the incorporation of 3D models in surgical planning, and the implementation of the Tei index in cardiology are paralleled with advancements in the humanistic foundations of medicine: how we can communicate with patients using a narrative approach; how we can Alyssa Conti improve medical education by adjusting the medical hierarchy; and, Editor-in-Chief, RCSIsmj 2019-2020

Director’s welcome

“We represented everything from paediatric cardiology to social work to detrimental effects of maltreatment and intimidation within medical public health, but we all loved to read and write. ‘Physicians ought to training, to a discussion on the importance of transgender health write,’ said another lecturer, Dr Louise Aronson, ‘for three reasons: to education and access, we trust that the topical works presented here will reflect, to memorialize, and to advocate.’ This mirrored physicians’ triple spark important discourse and reflection. obligation to self, patient, and society.” As always, the RCSIsmj would not be possible without the support and – Martina Scholtens MD encouragement of the Dean’s office, Prof. David Smith, many RCSI faculty members, and the tremendous publishing skills of Think Media – thank It is such a pleasure to present to you the 13th edition of the RCSIsmj, a you all. We hope you enjoy Volume 13! journal created and run entirely by students. Each year I am struck by the high calibre of research being undertaken, and articles being written, by RCSI students. Being involved with the RCSIsmj over the past three years has been a wonderful privilege. I have witnessed peer reviewers hone their skills in critical appraisal and leadership, we have published works from returning authors, and I’ve seen their passion for research and writing flourish from one year to the next. RCSI students continue to inspire and engage the RCSIsmj committee and our readers with the bold healthcare questions they ask and endeavour to Rachel Adilman answer in their articles; this year is no exception. From a look at the Director, RCSIsmj 2019-2020

Page 4 | Volume 13: Number 1. 2020 RCSIsmj prize

Ethics Challenge 2020/2021

The duty of candour: open disclosure of medical errors

The concept of open disclosure of medical error – and the ethicality of criminal repercussions for failure to disclose – is a current ‘hot button’ issue within the Irish medical system. For this year’s ethics challenge, we would like you to consider this debate from all angles, and construct an argument either in support of, or against, criminal sanctions for failure to properly disclose medical error.

Questions to address 1. Should open disclosure of medical error be mandated by law? 2. Should failure to properly disclose medical error result in criminal sanctions? What, if any, should be the criminal repercussions of failure to openly disclose? 3. Please discuss the ethical and legal issues surrounding this issue. 4. What professional impact might the threat of criminal sanctions have on physicians and trainees?

This is the twelfth installment of the RCSIsmj Ethics Challenge. Submission guidelines The editorial staff would like to congratulate Gerges Abdelsayed Please construct a lucid, structured, and well-presented discourse for on his winning essay in the 2019/2020 Ethics Challenge. Please the issues raised by this scenario. Please ensure that you have see page 6 for his submission. addressed all the questions highlighted and discuss these ethical We invite students to submit an essay discussing the ethical questions issues academically, making sure to reference when necessary. raised in the scenario presented. Medical ethics is an essential aspect Your paper should not exceed 2,000 words. of the medical curriculum and we hope to encourage RCSI Your essay will be evaluated on three major criteria: students to think critically about ethical situations that arise during 1. Ability to identify the ethical issues raised. their education and subsequent careers. All essays will be reviewed 2. Fluency of your arguments. by a faculty panel of experts and the winning essay will be published 3. Academic quality with regard to depth of research, appropriateness in the 2021 print edition of the RCSIsmj. The deadline for submission of references, and quality of sources. of entries will be separate from the general submission deadline for Good luck! the 2021 edition of the RCSIsmj. Please visit our website at www.rcsismj.com for specific dates. Please contact us at The winning entry will be presented with a prize at the launch [email protected] with any questions or concerns. of the next issue.

Volume 13: Number 1. 2020 | Page 5 RCSIsmj ethics challenge

ETHICS CHALLENGE WINNER 2019/2020 Conflicting clinician and parental wishes

Gerges Abdelsayed RCSI medical student

Introduction In 2019, the RCSIsmj introduced an ethical case challenge involving Neonatal care, at its core, is a very complex and multifaceted field in the conflicting clinician and parental wishes regarding the course of which ethical dilemmas often arise. Since neonates are not yet action for a newborn infant with hypoplastic left heart syndrome competent to make decisions regarding the care they receive, their (HLHS).1 Per the case, the newborn is currently on life-sustaining parents are assigned as surrogates. Parents, in collaboration with prostaglandin therapy, and has an estimated 75% chance of survival physicians, decide on the care the infant should receive.2 It is the at five years with surgical intervention. However, this intervention will physicians’ duty to act in the best interests of the neonate, attempting be very intensive, requiring three separate operations and a lengthy to maximise benefits and minimise harm to the infant, while still hospital stay. There is also a risk of neurological disability, and a attempting to respect and uphold parental wishes. Issues arise when chance that the child will require a heart transplant later in life. Due there is disagreement between parents and HCPs regarding the most to these factors, the child’s parents have requested that the appropriate management plan. The parents’ wishes should prostaglandin infusion be stopped, and the child be allowed to die. be respected within reason. However, who determines what is This request is contrary to the recommendations of the staff in the ‘within reason’? cardiology service, who suggest that the surgery be performed. This article aims to discuss the ethical and legal issues involved with Nonmaleficence this case, and how the clinical team should proceed. Using existing Nonmaleficence is defined as the duty to do no harm.3 HLHS is a research and guidelines on disagreements between parents and congenital heart malformation that occurs in approximately healthcare professionals (HCPs) within paediatric care, it asks: is the 0.016-0.036% of live births.4 It is described as a constellation of clinical team obligated to withdraw life-sustaining support, even cardiac malformations, all characterised by underdevelopment of the though they do not believe that it is in the child’s best interests? left ventricle.4 Before the Norwood procedure, which was first

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performed in 1979, HLHS was associated with 95% mortality, and application of medical futility as a reason to withdraw treatment was comfort care (palliation) was the accepted standard of care.4,5 featured prominently in the Charlie Gard v Great Britain case of 2017.10 Currently, intervention using the Norwood procedure confers Charlie Gard was an infant born with a severe genetic disorder.10 His 58-72% survival at five years of age.4 As surgical outcomes have parents requested treatment that his doctors believed to be futile. The improved, more neonatologists recommend surgical intervention for parents and doctors were unable to reach agreement on how to HLHS as opposed to end-of-life care.6 However, there is still a proceed, so the case was taken to the British Supreme Court. The significant risk of morbidity, reduced quality of life, and mortality with Court ruled in favour of the physicians, and Charlie’s artificial the procedure. Such morbidities include right ventricular (RV) ventilation was withdrawn.10 dysfunction, pulmonary artery occlusion and hypertension, This case was revolutionary in shifting the standards of medical thromboembolic strokes, developmental delay, hypoxic-ischaemic treatment for neonates, placing an emphasis on the patient’s best lesions, intracranial haemorrhage, and substantial functional interests rather than the family’s desires.10 Parents should be involved disability.4 Furthermore, there is very limited data on the long-term in decision making for their children; however, they do not have an prognosis with surgical intervention, as the oldest Norwood absolute, irrefutable right to refuse or require medical treatment for procedure survivors are still young adults.5 On account of these their child.10 factors, it is difficult to determine if the benefits of intervention In keeping with this, decisions on medical futility must be made on a outweigh the risks to the child and family, and the cost to the case-by-case basis, using patient beneficence to measure treatment healthcare system. These factors contribute to approximately 63% of futility. For a treatment to be deemed not futile, it must be beneficial parents opting for end-of-life comfort care.4 and in the patient’s best interest, improving their quality of life.7,8 The Norwood procedure meets these criteria when compared to no Since neonates are not yet competent intervention. However, the present lack of long-term follow-up and to make decisions regarding the care they survival data makes it difficult to determine whether or not the receive, their parents are assigned as procedure is compatible with a reasonable long-term quality of life in 11 surrogates. Parents, in collaboration with every HLHS case.

physicians, decide on the care the infant Autonomy should receive. Autonomy is defined as a patient’s right to make informed decisions on the care they receive.3 Due to the high risk of morbidity and Beneficence mortality, and uncertainty regarding prognosis with interventions for Beneficence is defined as the duty of a physician to act in a way that HLHS, obtaining informed consent is challenging. Parents are benefits the patient.3 Medical futility was first defined quantitatively burdened with deciding what plan of action is in the child’s best by Schneiderman as “any treatment that is ineffective in more than interest. They must consider the sanctity of life as compared to the 1% of attempts”.7 This definition depends solely on the physiological quality of life. Is survival better than death if it means an existence full outcome of the treatment, with no consideration of the benefits to of interventions and complications? To respect the parents’ autonomy the patient. Viewing medical futility in this way causes physician and assist them in deciding how to proceed, physicians must disclose paternalism and overtreatment of patients.8 One example of this is all available treatment options, and educate parents on the benefits illustrated by the Cruzan v Missouri Department of Health case in and risks of each.12 However, a study by Prsa et al. found that 99.7% 1990. This case involved a woman, Nancy Cruzan, who was left in a of paediatric cardiologists discussed surgery, 67% discussed persistent vegetative state following a road accident.9 Cruzan’s family transplantation, 62.2% discussed comfort care, and only 14.9% requested that she be taken off life support and allowed to die. discussed all possible options with parents of children with HLHS.6,13 However, Nancy’s doctors and the Missouri Supreme Court refused Furthermore, a study by Renalla et al. found that half of paediatric the request. This case facilitated the patients’ rights movement, residents and nurses would choose comfort care if their own infant helping to reform the laws behind the right to die. The Cruzan case had HLHS, a position found to be directly proportional to the number aided the establishment of better medical futility policies, as well as a of years spent as a paediatric healthcare professional.13,14 These new qualitative definition, where a treatment is now also considered findings are inconsistent with an open, shared decision-making model futile if it prolongs life without benefit to the patient.7,8 The of informed consent and respect for patient autonomy.15

Volume 13: Number 1. 2020 | Page 7 RCSIsmj ethics challenge

The role of a healthcare team is to show compassion, humility, The treatments are also very costly, leading to the debate on whether courage, honesty, and sensitivity, as well as to provide the patient or or not public health funds should be allocated to HLHS treatment. A guardians with all information regarding survival and follow-up typical Norwood procedure costs roughly $380,000 USD, and a statistics.2 HCPs should then assist the patient or decision makers typical cardiac transplant costs approximately $3,000,000 USD.18 Is with weighing the risks and benefits to come to a decision. Parents the allocation of these resources to such cases an injustice to other should be assured that the team will abide by their wishes, within patients who could have a larger benefit from the resources, or is it reason, and avoid desperate heroics. Hippocrates advised physicians unjust to limit resources to HLHS patients in this way by putting a “to refuse to treat those who are overmastered by their diseases, price on life? realising that in such case medicine is powerless”.7 A study by Bastek et al. found that, during consultations, a minority of neonatologists Decision helped parents to weigh the benefits and risks of treatment, and For a decision to be made, each of the four previously discussed rarely discussed ethical or social factors, or the infant’s quality of ethical principles must be weighted against one another. In such life.16 These findings are not in keeping with the current guidelines. cases, patient nonmaleficence should be given greater priority than Without being fully educated on all options, the parents’ decision beneficence. Patient autonomy is also very important; however, this may be driven by misinformation. Neonatologists must be expected is difficult in circumstances where the patient does not have the to discuss quality of life values, long-term outcomes, and other issues capacity to make their own decisions. Justice is a significant to give parents a chance at proper informed consent, allowing them consideration, as HCPs must take allocation of resources into to weigh all of their own options and come to an educated consideration. In this case, pursuing treatment using the Norwood decision.16 procedure may cause the neonate more harm than good, and may not be in their best interest. Deciding to perform the surgery would Studies have shown that mothers of also go directly against the parents’ wishes, breaching their infants with severe cardiovascular autonomy. Pursuing treatment would also cause unfairness in the disease, such as HLHS, suffer significant allocation of medical resources, as many other lives may be saved deterioration of mental well-being. with the healthcare costs required for this procedure. For these reasons, in this circumstance the parents’ decision should be Healthcare providers recognise these respected. factors, and a majority state that they Due to the nature of neonatal medicine, disagreements are bound to would not take a family to court for occur between physicians and parents. When this occurs, physicians refusing intervention for HLHS. should utilise the hospital’s ethics committee. A study by Schneiderman et al. found that 87% of HCPs and families agreed that Justice hospital ethics committees are a useful resource for managing Justice is defined as the fair and equitable distribution of healthcare.3 conflict.19 The committee would review the literature, then meet It is important to make an accepted standard of treatment available with the parents and physicians to further discuss moral and ethical to all infants born with HLHS. However, this is often not the case, as concerns regarding the case in question. large inequalities exist based on health system factors, such as organ The committee will also confirm that the parents are competent to availability, surgical skill, and facility quality.7 Many facilities do not make decisions on behalf of their infant.2,5 During these meetings, possess the resources or expertise required for HLHS treatments.4 If the committee will review the family’s motivation for their decision, treatment of a certain standard is offered to one infant with HLHS, to ensure that they are not acting out of fear, stress, lack of support, then it should be offered to all infants with HLHS at that same or misunderstanding. Children are not the possessions of their standard. Similarly, if end-of-life comfort care is offered to one family, parents, so the right of the parents to make decisions regarding care then it should be offered to all.17 Some physicians argue conscientious can be overridden in the case of incompetence, abuse, or neglect.7 objection, and may withhold end-of-life comfort care, even though it In the event that a decision cannot be reached by the committee, it is a reasonable and ethical option, due to their own beliefs.17 This is taken to the courts.19 injustice puts the physician’s autonomy above the patient’s and is an Due to the nature of HLHS and its treatment, a large financial and inexcusable exercise of power. emotional burden is placed on the family to care for the infant.

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Studies have shown that mothers of infants with severe cardiovascular can decide on the plan of action they wish to pursue. Infants with disease, such as HLHS, suffer significant deterioration of mental HLHS in Ireland are eligible for perinatal palliative care.21 However, well-being.20 Healthcare providers recognise these factors, and a parents do not always have the final say in such treatment decisions. majority state that they would not take a family to court for refusing If the healthcare team disagrees with the parents’ decision, they intervention for HLHS.5 should request further investigation into the case by the hospital’s ethics committee and the courts, who will then come to a decision Conclusion that should be respected by both the healthcare team and the family. Due to recent advances in treatment, HLHS has become a In this case, the parents’ decision should be respected. Overall, controversial condition. If left untreated, infant death occurs within intervention will come at a great cost to the infant, the family, and the three to four days.4 However, treatment may still carry considerable healthcare system. It will also provide very little benefit to the infant, risks to the patient, and may have little benefit to their quality of life. as risk of mortality still remains high. These factors must all be Due to the potential long-term impacts of surgical treatment, parents considered when making decisions with regard to conflicting parental must be given all available information on the condition so that they and clinician wishes.

References

1. RCSI Ethics Challenge. Royal College of Surgeons in Ireland Student 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430827/.

Medical Journal. 2019;12(1):5. 13. Isaacs D, Kilham HA. Ethical issues in hypoplastic left heart syndrome. J

2. Nadroo AM. Ethical dilemmas in decision making at limits of neonatal Paediatr Child Health. 2013;49(10):873.

viability. J IMA. 2012;43(3):188-92. 14. Renella P, Chang RKR, Ferry DA, Bart RD, Sklansky MS. Hypoplastic left heart

3. Gillon R. Medical ethics: four principles plus attention to scope. BMJ. syndrome: attitudes among pediatric residents and nurses towards fetal and

1994;309(6948):184-8. neonatal management. Prenat Diagn. 2007;27(11):1045-55.

4. Fruitman DS. Hypoplastic left heart syndrome: prognosis and management 15. Byrne PJ, Murphy A. Informed consent and hypoplastic left heart syndrome.

options. Paediatr Child Health. 2000;5(4):219-25. Acta Paediatr. 2007;94(9):1171-5.

5. Paul EA, Kohlberg EM, Orfali K. Growing discomfort with comfort care for 16. Bastek TK, Richardson DK, Zupancic JAF, Burns JP. Prenatal consultation

hypoplastic left heart syndrome: why we should still defer to parental practices at the border of viability: a regional survey. Pediatrics.

wishes. Am J Bioeth. 2017;17(7):67-8. 2005;116(2):407-13.

6. Prsa M, Holly CD, Carnevale FA, Justino H, Rohlicek CV. Attitudes and 17. Ross LF, Frader J. Hypoplastic left heart syndrome: a paradigm case for

practices of cardiologists and surgeons who manage HLHS. Pediatrics. examining conscientious objection in pediatric practice. J Pediatr.

2010;125(3):e625-30. 2009:155(1):12-5.

7. Pager CK. Dying of a broken heart: ethics and law in a case of hypoplastic 18. Urencio M, Greenleaf C, Salazar J, Dodge-Khatami A. Resource and cost

left heart syndrome. J Perinatol. 2000;20(8):535-9. considerations in treating hypoplastic left heart syndrome. Pediatric Health

8. Clark PA. Medical futility: legal and ethical analysis. Virtual Mentor Med Ther. 2016;7:149-53.

2007;9(5):375-83. 19. Linney M, Hain RDW, Wilkinson D, Fortune PM, Barclay S, Larcher V et al.

9. Taub S. “Departed, Jan 11, 1983; At Peace, Dec 26, 1990.” Virtual Mentor. Achieving consensus advice for paediatricians and other health

2001;3(7). professionals: on prevention, recognition and management of conflict in

10. Paris JJ, Ahluwalia J, Cummings BM, Moreland MP, Wilkinson DJ. The Charlie paediatric practice. Arch Dis Child. 2019;104(5):413-6.

Gard case: British and American approaches to court resolution of disputes 20. Grønning Dale MT, Solberg Ø, Holmstrøm H, Landolt MA,

over medical decisions. J Perinatol. 2017;37(12):1268-71. Eskedal LT, Vollrath ME. Well-being in mothers of children with

11. Malec E, Januszewska K, Kolczkolcz J, Pajak J. Factors influencing early congenital heart defects: a 3-year follow-up. Qual Life Res.

outcome of Norwood procedure for hypoplastic left heart syndrome. Eur J 2013;22(8):2063-72.

Cardio-thoracic Surg. 2000;18(2):202-6. 21. McGuinness D, Lalor JG. A systematic review of the evidence to support

12. Gossman W, Thornton I, Hipskind JE. Informed consent. [Updated 2019 July perinatal palliative care for the fetus and neonate. 2017. [Internet]. Available

10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; from: http://www.tara.tcd.ie/handle/2262/81703.

Volume 13: Number 1. 2020 | Page 9 RCSIsmj research spotlight

Biological differences matter

RCSI medical student AUDREY POTTS outlines research into sex-specific diagnosis of amnestic mild cognitive impairment.

Introduction The neurophysiological differences in brain structure and function patient care; however, these important findings are not accounted between binary biological sexes (male and female) are well for as often as they should be in the diagnosis of neurological established.1 These differences can lead to variations in the disease.5 susceptibility, presentation, clinical features, prognosis, and management of certain neurological diseases. For instance, it has Since there is no cure for Alzheimer’s been shown that there are clear sex-specific differences in the disease, early and accurate diagnosis is an behavioural manifestations of Alzheimer’s disease (AD), a important feature of the prognostic debilitating neurodegenerative disease that is the most common sequelae. This can potentially lead to cause of dementia worldwide.2 Ott et al. determined that biological improved patient outcomes and quality of males with AD show more apathy and vegetative signs, whereas life for a longer period of time. biological females show more reclusiveness and emotional lability.3 Further, in patients with AD who have moderate cognitive deterioration (Global Deterioration Scale score of 5 or 6), men Reducing diagnostic error in aMCI: accounting for more commonly demonstrate physical aggression, whereas women sex-specific verbal memory ability are more verbally agitated and have higher rates of anxiety and A recent cross-sectional study by Sundermann et al. has shown that depression.4 These differences allow clinicians to tailor AD using sex-specific verbal memory tests may more accurately diagnose management toward sex-specific presentations, leading to better amnestic mild cognitive impairment (aMCI), which is frequently

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attributed to early-stage AD.6 aMCI is defined as a “state of as well as cortical Aβ deposition, as biomarkers for AD pathology.6 circumscribed anterograde long-term memory impairment with The likelihood of having cortical amyloid positivity, an APOE e4 preserved general cognitive and social functioning”.2 Given the allele, and a positive CSF p-tau/Aβ ratio was significantly higher in strong predictability of the development of AD from aMCI, an FN women than true negative (TN) women. There were no accurate diagnosis of aMCI is crucial. differences in these rates in FN compared to true positive (TP) It is known that women outperform men in verbal memory, but the women, suggesting that the FN women were misdiagnosed, both usual non-sex-specific verbal memory tests typically used to using an objective measure of AD pathology as well as diagnosis aMCI and AD do not account for this difference.6 These neuropsychologically. Further, the likelihood of having cortical tests are adjusted for age and education level, but not sex. In this amyloid positivity, an APOE e4 allele, and a positive CSF p-tau/Aβ paper, the authors tested whether accounting for the difference in ratio was significantly lower in FP men than in TP men, suggesting verbal memory ability between sexes was associated with the opposite trend of aMCI diagnosis in men compared to women. under-diagnosis of aMCI in women and over-diagnosis in men, and whether the use of sex-stratified norms and cut-off scores can Conclusion improve these diagnostic errors.6 They also investigated whether This study has numerous implications for clinical practice. Firstly, it specific AD-associated markers, genetic markers, and biomarkers highlights the importance of recognising sex-specific differences validated these reclassifications. in neuropsychological ability to better diagnose and manage a The study included 453 women and 532 men selected from the patient with aMCI and, potentially, AD. Since there is no cure for Alzheimer’s Disease Neuroimaging Initiative (ADNI) database; these AD, early and accurate diagnosis is an important feature of the subjects did not have dementia and had neuropsychological and AD prognostic sequelae. pathological marker data at baseline.6 As expected, women This can potentially lead to improved patient outcomes and quality outperformed men on the Rey Auditory Verbal Learning Test of life for a longer period of time. Inaccurate diagnosis of aMCI and (RAVLT) and delayed recall test (p<0.001). When non-sex-specific AD may lead to unnecessary prescriptions, as well as undue stress for cut-off scores were used to diagnose aMCI, the frequency of aMCI patients and their families. Secondly, the study suggests that diagnosis was significantly higher in men than women. sex-specific neuropsychological testing can be useful in diagnosing However, when sex-specific norms and cut-off scores were used, other neurodegenerative or neurological conditions that use similar 10% of men were diagnosed as false positives (FP), and 10% of tests, such as Parkinson’s disease or non-Alzheimer’s dementia. This women were diagnosed as false negatives (FN).6 study is another example of the importance of accounting for These results correlated to the degree of AD pathology in the brain. sex-specific differences in neurology, and opens doors to new The authors used the presence or absence of the APOE e4 allele as a methods for diagnosis. Clinicians must be aware of these inherent genetic marker for AD pathology, and the cerebrospinal fluid (CSF) biological differences in order to provide more holistic and accurate ratio of hyperphosphorylated tau (p-tau181) to β-amyloid (Aβ42), patient care.

References

1. Attarian H, Brandes J, Dafer R, Gerard E, Giesser B. Sex differences in the 4. Zuidema SU, de Jonghe JF, Verhey FR, Koopmans RT. Predictors of

study of neurological illnesses. Behav Neurol. 2015;2015:676531. neuropsychiatric symptoms in nursing home patients: influence of gender

2. Keene CD, Montin TJ, Kuller LH. Epidemiology, pathology, and pathogenesis and dementia severity. Int J Geriatr Psychiatry. 2009;24(10):1079-86.

of Alzheimer disease. UpToDate. 2019. [Internet]. [cited 2019 October 20]. 5. Ott B, Lapane K, Gambassi G. Gender differences in the treatment of

Available from: https://www.uptodate.com/contents/epidemiology- behavior problems in Alzheimer’s disease. SAGe Study Group. Systemic

pathology-and-pathogenesis-of-alzheimer-disease. Assessment of Geriatric drug use via Epidemiology. Neurology.

3. Ott BR, Tate CA, Gordon NM, Heindel WC. Gender differences in the 2000;54(2):427-32.

behavioral manifestations of Alzheimer’s disease. J Am Geriatr Soc. 6. Sundermann EE, Maki P, Biegon A et al. Sex-specific norms for verbal

1996;44(5):583-7. memory tests may improve diagnostic accuracy of amnestic MCI.

Neurology. 2019;93(12):e1881-9.

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AMG 510: the kryptonite of G12C mutant KRAS

RCSI medical student LORI ISRAELIAN describes research that may have found a therapy for a gene mutation linked to millions of cancer deaths.

Over three decades of cancer therapy research have been dedicated adenocarcinomas.5 The substitution of guanine with nucleophilic to investigating the most frequently mutated oncogene: KRAS.1 cysteine disrupts the GTPase activity of KRAS so that it is persistently Approximately one million cancer deaths per year worldwide are active, forcing cells into a hyperproliferative state that increases traced to mutations in KRAS, which promote tumour formation and susceptibility to mutation.5 survival.2 Countless failed anti-KRAS therapies have deemed KRAS “undruggable”, as traditional medicinal chemistry seemed Not only did moderate doses of AMG 510 ill-equipped to design drugs against proteins, such as KRAS, with inhibit tumour progression in mice, 3 no obvious binding sites or “pockets”. Recently, the clinical but higher doses led to significant tumour development of a covalently binding small molecule known as regression. A similar result was found AMG 510 has suggested that it may be the most promising in immune-competent, CRISPR-designed anti-KRAS therapy.4 G12C KRAS resides within the RAS family of GTPase proteins described as mice that harboured the KRAS on/off switches for cell growth and proliferation. The desire to mutation. Such results prompted specifically target mutant KRASG12C stems from its presence in some of the advancement of AMG 510 the deadliest cancers, such as colorectal, pancreatic, and lung into clinical trials.

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Entry of AMG 510 into clinical trials marks milestone for treatment, one responder in the 180mg cohort exhibited a 34% anti-KRAS therapies reduction in tumour size, while a second responder, given 360mg, had AMG 510 is the first small molecule inhibitor of KRASG12C to enter clinical a 67% tumour shrinkage as shown via computed tomography (CT) trials.4 It was first discovered within a series of small molecule scans. An additional CT scan of the second responder, at 18 weeks from compounds, all of which were able to bind to an obscure pocket within treatment initiation, demonstrated total resolution of the target lesions.4 KRASG12C.4 Extensive electrophile screening and structure-based designs Insights into the mechanism of AMG 510 have also been discussed.4 have revealed that AMG 510 is able to bind to KRASG12C with substantially Immunophenotyping of KRASG12C tumours in mice following a four-day enhanced potency and specificity compared to any previously pursued course of AMG 510 showed heightened infiltration of T cells, primarily KRASG12C inhibitor.4 When irreversibly bound to AMG 510, KRASG12C is CD8+ cytotoxic T cells.4 held in an inactive state. Marked infiltration of macrophages was also reported. Of note, a Early functional assays conducted using KRASG12C mutant cell lines first specialised type of dendritic cell that is crucial for cytotoxic T cell priming showed that AMG 510 is able to inhibit KRASG12C and prevent the and activation was identified, one that may also be implicated in their downstream phosphorylation and activation of ERK, a mediator of cell recruitment.4 To determine whether the enhanced immunosurveillance proliferation.4 This result was supplemented by in vivo pharmacodynamic was a direct result of AMG 510 administration, KRASG12C tumour cells assays involving three separate KRASG12C tumour models, further were treated in vitro and immune-mediating genes were profiled. Of supporting its inhibitory effects on ERK-mediated tumour cell note, CXCL10 and CXCL11 were upregulated, two chemokines that are proliferation. known to play a pivotal role in anti-tumour immune responses.7 These In an additional component of the preclinical assessment, AMG 510 was results suggest that a heightened yet specific interplay of immune cells administered to mice xenografted with human tumours. Not only did may contribute to the efficacy of AMG 510. moderate doses of AMG 510 inhibit tumour progression in mice, but higher doses led to significant tumour regression.4 A similar result was Conclusion found in immune-competent, CRISPR-designed mice that harboured the The significance of the entry of a KRAS inhibitor to clinical trials cannot KRASG12C mutation.4 Such results prompted the advancement of AMG be overstated. Oncogenic KRAS has been referred to as the Holy Grail of 510 into clinical trials. certain cancers, indicating tremendous implications if AMG 510 is to Fast-tracked by the US Food and Drug Administration (FDA), AMG 510 succeed.8 Its inclusion in clinical trials is already an immense milestone for is currently undergoing clinical trials involving patients previously treated covalent, small molecule discovery, let alone anti-KRAS therapies. for metastatic non-small-cell lung carcinoma with a known KRASG12C Undoubtedly, the vast potential of novel technologies and inherent mutation.6 Participants were allocated to cohorts with escalating doses of competition among pharmaceutical companies will propel the orally administered AMG 510, with the first cohort receiving 180mg discovery of additional mutant KRAS inhibitors for treating cancers with (n=3) and the second cohort receiving 360mg (n=1).4 In just six weeks of poor prognoses.

References

1. Porru M, Pompili L, Caruso C, Biroccio A, Leonetti C. Targeting KRAS in 6. ClinicalTrials.gov. A phase 1/2, study evaluating the safety, tolerability,

metastatic colorectal cancer: current strategies and emerging opportunities. PK, and efficacy of AMG 510 in subjects with solid tumors with a

J Exp Clin Cancer Res. 2018;37(1):57. specific KRAS mutation (CodeBreak 100). 2019. [Internet]. [updated

2. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators 2019; cited 2019 December 18]. Available from:

in human disease. Cell. 2017;170(1):17-33. https://clinicaltrials.gov/ct2/show/NCT03600883.

3. Hobbs GA, Wittinghofer A, Der CJ. Selective targeting of the KRAS G12C 7. Tokunaga R et al. CXCL9, CXCL10, CXCL11/CXCR3 axis for immune

mutant: kicking KRAS when it’s down. Cancer Cell. 2016;29(3):251-3. activation – a target for novel cancer therapy. Cancer Treat Rev.

4. Canon J et al. The clinical KRAS (G12C) inhibitor AMG 510 drives 2018;63:40-7.

anti-tumour immunity. Nature. 2019;575(7781):217-23. 8. Agarwal A, Saif MW. KRAS in pancreatic cancer. Journal of the Pancreas.

5. Janes MR et al. Targeting KRAS mutant cancers with a covalent 2014;15(4):303-5.

G12C-specific inhibitor. Cell. 2018;172(3):578-89.

Volume 13: Number 1. 2020 | Page 13 RCSIsmj interview

Separating signal from noise

Senior staff writer KATIE NOLAN spoke to Prof. Catherine Godson about her life in research.

Diabetes is a condition that all medical students become well Diabetes is the leading cause of end-stage renal disease. As we acquainted with during medical school and on clinical understand more about the molecular mechanisms that drive diabetes placements. Your recent research has focused on mediators and its associated complications, it has become clear that inflammation of inflammation in diabetes-associated atherosclerosis plays an important role. and nephropathy. Can you tell our readers a little Inflammation is a vital process for the body to defend itself in response more about this? to trauma and infection. For inflammation to be effective, the ‘on Diabetes is a global healthcare crisis. Current statistics suggest that the switches’ and ‘off switches’ have to be very tightly regulated. We now global prevalence is almost 500 million persons and, alarmingly, appreciate that the same molecular processes that protect the body the greatest increase in prevalence is seen in low- and middle-income from trauma and infection are activated in numerous disease states countries. such as atherosclerosis, arthritis, chronic kidney disease, and diabetes. The impact of diabetes is mainly through the complications that arise. It For decades we have known the molecules that turn on inflammation is estimated that management and treatment of diabetes and associated and these have been the target of conventional pharmacological complications consume 10% of national health resources. Diabetes is interventions (anti-inflammatories). However, drugs that act as associated with macrovascular diseases such as atherosclerosis and anti-inflammatory agents may also compromise host defence and stroke, as well as microvasculature conditions, including retinopathy. cause other off-target effects. There is now an appreciation that specific

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molecules are generated that activate the ‘off switches’ in We hypothesise that mimicking the inflammation. We have found that these ‘off switches’ are vital to activity of such molecules might be an resolving inflammation and facilitating the return of tissues to the attractive therapeutic paradigm that pre-inflammatory state. We hypothesise that mimicking the activity could promote resolution without of such molecules might be an attractive therapeutic paradigm compromising the innate that could promote resolution without compromising the innate immune response. immune response. Working with Prof. Pat Guiry in the School of Chemistry at UCD, we have designed and characterised several novel small molecules that promote From your experience of mentoring clinical fellows, what the resolution of inflammation in cellular models and also in advice would you give for any medical student wishing to experimental models of disease characterised by acute inflammation pursue a joint clinician-scientist career path? including peritonitis, arthritis, and sepsis. Importantly, these molecules Take every opportunity you can with open arms. Start with modest do not compromise innate immune responses. We have also seen summer projects. Keep an open mind. Progress can be slow. Patience is efficacy of these molecules in chronic unresolved inflammation key. Approach principal investigators (PIs) who work in areas that you characterised by fibrosis, such as the micro and macrovascular find interesting, and with research teams that are accommodating and complications of diabetes. Fibrosis, as manifested in diabetic kidney have critical mass. Volunteer to help out in labs during the pre-clinical disease, has traditionally been considered an irreversible process leading years. Not only do you have the satisfaction of contributing, but it also to organ failure. The fact that our lead molecules drive the regression of helps consolidate some of the more arcane learning that you may be diabetic kidney disease and atherosclerosis is especially interesting, as it exposed to. It might be a cliché, but ‘I hear and I forget, I see and I suggests that fibrosis can be reversed and hints at the cellular plasticity remember, I do and I understand’! Participate in journal clubs and that may underlie regeneration and repair. These investigations are research meetings. Submit abstracts; learn to write scientific papers. Be part of an ongoing collaboration between Dr Eoin Brennan in my humble; it is the easiest way to learn. The resilience that you will develop lab, and Prof. Mark Cooper and Dr Phil Kantharidis in Melbourne. in a research environment will be an enabler for future career Our investigations are funded by the JDRF New York, Science development. Discovery and the generation of new knowledge is really Foundation Ireland, and the Australian National Health and Medical thrilling. Clinician-scientist training and careers in Ireland are relatively Research Council. under-developed, although this has greatly improved of late with the academic intern programmes and the Wellcome/Health Research Board What is the most fulfilling part of your work? Irish Clinical Academic Training (ICAT) programme. However, if you are Working as part of a team and watching more junior investigators not part of a dedicated structure, but are enthusiastic and committed, develop the rigour, integrity, and creativity that is really essential there are other routes and it is about finding your niche with the right PI to progress in research. It is great to be challenged by my colleagues and mentors to support you. and frequently proven wrong as they surpass me with their knowledge and insights. You conducted your postdoctoral research in the United States in both San Diego and Harvard. Did you find your As a professor of molecular medicine and with a long career time there gave you greater opportunity for your research? of medical research, how important do you think it is for Would you recommend this experience to Irish graduates? clinicians and junior doctors to understand and be involved I spent over 10 years working in leading academic institutions (UC San actively in research? Diego (UCSD) and Harvard). These were the most exhilarating times. I It is vital that clinicians and junior doctors have an appreciation of and had been rigorously trained, albeit with limited resources, during my exposure to research during their training. Every diagnostic, therapeutic, undergraduate and PhD degrees in Ireland. And to then find myself with and procedural decision that is made is based on the outcome of an extraordinary opportunity and an uncommonly supportive PI at research. Research is dynamic and the ability to critically evaluate UCSD was fantastic. I saw first hand the advantages of collaboration, processes and procedures is essential for any clinician. In an era of access to enabling technologies, and a critical mass of committed unqualified information, early exposure to research methodologies can researchers and very impressive MD PhD students. Within my first year, help students separate signal from noise. I had published a major paper. I also developed a great professional

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A life in science Prof. Catherine Godson has an undergraduate degree in biochemistry from UCD, completed her PhD in pharmacology at UCD, and undertook her postdoctoral research in Geneva, UC San Diego, and Harvard. She is the Director of the UCD Diabetes Complications Research Centre, Professor of Molecular Medicine in UCD, and Chair of the Royal Irish Academy Life and Medical Sciences Committee. In 2019, she was the recipient of the International Association of Inflammation Societies (IAIS) Women in Science Award, and presented a lecture on her research at the 14th World Congress on Inflammation in Sydney, Australia.

network and many enduring friendships, which have, in turn, as a mentor reflect some of these experiences. Prof. Paul Insel at generated opportunities for people in my lab and for colleagues. UCSD was a brilliant enthusiast who really empowered the people in A definite strength of our national biomedical research community is his lab with an expectation of excellence. After returning to UCD I that typically, PIs have spent time abroad. International exposure is worked closely with two highly complementary mentors: Prof. Finian really important for any biomedical research professional, not Martin and Dr Hugh Brady. The team in my lab and our international necessarily because things are always better, but because it is collaborators are a constant inspiration and challenge to be the important to see things done differently. Science is an international best. My immediate family (my husband and three young adult enterprise and we have to stay connected to stay meaningful children) have also guided me with regular reality checks and and competitive. supportive interest.

You received the IAIS 2019 Women in Science Award. As a Science is an international enterprise and trailblazer in medical research, do you find it rewarding to we have to stay connected to stay mentor future clinician-scientists? meaningful and competitive. The most rewarding aspect of my career is training the next generation of biomedical scientists to become independent, fulfilled scientists and clinician-scientists. What do you feel is your biggest career achievement to date? I take huge pride in their achievements and whatever contribution I My biggest career achievement and legacy are the independent may have made in getting them to the starting blocks from where their researchers that I have trained. I take great pride in the fact that within own knowledge and creativity will propel them forward. I was two years of returning from the United States, we were publishing at delighted to receive the IAIS Award on behalf of my lab members, past the same level from our Mater/UCD lab as I had previously been and present. This award from the World Congress of Inflammation publishing from Massachusetts General Hospital/Harvard. We recognises their contributions at the highest level. have made some discoveries about fundamental biological processes regulating the initiation, progression, and regression of Who inspired you/guided you along your career path? diabetic complications. My parents were very supportive of all their kids’ academic Very importantly, these findings have been replicated in numerous aspirations. At school, my introduction to the periodic table in first international labs. As explained above, these investigations have made year ignited my fascination with science. As an undergraduate at significant contributions to develop novel therapeutic strategies that UCD, I was really inspired by the remarkable Dr Maura Beary. I did my mimic endogenous processes promoting the resolution of undergrad research project in her lab. I still remember how exciting it inflammation. It has been a significant achievement to keep a basic was to take responsibility for my own experiments. I have been very biomedical research lab open and contributing at an internationally fortunate in being supported by extraordinarily generous and competitive level through the catastrophic changes in funding policy ambitious mentors throughout my career and I hope that my efforts we have endured over the past several years.

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A case of spontaneous pneumomediastinum in an asthmatic young adult

Abstract Spontaneous pneumomediastinum (SPM), also known as Hamman’s syndrome, refers to the presence of air in the mediastinum. It is an unusual cause of chest pain and dyspnoea in the adult and paediatric populations, with smoking and acute asthma exacerbations being significant causative factors. The diagnosis of SPM requires either chest radiography or computed tomography (CT), and management is conservative therapy with oxygen and analgesia. This review presents the case of a 20-year-old female who presented to the Accident and Emergency Department with SPM resulting from poorly controlled asthma, air travel, and strenuous exercise.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 17-21.

Introduction Spontaneous pneumomediastinum (SPM), also increased in centres that screen patients with Isobel Dobbin-Sears known as Hamman’s syndrome, is a rare cause of dyspnoea and chest pain.1 It should be considered RCSI medical student chest pain in the paediatric and adult populations. in patients presenting with these symptoms. It is an uncommon, underdiagnosed condition in Pneumomediastinum may be spontaneous, Mary Wang which gas accumulates in the mediastinum as a traumatic, or iatrogenic. SPM is induced by Medical resident, Cleveland result of either alveolar rupture or, more rarely, sudden pressure changes in the mediastinum and Clinic, Ohio, USA through direct entry from the gastrointestinal tract increased alveolar pressure.1-3 The risk factors for or the upper airway.1 It occurs in 1 in 800 to 1 in SPM include medical and surgical conditions, such 42,000 hospital patients, although diagnosis is as chronic obstructive pulmonary disease and

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oesophageal rupture, and respiratory manoeuvres such as inhaling was also having nocturnal asthma exacerbations approximately five deeply, strenuous exercise, coughing, and vomiting, which trigger nights per week, which woke her from sleep. She used an additional the Valsalva manoeuvre.1 It is usually seen in young men.1-3 One of the 10 puffs of salbutamol during these events. MW was also using a most common precipitants of SPM is an acute asthma exacerbation, maintenance inhaler: fluticasone propionate/salmeterol (250/25mcg) during which bronchoconstriction results in increased pressure in the twice daily. She was not taking any form of contraception and took alveoli and can lead to alveolar rupture and subsequent leakage of air no other medications. MW disclosed no known allergies, although into the mediastinum.1,2 she did report having childhood eczema and a mild contact allergy to SPM presents most commonly with retrosternal pleuritic chest pain, latex, resulting in a rash. There was no other medical or surgical dyspnoea, and Hamman’s sign, defined as mediastinal crackles during history of note. systole.1,3,4 Before a diagnosis of SPM is made, more sinister cardiac, pulmonary, and pleural causes of the patient’s signs and symptoms Clinical examination must be ruled out.3 The patient’s vital signs on presentation were as follows: respiratory The diagnostic gold standard is computed tomography (CT) of the rate 28 breaths/minute; heart rate 114 beats/minute; temperature chest.5 Management is usually conservative, and the prognosis is very 36.8º Celsius; oxygen saturation 98% on room air; and, blood good.1,5 Despite complications being rare, they can be quite severe pressure 122/81mmHg. and include pneumopericardium, pneumothorax, compression of the In A&E, the patient was in obvious respiratory distress and was structures of the thorax, and pneumorrhachis.1,5 These should be tachypnoeic. MW was holding a tripod position, with expiratory and considered in any patient presenting with SPM. inspiratory wheezing audible at the bedside, and she had a non-productive cough. She was alert and orientated to person, Case summary time, and place, and was not cyanotic. Examination of the hands MW, a 20-year-old female, presented by car to the accident and and skin was unremarkable; there was no swelling, colour change, emergency (A&E) department with recent-onset chest pain and or tenderness in the lower extremities. Closer inspection of the shortness of breath, after a seven-hour transatlantic flight. anterior and posterior chest wall showed symmetrical movement; Approximately three hours after the flight, at 19.00 hours, MW was however, chest wall expansion was decreased at 4cm. The playing ice hockey and began to experience chest pain and the percussion note was mildly hyper-resonant bilaterally. Expiratory sensation of “not being able to take in a full breath”. and inspiratory wheezes, louder on expiration, were present This pain continued to increase throughout the evening, and MW diffusely throughout the lungs, with decreased air entry bilaterally. experienced dyspnoea beginning at approximately 22.00 hours. MW Cardiac examination was unremarkable with the exception of attributed this shortness of breath to her poorly controlled asthma. tachycardia. At 02.00 the following morning, MW was awakened from sleep by chest pain and severe shortness of breath, prompting her to attend Management and outcome the A&E. After triage assessment, the patient was admitted to an At the hospital, her chest pain was 5/10 in severity, and was described observation bed within the emergency department. Continuous as a crushing, retrosternal pain that felt sharp on inhalation, and electrocardiograph (ECG) monitoring and pulse oximetry was radiated into her shoulders and neck. Nothing alleviated the pain, commenced. Blood was taken for a full blood count with which was constantly present since onset, and had been increasing in differentials, serum chemistry, coagulation studies including intensity since it began at 19.00 hours the previous day. She denied d-dimer, and cardiac enzymes. any leg pain, changes in appearance to her legs, pre-syncope, or loss Anterior-posterior and lateral chest radiographs were performed, of consciousness, but she reported feeling anxious and fatigued. MW with no findings suggestive of pneumothorax, pulmonary used salbutamol but denied any other drug use, including illicit embolus, or other focal lung abnormalities. Her blood work substances. showed negative cardiac markers and a positive d-dimer (Table 1). At the time of her presentation, MW was only able to speak in short Beta human chorionic gonadotropin was negative. Pre-emptive sentences. She indicated that she had poorly controlled asthma with heparin was administered. A chest CT with contrast was ordered, nearly constant daytime exacerbations. These were relieved with the which showed an extensive pneumomediastinum (Table 2 and use of salbutamol as needed, approximately 15-20 puffs per day. MW Figure 1).

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Table 1: Laboratory tests.

Test: CBC with differentials Collected 22/12/2014 05.11 Result name Results Units Reference range

Leukocyte count 11.8 H X 109/L 4.0-11.0 Erythrocyte count 4.72 X 109/L 3.80-5.20 Haemoglobin 124 g/L 115-165 Haematocrit 0.385 0.360-0.460 Mean cell volume 82 fL 78-100 Mean cell haemoglobin 26.3 L pg 27.0-34.0 Mean cell haemoglobin concentration 323 g/L 320-370 Red cell distribution width 15.5 H % 11.5-14.5 Platelet count 348 X 109/L 150-400 Mean platelet volume 9.2 fL 3.0-11.0 Neutrophils 0.7 Lymphocytes 0.18 Monocytes 0.06 Eosinophils 0.05 Basophils 0.01 Neutrophils # 8.3 H X 109/L 1.5-8.0 Lymphocytes # 2.1 X 109/L 1.0-4.8 Monocytes # 0.8 X 109/L 0.0-1.5 Eosinophils # 0.6 X 109/L 0.00-0.50 Basophils # 0.1 X 109/L 0.0-0.3

Test: Routine blood chemistry-serum Collected 22/12/2014 05.11 Result name Results Units Reference range

Glucose-random 4.6 mmol/L Urea 4.9 mmol/L 2.3-7.6 Creatinine 67 mmol/L 46-92 Sodium 141 mmol/L 135-145 Potassium 3.7 mmol/L 3.6-5.0 Chloride 107 mmol/L 98-108 Bicarbonate 24 mmol/L 21-31 Anion gap 10.9 mmol/L AST 21 U/L 14-36 ALT 21 U/L 6-52 ALP 61 U/L 40-142 CK 176 H U/L 20-135 Total bilirubin 6 µmol/L 3-22 Amylase 49 U/L 30-110 Lipase 90 U/L 23-300 Troponin-I <0.012 µg/L 0.000-0.034

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Table 1: Laboratory tests (cont’d).

Test: Coagulation studies Collected 22/12/2014 05.11 Patient not on anticoagulation therapy Result name Results Units Reference range

INR 1.0 0.9-1.1

PTT 32 Seconds 28-36

D-dimer 387 H ng/ml 0-230

Test: Urine HCG Collected 22/12/2014 07.40 Result name Result Reference range

Urine HCG Negative Negative

Minimum detection level: 25I U/L

Table 2: Radiology report.

Test: Chest x-ray, two views There is extensive pneumomediastinum noted on the current exam Report dictated: 12/22/2014 08.51.25 extending towards the neck into the mediastinum and mildly Findings: The lung and pleural spaces are clear. The cardiomediastinal surrounding the heart. Even in retrospect, this is essentially contour is within normal limits. The bones are normal. non-appreciable by plain radiograph. Impression: Normal chest radiograph Thyroid is unremarkable. Aorta and main pulmonary artery are within normal limits. The heart is unremarkable. Trachea Test: CT chest (rule out pulmonary embolism) and oesophagus are midline and unremarkable. No evidence Report dictated 12/22/2014 09.25.59 of enlarged mediastinal lymph nodes. Soft tissues are within Technique: Axial images were acquired through the chest with normal limits. multiplanar reformats with intravenous contrast. Lung and pleural spaces are clear. Findings: No evidence of pulmonary embolus to the level of the No aggressive bony lesions. subsegmental pulmonary arteries. Impression: Extensive pneumomediastinum.

FIGURE 1: Chest CT images. A. Axial chest CT image with contrast, showing pneumomediastinum. B. Axial chest CT image with contrast, showing pneumomediastinum. C. Sagittal chest CT image with contrast, showing air in anterior mediastinum.

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The patient completed three rounds of eight puffs of salbutamol yield indicative signs, including the ‘thymic sail sign’, indicating air 100mcg and eight puffs of ipratropium 34mcg. The patient’s around the thymus, and the ‘tubular artery sign’, indicating air audible wheeze improved, and her respiratory rate decreased to around the great vessels; however, CT scan with oral contrast is the approximately 24 breaths per minute. Because her pain was gold standard for diagnosis, and indeed it revealed SPM in this tolerable she did not receive analgesia. She was monitored until patient.3,5 Endoscopy may be required if bronchial or oesophageal her respirations became stable. The patient was subsequently rupture is suspected.5 discharged with a referral to a pulmonary specialist to manage Ultrasound has recently been found to be a useful screening and the pneumomediastinum, assess lung function, and optimise diagnostic tool in SPM, particularly given its ease of use in the asthma management. emergency room setting; of note, ultrasound findings must be confirmed using other imaging techniques.1 This case illustrates the importance SPM has a very good prognosis and very low recurrence rates.1,5 of considering the rare diagnosis of Conservative management with supplemental oxygen and SPM in young patients presenting with analgesia, when required, is effective in adult and paediatric 3,4,7 unexplained chest pain and dyspnoea, populations. In cases where inflammatory markers are deranged, antibiotics may also be given.4 Although SPM is usually particularly in patients with benign, careful patient monitoring should be considered multiple risk factors. as complications may arise, including pneumothorax, pneumopericardium, cardiac tamponade, and respiratory Discussion failure.1,3,5 MW’s history of respiratory pathology and the onset of chest pain during exertion suggested that the likely origin of her SPM was a Conclusion combination of poorly controlled asthma, recent air travel and This case illustrates the importance of considering the rare barometric pressure changes, recent exertion causing Valsalva diagnosis of SPM in young patients presenting with unexplained manoeuvres, and the frequent inhalation of salbutamol. chest pain and dyspnoea, particularly in patients with multiple risk These precipitants each resulted in increased intrathoracic factors. Lack of early intervention and monitoring may lead to pressure, leading to alveolar rupture and, ultimately, dissection complications, including pneumopericardium, pneumothorax, of air through the perivascular and peribronchial sheaths into compression of the structures of the thorax, and pneumorrhachis the mediastinum.1-3,6 – all life-threatening conditions.1,3,5 Despite these risks, most The initial investigation for suspected SPM is usually a chest patients with SPM can be well controlled in the hospital setting radiograph with anterior-posterior and lateral views.5 Radiographs and have an excellent prognosis.1,5

References 1. Alishlash AS, Janahi IA. Spontaneous pneumomediastinum in children and 4. Langwieler TE, Steffani KD, Bogoevski DP, Mann O, Izbicki JR. Spontaneous

adolescents. UpToDate. 2019. [Internet]. [cited 2019 Oct 19]. Available from: pneumomediastinum. Ann Thorac Surg. 2004;78(2):711-3.

https://www.uptodate.com/contents/spontaneous-pneumomediastinum-in-c 5. Mohamed W, Exley C, Sutcliffe IM, Dwarakanath D. Spontaneous

hildren-and-adolescents. pneumomediastinum (Hamman’s syndrome): presenting as acute severe

2. Caceres M, Ali SZ, Braud R, Weiman D, Garrett HE. Spontaneous asthma. J R Coll Physicians Edinb. 2019;49(1):31-3.

pneumomediastinum: a comparative study and review of the literature. Ann 6. Kouritas VK, Papagiannopoulos K, Lazaridis G et al. Pneumomediastinum. J

Thorac Surg. 2008;86(3):962-6. Thorac Dis. 2015;7(Suppl. 1):S44-9.

3. Kara H, Uyar HG, Oncel M. Dyspnoea and chest pain as the presenting 7. Noorbakhsh KA, Williams AE, Langham JJW. Management and outcomes of

symptoms of pneumomediastinum: two cases and a review of the literature. spontaneous pneumomediastinum in children. Pediatr Emerg Care. 2019:

Cardiovasc J Afr. 2005;26(6):e1-4. doi: 10.1097/PEC.0000000000001895 [epub ahead of print].

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Morvan syndrome: rare or underdiagnosed?

Abstract Morvan syndrome is a rare form of encephalitis with a highly variable presentation, making it largely unknown and under-reported. Patients who remain undiagnosed are likely to undergo rapid clinical deterioration. Quick diagnosis and treatment with immunomodulatory drugs such as steroids and intravenous immunoglobulin may reduce complications, and in many cases has been demonstrated to be curative. Presented here is the case of an 82-year-old man who received a delayed diagnosis of Morvan syndrome after presenting with vague symptoms that Hannah Suchy did not prompt immediate neurological review. The case illustrates the unique nature of Dylan Viani Walsh Morvan syndrome, as well as the importance of early recognition and treatment of the RCSI medical students condition.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 22-25.

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Background Case report Morvan syndrome is a rare neurological condition that was first JM is an 82-year-old previously well man, who presented to the described in 1890. Few cases have been documented, with only 80 emergency department (ED) following an episode of loss of reported in the literature as of April 2019.1 This form of consciousness lasting 10 to 15 minutes that was witnessed by his encephalitis is characterised by hyperexcitability of the central, family. During this episode his eyes were open, he was unresponsive peripheral, and autonomic nervous systems due to production of to vocal stimuli, and he exhibited no tonic or clonic movements. antibodies against voltage gated potassium channels (VGKC), There was no facial droop, limb weakness, or slurred speech. He which function in neuronal signal transmission.1 There are multiple reported no chest pain or palpitations. proteins that make up the VGKC complexes, resulting in the potential for numerous types of antibodies associated with At the time of presentation, the the disease. differential diagnosis for JM included The most common antibodies that have been identified to date cardiac syncope, delirium, transient 1 target two key proteins, known as Caspr2 and LGI1. These ischaemic attack, and early dementia, proteins are believed to be critical for proper central and and thus he did not initially receive autonomic nervous system function, and the resulting antibodies a neurology consultation. cause neuronal hyperexcitation.1 Consequently, typical features of reported cases of Morvan syndrome include encephalopathy, insomnia, hallucinations, JM’s past medical history was significant for hypertension, diverticular delirium, confusion, autonomic instability, and peripheral disease, and depression. JM had also been suffering with insomnia for nervous system features such as neuropathic pain, areflexia, the previous six weeks, and had been treated for two weeks prior to and myokymia.1 his ED admission. Subsequent history taking also revealed that, for the The precise aetiology of Morvan syndrome has not yet been previous six weeks, JM had been experiencing difficulty with balance elucidated, though it is currently believed to be autoimmune in accompanied by a burning sensation in his feet, along with two origin. However, several cases report an association with thymoma recent falls and intermittent confusion. or other malignancy, and thus diagnostic work-up may involve On initial examination in the ED, JM was alert and oriented to person, imaging to assess for evidence of a tumour.1 place, and time. Glasgow Coma Scale (GCS) was 15/15 with a normal Interestingly, the disease is noted to affect males almost exclusively, neurological exam at the time aside from some instability on with only one case documented in a female in the English standing. Respiratory and cardiovascular exams were grossly literature, resulting in an additional hypothesis that the unremarkable, though a right bundle branch block was noted on male reproductive system produces antigens to which the electrocardiogram (ECG). He had mildly impaired renal function but antibodies bind.2 otherwise normal laboratory results. At the time of presentation, the Unfortunately, given its highly variable presentation and differential diagnosis for JM included cardiac syncope, delirium, non-specific symptoms, making a diagnosis of Morvan syndrome is transient ischaemic attack, and early dementia, and thus he did not challenging and often results in delayed treatment. This is the case initially receive a neurology consultation. of JM, an 82-year-old man who, after extensive work-up, was Within a few days of admission to the hospital, JM was found to have ultimately diagnosed with Morvan syndrome. regular, asymptomatic premature ventricular contractions (PVCs) on ECG, and suffered numerous falls presumed to be the consequence of Interestingly, the disease is noted to severe postural hypotension, as significant drops in systolic blood affect males almost exclusively, with pressure were noted when JM moved from sitting to standing. Level only one case documented in a female of consciousness deteriorated (GCS 11/15) over the course of his in the English literature, resulting in admission, and JM developed intermittent confusion, profound drowsiness, and visual hallucinations in which he reported seeing an additional hypothesis that the people who weren’t there. Initially, this progression was put down to male reproductive system produces delirium resulting from infection as he, at one point, became febrile antigens to which the antibodies bind. with a cough and right lower lobe crepitations. However, he was

Volume 13: Number 1. 2020 | Page 23 RCSIsmj case report

Double negative LGI1 Caspr2 Caspr2 and LGI1

Seizure + ++++ +++ +

Faciobrachial dystonic seizures (FBDS) - +++ - + CNS

Amnesia + ++++ +++ ++

Personality change + +++ ++ ++

Movement disorder + + + +

Dysautonomia - + +++ +++ PNS Neuromyotonia + + ++ +++

Pain + + ++ +++

Tumour + + ++ +++ Other Other neurological diseases + - ± -

Healthy controls + - - -

FIGURE 1: Clinical presentation of Morvan syndrome based on presence of autoantibodies: double negative, LGI1, Caspr2, and double positive (both Caspr2 and LGI1 antibodies).4 treated with antibiotics, which failed to improve his cognition and symptoms and deterioration. Assessment of cerebrospinal neurological symptoms. Consequently, he had a tonic-clonic seizure. fluid ruled out infection, while a routine electroencephalogram This clinical deterioration prompted neurological review. (EEG) ruled out active epileptiform discharges while on A full neurological exam, performed two weeks after JM’s admission, anti-seizure treatment. demonstrated profound orthostatic hypotension and fluctuating Electromyogram (EMG) was technically difficult and failed to reveal levels of consciousness. On examination of the lower limbs, there was myokymia or neuromyotonia. Once a consultant neurologist 5/5 power, bilateral hyporeflexia (+1) of the knee jerk reflex, loss of became involved, the progressive decline in cognition and ankle jerk reflexes bilaterally, absent vibratory sensation below the autonomic dysfunction alerted her to have a high clinical suspicion thighs bilaterally, absent proprioception bilaterally, and fasciculations of Morvan syndrome and empirical treatment with intravenous in the hamstrings and calf muscles. On examination of the upper immunoglobulin (IVIG) and high-dose intravenous steroid limbs, JM had 5/5 power bilaterally, hyporeflexia (+1) on left and was started. right bicep and tricep reflexes, absent proprioception, but preserved vibration bilaterally. He had also experienced progressive On examination of the lower limbs, weight loss since admission. At the time of the exam, he had been there was 5/5 power, bilateral unable to walk for the previous 48 hours due to imbalance and hyporeflexia (+1) of the knee jerk reflex, weakness. JM’s confusion and fatigue worsened to a point where loss of ankle jerk reflexes bilaterally, he became bedbound. absent vibratory sensation below the

thighs bilaterally, absent proprioception Management JM underwent a full laboratory work-up, echocardiogram, CT bilaterally, and fasciculations in the brain, and MRI brain, all of which failed to explain the cause of his hamstrings and calf muscles.

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Subsequently, serum and cerebrospinal fluid were found to be evidenced by this case, a delay in neurological review may result in positive for antibodies against VGKC and Caspr2, and weakly clinical deterioration and a delay in treatment, with detrimental positive for LGI1 antibodies, confirming the clinical suspicion of effects for the patient.5 Should physicians be unaware of this Morvan syndrome. A full body PET scan ruled out any condition, or the appropriate autoimmune antibody tests malignancies. Although his encephalopathy and seizures resolved, required in order to make a diagnosis are not conducted, severe mood issues persisted, along with ongoing autonomic some patients may go undiagnosed. Worse yet, patients may dysfunction. Additional courses of IVIG and a single course of receive more radical, unnecessary treatments if alternative rituximab were given, subsequently stabilising the condition. He diagnoses are suspected. was transferred to a rehabilitation centre after five months in Thus, Morvan syndrome may not, in fact, be as rare as it is hospital. He made some recovery in autonomic function and currently thought to be; it may simply be underdiagnosed and mobility; however, death occurred nine months after the onset of under-reported. Therefore, such case reports are an important symptoms secondary to lower respiratory tract infection. contribution to the neurology literature to raise awareness of the signs and symptoms of this disease. Diagnosis of Morvan syndrome requires a The prognosis of Morvan syndrome has been demonstrated to be detailed history to recognise any patterns highly variable. Although some forms may resolve spontaneously, of change in behaviour, personality, many require treatment with IVIG and intravenous corticosteroids 1 cognition, or other symptomatology in order to induce partial or complete remission. As symptoms resolve, consultation with occupational and physical therapy is over the preceding months. important to regain strength and ensure that the patient is safe in Discussion their activities of daily life. Autoimmune encephalitis is increasingly recognised in elderly individuals, and prompt immunotherapy is essential for recovery.3 Conclusion The typical presentation of Morvan syndrome is difficult to define This case describes the presentation, evaluation, and treatment of as it differs depending on which antibodies are present (Figure 1); Morvan syndrome, an incredibly rare form of autoimmune limbic however, this patient showed a typical presentation of the encephalitis, in an octogenarian. Diagnosis of Morvan syndrome anti-Caspr2+ cohort.3,4 The initial symptomatology was very similar requires a detailed history to recognise any patterns of change in to a presentation of underlying cardiovascular aetiology in this age behaviour, personality, cognition, or other symptomatology over group, or evolving dementia such as Lewy body dementia, which the preceding months. Furthermore, consultation from a made it challenging to diagnose an underlying autoimmune neurology team and a complete neurological exam is critical in aetiology. As most routine investigations will not aid in the correct making the diagnosis. Awareness of this autoimmune disease diagnosis, this rare condition may prove difficult to identify if it is among physicians, as well as in emergency departments where not known to the treating physician, and definitive diagnosis these patients may present initially, is critical for reaching a prompt requires specific antibody tests that are not universally available. As diagnosis and initiating treatment.

References 1. Masood W, Sitammagari KK. Morvan Syndrome (Morvan Fibrillary Chorea, 4. Binks SNM, Klein CJ, Waters P, Pittock SJ, Irani SR. LGI1, CASPR2 and related

MFC). StatPearls [Internet]: StatPearls Publishing, 2018. antibodies: a molecular evolution of the phenotypes. J Neurol Neurosurg

2. Irani SR, Pettingill P, Kleopa KA, Schiza N, Waters P, Mazia C et al. Morvan Psychiatry. 2018;89(5):526-34.

syndrome: clinical and serological observations in 29 cases. Ann Neurol. 5. van Sonderen A, Ariño H, Petit-Pedrol M, Leypoldt F, Körtvélyessy P,

2012;72(2):241-55. Wandinger KP et al. The clinical spectrum of Caspr2 antibody-associated

3. Behrman S, Lennox B. Autoimmune encephalitis in the elderly: who to test disease. Neurology. 2016;87(5):521-8.

and what to test for. Evid Based Ment Health. 2019;22(4):172-6.

Volume 13: Number 1. 2020 | Page 25 RCSIsmj original article

Patient perception of health status in the setting of multimorbidity and polypharmacy: a preliminary analysis of baseline SPPiRE trial data

Abstract Introduction: Polypharmacy and multimorbidity are becoming increasingly common in an ageing population. Older people also exhibit greater utilisation of health services. Minimising adverse drug reactions and drug-drug interactions is becoming increasingly important; however, de-prescribing efforts often neglect to incorporate patient preferences. Methods: A total of 355 patients over the age of 65, who were prescribed more than 15 medications, filled out a self-reported questionnaire that included multiple health-related quality of life scales and demographics. Prescription data was obtained from the patients’ general practice, and potentially inappropriate prescriptions (PIPs) were identified by a pharmacist. Univariate and multivariate regression analysis was carried out using the EuroQoL Visual Analogue Scale (EQ-VAS) as the outcome variable. Results: There was limited evidence for a relationship between patient characteristics (age, gender, education, number of medications, PIPs) and EQ-VAS score. Univariate analysis showed significant changes in EQ-VAS score corresponding with changes in various health-related quality of life subscale scores, particularly daily activities and pain. Discussion: Both pain and the ability to carry out daily activities have a large impact on patients’ global perception of their health. This study found no evidence to suggest that, in the Clare Lambert setting of polypharmacy and multimorbidity, the number of medications or number of PIPs RCSI medical student affects patients’ perception of their own health.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 26-33.

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Introduction Study objectives Multimorbidity, defined as the presence of at least two chronic This study aims to investigate patients’ perceptions of their own conditions, has become increasingly common in older people, and health status in the setting of polypharmacy, and explore patients’ is associated with poorer health outcomes and significant preferences regarding de-prescribing. A secondary aim is to polypharmacy.1,2,3 As a result, these patients tend to have high characterise this patient cohort using self-reported measures of rates of health service utilisation.4 health-related QoL. Many elderly patients are diagnosed with more than one chronic condition and may be treated by a number of specialist consultants Physicians aim to find the perfect in addition to their general practitioner (GP).5,6 In the setting of balance between medications that numerous chronic diseases, complex treatment regimens may optimise health, while minimising PIPs be assigned by different specialists and left to the GPs to manage and adverse drug interactions. long term.4 While each prescription aligns with specialty treatment algorithms, this fragmented approach to healthcare can leave Methods patients at risk of potentially inappropriate prescriptions (PIPs).7 This study utilised baseline data from an ongoing prospective cluster Past research has demonstrated that patients over age 65 in randomised controlled trial entitled Supporting Prescribing in Older Ireland may be taking anywhere from one to 19 medications, People with Multimorbidity and Significant Polypharmacy in Primary where 15.8% of patients have at least one PIP.8 Research in the Care (SPPiRE).9 The aim of the SPPiRE study is to assess the field of primary practice has identified the need for additional effectiveness of an intervention designed to support GPs in reducing support in managing polypharmacy in older patients.9,10 PIPs and consider de-prescribing in older people with multimorbidity Alongside a deterioration in physical health, patient quality of life and significant polypharmacy in Irish primary care. Inclusion criteria (QoL) can also decline with age.11 required that patients be over 65 years old and taking more than Patients’ perception of their own health may differ significantly 15 medications. from how physicians view patients’ health in a number of ways. From a pharmacological standpoint, physicians aim to find the Data collection perfect balance between medications that optimise health, while Irish GPs were asked to provide medical records, from which the minimising PIPs and adverse drug interactions.6,12 However, the baseline number of medications and PIPs were determined based on patient may have different priorities and needs that predominate, the published protocol.9 Patients were asked to fill out a self-report such as maintaining independence and keeping up with their questionnaire that consisted of: daily routine.13 Polypharmacy in the elderly cohort is well established and ■ basic demographic information: age, gender, marital status, growing, yet there has been a relative lack of scientific evidence to language, education level, employment, medical insurance guide prescription writing for an elderly population due to their coverage, and distance from GP; exclusion from clinical trials.7,10,14,15 ■ patient-reported health service utilisation: GP visits, out-of-hours In an effort to combat polypharmacy in older patients, GP visits, emergency department (ED) visits, inpatient hospital de-prescribing models and algorithms are being developed to stays, outpatient department visits, physiotherapist visits, support prescribers in managing complex patients.10,16 However, occupational therapist visits, speech therapist visits, public health these programmes may neglect to incorporate patient nursing service visits, optician visits, and dental visits; preferences.15,17 ■ health-related QoL measures: Five Level EuroQol Five Dimension In an ageing population, it is essential to understand how patients scale (EQ-5D-5L; dimensions: mobility, self-care, usual activities, view their health status in the setting of polypharmacy and pain/discomfort, and anxiety/depression), and EuroQoL Visual multimorbidity, while also exploring patient preferences about Analogue Scale (EQ-VAS; patient’s self-rated health on a vertical de-prescribing. This information can provide targeted areas of visual analogue scale);18 focus for healthcare providers when attempting to formulate ■ Multimorbidity Treatment Burden Questionnaire (MTBQ);19 and, long-term management plans for these complex patients. ■ revised Patient Attitudes Towards De-Prescribing scale (rPATD).20

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Outcome variable Table 2: Patient health-related quality of life indicators The EQ-VAS is a visual analogue scale that provides additional insight descriptive statistics. into patients’ perception of their overall health by selecting a point Patient quality of life indicators (%) N and marking an ‘x’ on a 20cm scale ranging from 0 to 100, where

18 100 is indicative of perfect health and 0 of very poor health. EQ-5D: Mobility score I have no problems in walking about 61 (17.5%) Analysis I have slight problems in walking about 77 (22.2%) I have moderate problems in walking about 104 (29.9%) 348 Descriptive statistics were used to explore patient characteristics and I have severe problems in walking about 90 (25.9%) perceptions of health. Results were recorded as mean/standard deviation I am unable to walk about 16 (4.6%) (SD) for continuous variables, median/interquartile range (IQR) for variables that showed some evidence of skew, and range or EQ-5D: Self-care score count/percentage for categorical variables, where applicable. Spearman I have no problems with self-care 199 (57.2%) I have slight problems with washing or correlations and scatter plots were also carried out on variables of dressing myself 56 (16.1%) interest and EQ-VAS to explore relationships and determine if r I have moderate problems with washing or 348 egression was suitable. dressing myself 57 (16.4%) Univariate and multivariate mixed effects regression models, with GP as a I have severe problems with washing or random effect to account for the correlation between patients with the dressing myself 22 (6.3%) I am unable to wash or dress myself 14 (4.0%) same GP, were used. EQ-VAS score was the primary outcome variable. Two models were carried out using Stata’s xtmixed command to examine the EQ-5D: Pain score Table 1: Patient demographic descriptive statistics. I have no pain or discomfort 37 (10.6%) I have slight pain or discomfort 81 (23.3%) I have moderate pain or discomfort 126 (36.2%) 348 Variable Summary statistic N I have severe pain or discomfort 86 (24.7%) I have extreme pain or discomfort 18 (5.2%) Gender: % males 44.6% 352 Mean age (SD) 76.7 (7.0) 343 EQ-5D: Activities score I have no problem doing my usual activities 92 (26.4%) Healthcare usage I have slight problems doing my usual activities 79 (22.7%) Median number of GP visits I have moderate problems doing my usual activities 83 (23.9%) 348 in 12 months (IQR, min, max) 6 (8, 0, 70) 343 I have severe problems doing my usual activities 55 (15.8%) No. patients who used ED I am unable to do my usual activities 39 (11.2%)

in last 12 mo. (%) 143 (41.5%) 345 Average anxiety/depression score (1-5 scale) No. patients who were an I am not anxious or depressed 154 (44.9%) inpatient in last 12 mo. (%) 145 (42.2%) 344 I am slightly anxious or depressed 94 (27.4%) No. patients who attended I am moderately anxious or depressed 75 (21.9%) 343

OOH GP in last 12 mo. (%) 70 (20.23%) 346 I am severely anxious or depressed 12 (3.5%) I am extremely anxious or depressed 8 (2.3%) No. of patients who were day

patients in the last 12 mo. (%) 232 (67.6%) 343 Mean EQ-VAS score – out of 100 (SD) 60.4 (21.2) 338

No. of patients who were

outpatients in the last 12 mo. (%) 218 (64.7%) 337 Mean MTBQ summary score – out of 65 (SD) 17.55 (8.0) 345

No. who used a public health nurse Mean rPATD Involvement summary score – out of 30 (SD) 20.9 (4.0) 329 in the last 12 mo. (%) 120 (34.8%) 345 Indicators of polypharmacy Mean rPATD Burden summary score – out of 30 (SD) 15.1 (4.3) 317 Mean no. of repeat medications (SD) 16.9 (3.1) 270

Median no. of PIPs at baseline Median rPATD Global Willingness to Stop

(IQR, min, max) 2 (1, 0, 5) 270 summary score – out of 5 (IQR) 4 (1) 343

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relationship between patient characteristics and EQ-VAS score. Regression results were reported as beta coefficients, 95% confidence intervals (95% CI), and p-values. Model 1 examined the effect of patient characteristics (Table 2 continued) (including age, gender, education level, healthcare service usage, and

Mean rPATD Appropriateness summary score number of medications) and number of PIPs on EQ-VAS score. Model 2

– out of 25 (SD) 15.8 (4.2) 324 examined the impact of the EQ-5D-5L subscales, MTBQ summary score,

and rPATD Burden and Involvement subscale on EQ-VAS scores.

Mean rPATD Concern About Stopping summary score

– out of 25 (SD) 13.4 (3.9) 328 Results

Descriptive statistics

rPATD Concern Subscale Question of Interest (Q19): To date, 31 practices and 355 patients have been recruited into the

I would be reluctant to stop a medicine that I had been taking for a long time. SPPiRE study. Patient demographics, health-related QoL scales, and

Strongly agree 27 (7.7%) medication data were recorded (Tables 1 and 2). A total of 44.6% of

Agree 65 (18.8%) 345

Unsure 66 (19.1%) 150 Disagree 117 (33.9%)

Strongly disagree 70 (20.3%)

100

Frequency

rPATD Concern Subscale Question of Interest (Q21): I get stressed whenever changes 50

are made to my medicines.

Strongly agree 67 (18.5%) 0 1 2 3 4 5 Agree 151 (43.9%) 344 Anxiety/depression Unsure 44 (12.8%) 200 Disagree 58 (16.9%)

Strongly disagree 24 (7.0%) 150 100 Frequency 100 50 80 0 60 1 2 3 4 5 Self-care 40 Frequency 20 150 0 1 2 3 4 5 Mobility 100 100 Frequency 50 80 60 0 1 2 3 4 5 40 Frequency Pain

20 FIGURE 1 (above and left): Histogram distribution of the five sections of the

0 EQ-5D-5L. The x-axis denotes the subscale (mobility; self-care; daily 1 2 3 4 5 activities; pain; and, anxiety/depression). These subscales are five-point Likert Daily activities scales where 1 indicates no problems and 5 indicates extreme problems or the most ‘ill’ state with regard to the specific scale.

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patients were male and 55.4% were female. Patients in this cohort score was observed in association with increasing EQ-5D-5L subscale had a mean age of 76.7±7 years and the majority were married (51%) scores. Due to collinearity between the selected QoL variables, or widowed (28.9%). multivariable regression analysis was not carried out (Appendix A). Some 85.5% of the patients were medical card holders living on average 5±5.2km away from their GP’s office. The vast majority of Discussion patients (98.3%) had visited their GP in the last year, with a median The clinical cohort investigated in this study included elderly patients of six visits in the last 12 months (IQR 8). A total of 41.5% and 42.2% on a substantial number of medications, making them a niche subset of patients reported at least one use of the ED and inpatient of GP service users in Ireland. Prescription records indicated that department, respectively, in the last 12 months. Patients in this cohort patients in this study were on an average of 16.9±3 medications and were on an average of 16.9±3.1 medications and had a median of had a median of two (IQR 1) PIPs at baseline, which many may two (IQR 1) PIPs. There was variability in the results of the EQ-5D-5L consider grounds for a de-prescribing intervention to be subscale scores; exact frequencies and percentages are listed in Table implimented.10 However, 88 patients, just over one-quarter of the 2 and visually demonstrated in Figure 1. cohort (Figure 1), rated their health as 80/100 or better, despite The majority of patients on greater than 15 medications being on 15 or more medications. demonstrated moderate problems with mobility and pain, while they reported no problems with self-care, anxiety, or depression. There Physicians are tasked with finding a appeared to be a wide variability in the daily activities subscale scores. balance between treatment needs The mean MTBQ summary score was 17.55±8, where a score of 65 (based on disease burden and limiting indicated a large burden and 0 indicated no burden. Patients rated potential therapeutic interactions) their global health as 60.4±21 out of 100 on the EQ-VAS, which was and treatment regime acceptability the main outcome variable. (based on side effects and Patients’ willingness and barriers to de-prescribe were assessed with the rPATD subscales (Table 2). Patients scored an average of 13.4±4 adverse reactions). on the rPATD Concern subscale, where 25 indicated the most concern about stopping a medication, and a score of 5 indicated no concern Age, gender, education, PIPs, and number of medications did not about stopping. appear to have any impact on perceived health (Table 3), suggesting that perception of overall health in this cohort was not influenced by There is a high degree of heterogeneity in polypharmacy. However, this population represents only a small the healthcare experience, which is subpopulation of those over age 65, and all patients included had a inherently difficult to capture on paper. In significant medication burden. A study of the entire over-65 addition, day-to-day variability in one’s population in Ireland may yield different findings. Univariate analysis (Table 4) demonstrated that with decreasing health perception presents a challenge scores on predictor variables, particularly the EQ-5D-5L subscales, when interpreting EQ-VAS results. there was a corresponding and stepwise decrease in EQ-VAS score. This indicated that the EQ-VAS was performing well as an indicator of Relationships between patient characteristics and EQ-VAS overall global health, inclusive of various facets of health-related QoL Model 1, involving univariate regression (Table 3), showed no examined in the EQ-5D-5L. Similar findings have been demonstrated evidence of a relationship between patient characteristics and EQ-VAS in previous research.21 with the exception of ED usage (β=-5.77; p<0.05; 95% CI: -10.27, Given the ability of the EQ-VAS to accurately describe health status, it -1.27) and inpatient usage (β=-6.00; p<0.05; 95% CI: -10.36, -1.43). is particularly interesting that no characteristics, such as age or There was no evidence for any relationship between patient number of medications, were able to account for variance in EQ-VAS characteristics and EQ-VAS in the multivariable analysis. Model 2 scores. The strongest driver of health status, based on unadjusted (Table 4), involving univariate analysis, showed a significant change analysis (Table 3), was self-reported daily activities and pain. Being in EQ-VAS score for almost all variables, excluding the rPATD Burden unable to perform daily activities showed a decrease in EQ-VAS of and Involvement subscales. A pattern of stepwise decline in EQ-VAS 33.56 (95% CI: -40.15, -27.00), and being in extreme pain showed a

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34.52-point drop in EQ-VAS (95% CI: -45.21,-23.84). Physicians are who rated their health as only 10/100, also listed ‘maintaining tasked with finding a balance between treatment needs (based on independence and treating pain’ as their goals of care. Interestingly, disease burden and limiting potential therapeutic interactions) and over one-quarter (26.7%) of patients ‘agreed’ or ‘strongly agreed’ treatment regime acceptability (based on side effects and adverse that they would be reluctant to stop taking a medication that they reactions).22 However, these preliminary findings suggest that this had been taking for a long time. In addition, 63.4% of patients cohort of patients may not share the same treatment goals as ‘agreed’ or ‘strongly agreed’ with the statement: ‘I get stressed when their physicians. changes are made to my medicines’. One patient, who rated their health as 100/100, listed their Some patients may be unconcerned with their medication load and healthcare priority as ‘maintaining independence’. Another patient, disinterested in changing their medicine regime. In this case, it is

Table 3: Regression model 1.

Model 1: Patient characteristics Do patient baseline factors such as age, gender, healthcare use, and polypharmacy predict perception of health?

Variable Univariate analysis P value Multivariable regression P value Beta co-efficeint (CI) Beta co-efficeint (CI)

Age 0.05 (-0.28, 0.38) 0.761 0.03 (-3.7, 0.44) 0.875

Gender -4.30 (-8.72, 0.13) 0.057 -4.48 (-9.91, 0.95) 0.106

Education level

(baseline of no schooling)

i. primary school only 18.06 (-23.15, 59.27) 0.390 – –

ii. some secondary 18.38 (-22.96, 59.73) 0.384 2.88 (-3.72, 9.48) 0.393

iii. complete secondary 17.73 (-23.75, 59.20) 0.402 -1.99 (-9.76, 5.78) 0.616

iv. some third level 23.18 (-18.49, 64.85) 0.276 2.56 (-8.29, 13.41) 0.644

v. complete third level 18.65 (-23.12, 60.43) 0.382 2.82 (-7.5, 13.15) 0.593

GP usage in 12 mo.

(baseline of ⩾5 uses)

i. 6-10 uses -0.10 (-5.56, 5.36) 0.971 3.42 (-2.93, 9.77) 0.291

ii. 11-15 uses -6.93 (-13.66, -0.20) 0.044 -3.48 (-11.38, 4.43) 0.389

iii. >15 uses -7.00 (-16.00, 2.00) 0.127 -1.24 (-11.44, 8.96) 0.811

ED usage (yes or no) -5.77 (-10.27, -1.27) 0.012 -3.16 (-9.42, 3.10) 0.323

Inpatient usage (yes or no) -6.00 (-10.36, -1.43) 0.010 -1.52 (-7.80, 4.76) 0.635

Number of medications -0.41(-1.21, 0.40) 0.323 -0.30 (-1.23, 0.64) 0.534

PIP -0.91 (-3.13, 1.31) 0.423 -0.53 (-3.05, 1.98) 0.678

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Table 4: Regression model 2. increasingly important for doctors to focus on individual patient Model 2: Univariate analysis priorities about health, while simultaneously keeping the patient safe, Are there any particular aspects of health-related quality of life that drive a patient’s self-rated global perception of helath as indicated by monitoring for potentially unsafe drug combinations, and the EQ-VAS? de-prescribing when appropriate. The findings in this study must be interpreted with caution, as the Variable N Univariate analysis P-value intent of the study was to investigate polypharmacy and the effect of Beta co-efficient (CI) a support intervention to assist GPs with medication review. There is

a high degree of heterogeneity in the healthcare experience, which is Mobility inherently difficult to capture on paper. In addition, day-to-day i. Normal mobility 59 variability in one’s health perception presents a challenge when ii. Slight problems 77 -5.17 (-11.39, 1.04) 0.103 iii. Moderate problems 101 -20.17 (-25.02, -14.32) 0.000 interpreting EQ-VAS results. In order to draw conclusions with regard iv. Severe problems 89 -27.03 (-33.01, -21.05) 0.000 to patient preferences and goals in the setting of polypharmacy and v. Unable to walk 15 -20.18 (-30.31,-10.04) 0.000 multimorbidity, qualitative survey research must be conducted in this cohort. Self-care i. Normal self-care 194 The findings in this study must be ii. Slight problems 55 -12.21 (-17.89, -6.62) 0.000 interpreted with caution, as the intent iii. Moderate problems 56 -32.10 (-28.52, -17.68) 0.000 of the study was to investigate iv. Severe problems 22 -26.65 (-34.80, -18.49) 0.000 polypharmacy and the effect of a v. Unable to wash/bathe 14 -21.62 (-31.65, -11.59) 0.000 support intervention to assist GPs

Pain with medication review. i. No pain 37 Conclusion ii. Slight pain 81 -7.66 (-15.11, -0.20) 0.044 Polypharmacy is on the rise, particularly in an ageing population that iii. Moderate pain 122 -12.40 (-19.39,-5.41) 0.001 is living longer and accumulating greater disease burden over the iv. Severe pain 84 -24.98 (-32.30, -17.66) 0.000 course of their lifetime. Elderly patients with a high disease burden are v. Extreme pain 17 -34.52 (-45.21, -23.84) 0.000 often managed by numerous consultant services, which each focus only on their own area of specialisation. GPs are tasked with Doing daily activities managing multiple medication regimes that align with different i. Able to do activty 90 specialty treatment algorithms. An increasing rate of PIPs in Irish ii. Slight problems 78 -10.10 (-15.38, -4.80) 0.000 geriatric care has prompted research in the field on how to limit the iii. Moderate problems 81 -19.62 (-24.78, -14.46) 0.000 number of medications and provide closer surveillance for PIPs in iv. Severe problems 54 -29.96 (-35.77, -24.14) 0.000 older patients. v. Unable to do activities 38 -33.58 (-40.16, -27.00) 0.000 It remains important for GPs to prevent morbidity related to drug

interactions in the setting of multiple PIPs; however, it is also Anxiety and depression important to keep in mind patients’ priorities and what contributes i. None 153 to their own sense of ‘healthiness’.12,22 i. Slight anx/dep 92 -8.12 (-13.17, -3.08) 0.002 Perception of health in this patient cohort was found to be more ii. Moderate anx/dep 74 -15.89 (-21.32, -10.46) 0.000 heavily influenced by maintaining daily routine and independence iii. Severe anx/dep 11 -23.29 (-34.71, -11.86) 0.000 rather than medication burden as assessed by number of iv. Extreme anx/dep 7 -30.53 (-44.56, -16.50) 0.000 medications prescribed. However, this finding may not hold true in

the wider population. As de-prescribing algorithms come into MTBQ -1.14 (-1.40, -0.88) 0.000 general practice, it will become increasingly important for rPATD – Involvement 0.61 (0.05, 1.17) 0.032 physicians to be conscious of patient priorities and goals when rPATD – Burden -0.23 (-0.77, 0.31) 0.397 making final de-prescribing decisions.

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Appendix A: Correlation table. Variables EQ-VAS Cohen’s standard effect size Age Not significant Number of medications Not significant PIPs at baseline Not significant GP times used -0.134, p<0.05 Small ED times used -0.159, p<0.01 Small Inpatient night stays -0.143, p<0.05 Small Healthcare usage -0.236, p<0.01 Small Involvement sub score (rPATD) 0.140, p<0.05 Small Burden sub score (rPATD) Not significant Concern about stopping sub score (rPATD) 0.140, p<0.05 Small Appropriateness of medication score (rPATD) Not significant Global willingness to stop Not significant Mobility -0.456, p<0.01 Medium Daily activities -0.569, p<0.01 Large Pain -0.425, p<0.01 Medium Self-care -0.487, p<0.01 Medium Anxiety and depression -0.369, p<0.01 Medium Multimorbidity treatment burden score -0.380, p<0.01 Medium

References 1. Field TS, Gurwitz JH, Avorn J et al. Risk factors for adverse drug events 13. Ferrera PC, Bartfield JM, D’Andrea CC. Geriatric trauma: outcomes of among nursing home residents. Arch Intern Med. 2001;161(13):1629-34. elderly patients discharged from the ED. Am J Emerg Med. 2. Goulding MR. Inappropriate medication prescribing for elderly ambulatory 1999;17(7):629-32. care patients. Arch Intern Med. 2004;164(3):305-12. 14. Walckiers D, Van der Heyden J, Tafforeau J. Factors associated with 3. World Health Organization. A glossary of terms for community health care excessive polypharmacy in older people. Arch Public Health. and services for older persons. WHO; 2004. Available from: 2015;73(1):50. https://apps.who.int/iris/handle/10665/68896. 15. Spinewine A, Schmader KE, Barber N, Hughes C, Lapane KL, Swine C et al. 4. Palladino R, Tayu LJ, Ashworth M, Triassi M, Millett C. Associations Appropriate prescribing in elderly people: how well can it be measured between multimorbidity, healthcare utilisation and health status: evidence and optimised? Lancet. 2007;370(9582):173-84. from 16 European countries. Age Ageing. 2016;45(3):431-5. 16. Farrell B, Pottie K, Rojas-Fernandez CH, Bjerre LM, Thompson W, Welch V. 5. Sinnott C, McHugh S, Browne J, Bradley C. GPs’ perspectives on the Methodology for developing deprescribing guidelines: using evidence and management of patients with multimorbidity: systematic review and GRADE to guide recommendations for deprescribing. PLoS One. synthesis of qualitative research. BMJ Open. 2013;3(9):1-11. 2016;11(8):1-12. 6. Bokhof B, Junius-Walker U. Reducing polypharmacy from the perspectives 17. Reeve E, Wiese MD, Hendrix I, Roberts MS, Shakib S. People’s attitudes, of general practitioners and older patients: a synthesis of qualitative beliefs, and experiences regarding polypharmacy and willingness to studies. Drugs Aging. 2016;33(4):249-66. deprescribe. J Am Geriatr Soc. 2013;61(9):1508-14. 7. Gurwitz JH. Polypharmacy: a new paradigm for quality drug therapy in the 18. Rabin R, Oemar M, Oppe M, Janssen B, Herdman M. EQ-5D-3L user guide. elderly? Arch Intern Med. 2004;164(18):1957-9. Basic information on how to use the EQ-5D-5L instrument. Rotterdam: 8. Ryan C, O’Mahony D, Kennedy J, Weedle P, Byrne S. Potentially EuroQol Group. 2011. Available from: inappropriate prescribing in an Irish elderly population in primary care. Br https://euroqol.org/wp-content/uploads/2019/10/EQ-5D-3L-User-Guide_ J Clin Pharmacol. 2009;68(6):936-47. version-6.0.pdf. 9. McCarthy C, Clyne B, Corrigan D, Boland F, Wallace E, Moriarty F et al. 19. Duncan P, Murphy M, Man MS, Chaplin K, Gaunt D, Salisbury C. Supporting prescribing in older people with multimorbidity and significant Development and validation of the Multimorbidity Treatment Burden polypharmacy in primary care (SPPiRE): a cluster randomised controlled Questionnaire (MTBQ). BMJ Open. 2018;8(4):e019413. trial protocol and pilot. Implement Sci. 2017;12(1):99-112. 20. Reeve E, Low LF, Shakib S, Hilmer SN. Development and validation of the 10. Anthierens S, Tansens A, Petrovic M, Christiaens T. Qualitative insights into revised patients’ attitudes towards deprescribing (rPATD) questionnaire: general practitioners views on polypharmacy. BMC Fam Pract. versions for older adults and caregivers. Drugs Aging. 2010;11(1):65-71. 2016;33(12):913-28. 11. Kai I, Ohi G, Kobayashi Y, Ishizaki T, Hisata M, Kiuchi M. Quality of life: a 21. Whynes DK. Correspondence between EQ-5D health state classifications possible health index for the elderly. Asia Pac J Public Health. and EQ VAS scores. Health Quol Life Outcomes. 2008;6(1):94-103. 1991;5(3):221-7. 22. Fried TR, Tinetti ME, Iannone L, O’Leary JR, Towle V, Van Ness PH. Health 12. Scott IA, Le Couteur DG. Physicians need to take the lead in deprescribing. outcome prioritization as a tool for decision making among older persons Intern Med J. 2015;45(3):352-6. with multiple chronic conditions. Arch Intern Med. 2011;171(20):1856-8.

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Have you tried zapping it? Neuromodulatory treatments for drug-resistant epilepsy

Abstract One-third of the 50 million people worldwide who experience epilepsy do not respond to pharmacological treatment. For some of these patients, surgically removing the part of their brain that is misfiring can be a curative treatment. However, neurotechnology and neuromodulation are providing an alternate treatment route for patients. Treatments such as vagus nerve stimulation, deep brain stimulation, and responsive neurostimulation use varying methods to send electrical impulses to the brain or the epileptic foci in order to treat seizures. Advancements in technology, research, and neuromodulatory therapies, outlined here, hold promise for patients afflicted with refractory epilepsy.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 34-38.

Introduction Approximately 50 million people worldwide live Treatment of DRE depends on the nature of the with epilepsy, and roughly one-third of these suffer patient’s epilepsy and the region(s) of the brain from a form of epilepsy that does not respond to from which the seizures emanate, also known as pharmacological treatment, called drug-resistant the focus or foci. One curative option for eligible epilepsy (DRE).1,2 Also known as refractory epilepsy patients is resective surgery to remove the part of or pharmaco-resistant epilepsy, DRE is defined by the brain that is responsible for their seizures.2-4 the task force of the International League Against A randomised trial showed that 77% of patients Vrinda Munjal Epilepsy (ILAE) as epileptic seizures that still persist who received surgical treatment for their epilepsy RCSI medical student following a trial of “two tolerated, appropriately were seizure free after 12 months, compared to chosen, and used antiepileptic drug schedules 7% of the medically treated group (p<0.001).3 (whether as monotherapies or in combination)”.1 Neuromodulatory treatment options that are now

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approved by the National Health Service (NHS) of the United Furthermore, the degree of irreversibility associated with Kingdom and the Food and Drug Administration (FDA) of the United neurosurgery and its complications may deter parents of children States are giving adult and paediatric patients with DRE alternative with epilepsy from choosing this treatment route. For these options. These options, however, still face considerable challenges in reasons, the emergence of neurotechnology and neuromodulation their availability and use. An overview of standard surgical therapy has made waves in the field of epilepsy treatment by introducing and contemporary developments in neurotechnologies, such as vagus an option that has fewer risks and reduced invasiveness. nerve stimulation (VNS), deep brain stimulation (DBS), and responsive neurostimulation (RNS), is presented here, with a focus In particular, eligible candidates include on the application, mode of action, and barriers to use of patients with medial temporal lobe these techniques. epilepsy, epileptic foci in the amygdala or hippocampus, Standard surgical intervention or lesional epilepsy. Treatment methods for refractory epilepsy include surgical intervention and, for those patients who do not respond to medication and do not meet the requirement for surgery, Vagus nerve stimulation neuromodulation.4 Surgical interventions aim to create lesions in or VNS utilises a pacemaker-like device that is inserted beneath the remove the part of the brain that is creating the abnormal electrical skin of the left chest wall with wires that attach to the left vagus activity.4 These interventions include focal resection, nerve. This provides electrical stimulation to the brain via the vagus hemispherectomy, lobar resection, amygdalectomy, and corpus nerve, which helps to control seizures. Newer models of this device callosotomy. Focal cortical resection is considered for drug-resistant have three modes: (i) the standard mode, which is used to prevent patients with focal epilepsy where the seizures arise from a cortical regular seizures by sending electrical stimulation at regular region that can be excised with minimal risk of disability.4 In intervals throughout the day; (ii) a ‘detect and respond’ setting, particular, eligible candidates include patients with medial temporal which sends an electrical impulse when the system detects an lobe epilepsy, epileptic foci in the amygdala or hippocampus, or increase in heart rate, which is associated with seizures, in hopes of lesional epilepsy.5 preventing or reducing the impending seizure; and, (iii) a ‘magnetic mode’, which allows the patient or a caregiver to Although brain surgery is becoming manually send an electrical impulse in order to prevent or reduce increasingly precise and safe with the the seizure once it starts.9 emergence of technologies such as While the mechanism of action of VNS is not completely understood, scientists theorise that it induces changes ultrasound-guided surgery and in neuroelectrophysiology, neurotransmitter release, and levels radiosurgery, some patients of inflammation.10 may not be ready to take In terms of neuroelectrophysiology, VNS blocks interictal spikes, on these risks. thereby increasing the threshold of amygdalar seizures, mediating the amygdala neuron firing rate, and altering the expression of Although surgery is the only curative option, many patients with proteins such as neurexin-1α, cadherin 13, and various DRE are not eligible for surgery due to factors such as bilateral voltage-dependent calcium channels.10-13 VNS has also been and/or multifocal seizure onset, diagnosis of generalised onset shown to increase norepinephrine and gamma aminobutyric acid epilepsy, high risk of postoperative functional damage, and other (GABA) levels, while decreasing glutamate in different parts of the medical comorbidities.5 As with any other surgery, neurosurgery brain.14,15 The direct link between the reduction of inflammatory carries a risk of complications, such as memory loss, learning cells and cytokines via VNS and its effect on epilepsy is not as clear; difficulties, and visual defects.6-8 Although brain surgery is however, because VNS has been used to relieve other becoming increasingly precise and safe with the emergence of inflammatory disorders, the indirect link may point to an alternate technologies such as ultrasound-guided surgery and radiosurgery, mechanism of action.10 Side effects of VNS relate to the vagus some patients may not be ready to take on these risks. nerve’s branches in the larynx and pharynx, with the potential to

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cause hoarseness, cough, voice changes and, in some cases, important structure in the spread of seizures. Furthermore, paraesthesia.10 high-frequency electrical stimulations and lesions made to the ANT VNS was first used to treat DRE in 1988, but was formally approved have stopped the spread of seizures in the abovementioned by the FDA to treat DRE in patients aged 12 years and older in models. Activity in the ANT is correlated to activity within the 1997.16 It took 20 more years for VNS to be approved in younger hippocampus, where stimulation with DBS has been shown to children, extending the age range to four years and older.16 Two increase GABAergic receptors.21 This increase in GABA stimulation randomised trials have shown that high-frequency VNS is is proposed to have a net reduction in excitability and thus to associated with greater reduction in seizure frequency compared prevent seizure propagation. to low-frequency VNS when taken with anti-epileptic drugs.17,18 A 2010 randomised trial analysing bilateral stimulation of the ANT Handforth et al. reported that in a sample of patients with showed a reduction in seizure frequency, especially with respect to refractory partial-onset seizures, with at least six episodes over 30 severe seizures.22,23 days, there was a 28% reduction in seizure frequency after The responder rate was sustained and improved at the five-year receiving high-stimulation VNS, whereas there was only a 15% mark, showing long-term efficacy. In 2018, the FDA approved the reduction with low stimulation (p=0.04).18 use of DBS in the ANT as an adjunct therapy in patients with DRE, Similarly, Ben-Menachem et al. reported a 30.9% reduction in with focal epilepsy, aged 18 years and older.24 However, in the mean seizure frequency following high VNS compared to an same year, the NHS released a statement stating that, due to a lack 11.3% reduction with low VNS (p=0.029) in patients with of sufficient evidence, it would not fund DBS for refractory refractory partial seizures.17 Similar findings were reported by a epilepsy.25 Patients with refractory epilepsy are still able to receive retrospective study conducted in 2016.19 VNS; however, if they fail to respond to VNS, treatment options are limited.26 In 2018, the FDA approved the use of deep brain stimulation Responsive neurostimulation in the anterior nucleus of the thalamus The RNS device is different from the aforementioned devices (ANT) as an adjunct therapy in because it only administers electrical impulses to the epileptic focus when the monitor detects the onset of a seizure.27,28 The patients with DRE, with focal stimulator is placed in the skull with leads placed into the epileptic epilepsy, aged 18 years and older. foci. Along with neurostimulation, RNS can be used for chronic ambulatory electrocorticography (ECoG), which allows for Deep brain stimulation monitoring of the number of seizures, timing of seizures, DBS uses electrodes implanted in the brain to send electrical pharmacological response, and surgical planning.27,28 A impulses to treat seizures. Prior to insertion of the deep brain randomised controlled trial of 230 patients found the median electrodes, an electroencephalogram (EEG) is performed to seizure reduction to be 44% at one year, 53% at two years, and up determine the focus of seizures in the brain, and magnetic to 66% from three to six years post implant.29 resonance imaging (MRI) of the brain is conducted to detect any Another clinical trial, conducted on 126 patients, has shown the structural abnormalities. A two-part surgery is then performed to safety and efficacy of the RNS device by demonstrating a median insert electrodes into the brain, and thereafter a neurostimulator is seizure reduction of 44% at the end of two years, and a 61-76% implanted under the skin of the chest. The electrical stimulation is reduction after five and six years.30 Some 26% of patients in this then titrated to find a setting that is personalised to the patient.20 sample also reported a six-month seizure-free period.30 The Dell et al. have described the therapeutic potential of DBS and researchers also reported a low rate of adverse events related to summarised the mechanism by which it has its clinical effects.21 surgery or device implantation.30 According to their study, DBS increases GABA activity in the A recent trial, conducted in 2019, used RNS to assess the response hippocampus and possibly re-establishes a balance between to anti-seizure medication. Researchers found that detection excitatory and inhibitory inputs via stimulation of the anterior rates of medication response within the first one to two weeks, nucleus of the thalamus (ANT). They also mention that EEG via RNS, may provide an early and objective measure of examination of animal models has shown that the ANT is an medication efficacy.31

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Although this device is FDA approved, it can only be used to treat Conclusion patients who are 18 years or older, creating a gap in paediatric DRE Neuromodulation therapies such as VNS, DBS, and RNS may treatment.32 In 2018, however, researchers and clinicians studied provide alternate treatment options for patients who are either not the off-label use of RNS devices in two paediatric DRE patients as a eligible for resective surgery or do not want to undergo high-risk palliative option. brain surgery. The frequent improvements in neurotechnology are The first patient, a 14-year-old male with severe developmental making waves in the world of epilepsy treatment, and also show delays, bilateral seizure onset, and type 1 cortical dysplasia, promise for other neurological disorders such as Parkinson’s experienced a reduction in seizure frequency from a baseline of 15 disease, obsessive compulsive disorder (OCD), and chronic to 30 seizures per day down to three seizures per day.32 pain.34-36 The second patient, a nine-year-old female with an unresectable Although these treatment options are becoming more popular, seizure focus, underwent RNS, which, over a 17-month period, there are still barriers to accessing these therapies due to age reduced her seizure count from 12 per month to two per month; limitations and insurance coverage approval in certain geographic 21 months after RNS she had been seizure free for four months.33 regions.37 Notably, there is a gap in paediatric DRE treatment options, which should be addressed with further research into The frequent improvements in neuromodulation in children, especially following the recently neurotechnology are making waves in the successful, off-label use of RNS in the paediatric population. Since world of epilepsy treatment, and also both DBS and RNS remain unapproved for paediatric treatment, show promise for other neurological the recommended therapies for children with refractory epilepsy remain resective surgery, VNS, and a ketogenic diet.38 disorders such as Parkinson’s disease, Neuromodulation provides a lower-risk and non-permanent obsessive compulsive disorder (OCD), alternative to resective surgery for patients with DRE, and offers an and chronic pain. alternative option for the families and caregivers of these patients who may have to make life-altering treatment decisions.

References 1. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Perucca E, Wiebe S et al. 7. Dulay MF, Levin HS, York MK, Li X, Mizrahi EM, Goldsmith I et al. Changes

Definition of drug resistant epilepsy: consensus proposal by the ad hoc task in individual and group spatial and verbal learning characteristics after

force of the ILAE Commission on Therapeutic Strategies. Epilepsia. anterior temporal lobectomy. Epilepsia. 2009;50(6):1385-95.

2010;51(6):1069-77. 8. Hader WJ, Tellez-zenteno J, Metcalfe A, Hernandez-ronquillo L, Wiebe S,

2. Engel J. The current place of epilepsy surgery. Curr Opin Neurol. Kwon C et al. Complications of epilepsy surgery: a systematic review of focal

2019;31(2):192-7. surgical resections and invasive EEG monitoring. Epilepsia.

3. Kalaivani M, Garg A, Bal CS, Tripathi M, Dwivedi SN et al. Surgery for 2013;54(5):840-7.

drug-resistant epilepsy in children. N Engl J Med. 2017;377:1639-47. 9. LivaNova. How VNS therapy works. [Internet]. [cited 2019 Oct 30]. Available

4. Gadgil N, LoPresti MA, Muir M, Treiber JM, Prablek M, Karas PJ et al. An from: https://us.livanova.cyberonics.com/learn-more/how-it-works.

update on pediatric surgical epilepsy: part I. Surg Neurol Int. 10. Fan JJ, Shan W, Wu JP, Wang Q. Research progress of vagus nerve stimulation

2019;10(257):1-5. in the treatment of epilepsy. CNS Neurosci Ther. 2019;25(11):1222-8.

5. Cascino GD. Surgical treatment of epilepsy in adults. 2019 [Internet]. Available from: 11. Zanchetti A, Wang SC, Moruzzi G. The effect of vagal afferent stimulation

https://www.uptodate.com/contents/surgical-treatment-of-epilepsy-in-ad on the EEG pattern of the cat. Electroencephalogr Clin Neurophysiol.

ults. 1952;4(3):357-61.

6. Baxendale S, Thompson PJ, Duncan JS. Improvements in memory function 12. Alexander GM, McNamara JO. Vagus nerve stimulation elevates seizure

following anterior temporal lobe resection for epilepsy. Neurology. threshold in the kindling model. Epilepsia. 2012;53(11):2043-52.

2008;71:1319-25. 13. Alexander GM, Huang YZ, Soderblom EJ, He X-P, Moseley A, McNamara JO.

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Vagal nerve stimulation modifies neuronal activity and the proteome of 26. National Health Service UK. Clinical Commissioning Policy: Vagal Nerve

excitatory synapses of amygdala/piriform cortex. J Neurochem. Stimulation for Epilepsy. 2013. [Internet]. Available from:

2017;140(4):629-44. https://www.england.nhs.uk/wp-content/uploads/2018/07/Vagal-nerve-sti

14. Raedt R, Clinckers R, Mollet L, Vonck K, El Tahry R, Tine W et al. Increased mulation-for-epilepsy.pdf.

hippocampal noraderenaline is a biomarker for efficacy of vagus nerve 27. Acharya JN. Responsive neurostimulation for epilepsy: more than

stimulation in limbic seizure model. J Neurochem. 2011;117(3):461-9. stimulation. Clin Neurophysiol Pract. 2018;3:120-1.

15. Walker BR, Easton A, Gale K. Regulation of limbic motor seizures by GABA 28. NeuroPace. NeuroPace RNS system. [Internet]. [cited 2019 Nov 1]. Available

and glutamate transmission in nucleus tractus solitarius. Epilepsia. from: https://www.neuropace.com/the-rns-system/.

1999;40(8):1051-7. 29. Bergey GK, Morrell MJ, Mizrahi EM, Cole A, Cash SS, Noe K et al. Long-term

16. FDA. Summary of safety and effectiveness data (SSED). VNS treatment with responsive brain stimulation in adults with refractory partial

Therapy System. 2017. p. 1-30. [Internet]. Available from: seizures. Neurology. 2015;84(8):810-7.

https://www.accessdata.fda.gov/cdrh_docs/pdf/p970003s207b.pdf. 30. Jobst BC, Kapur R, Barkley GL, Bazil CW, Berg MJ, Gregory K et al.

17. Ben-Menachem E, Mañon-Espaillat R, Ristanovic R, Wilder BJ, Stefan H et al. Brain-responsive neurostimulation in patients with medically intractable seizures arising from eloquent and other neocortical areas. Epilepsia. Vagus nerve stimulation for treatment of partial seizures: 1. A controlled 2017;58(6):1005-14. study of effect on seizures. Epilepsia. 1994;35(3):616-26. 31. Quraishi IH, Mercier MR, Hirsch LJ. Early detection rate changes from a 18. Handforth A, Degiorgio CM, Schachter SC, Uthman BM, Naritoku DK, brain-responsive neurostimulation system predict efficacy of newly added Henry TR et al. Vagus nerve stimulation therapy for partial-onset seizures: a antiseizure drugs. Epilepsia. 2020;61(1):138-48. randomized active-control trial. Neurology. 1998;51(1):48-55. 32. U.S. Food and Drug Administration. Pre Market Approval – Neuropace RNS 19. Ozdogan S, Nurhat RH, Duzkalir AH, Yuce D, Sabuncuoglu H. Vagal nerve System. [Internet]. [cited 2019 Nov 4]. Available from: stimulation effects on generalized-partial seizures and medication in adult https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P drug-resistant epilepsy patients. Turk Neurosurg. 2016;26(3):347-51. 100026. 20. Medtronic. Getting DBS: What to expect – DBS Therapy for 33. Kokoszka MA, Panov F, LA Vega-Talbott M, McGoldrick PE, Wolf SM, Ghatan Epilepsy [Internet]. [cited 2019 Oct 31]. Available from: S. Treatment of medically refractory seizures with responsive https://www.medtronic.com/us-en/patients/treatments-therapies/deep-bra neurostimulation: 2 pediatric cases. J Neurosurg Pediatr. 2018;21(4):421-7. in-stimulation-epilepsy/about/getting-dbs.html. 34. Chakravarthy K, Chaudhry H, Williams K, Christo PJ. Review of the uses of 21. Dell KL, Cook MJ, Maturana MI. Deep brain stimulation for epilepsy: vagal nerve stimulation in chronic pain management. Curr Pain Headache biomarkers for optimization. Curr Treat Options Neurol. 2019;21(10):47. Rep. 2015;19(12):54.

22. Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R et al. Electrical 35. Temperli P, Pollo C, Pralong E, Ghika J. Subthalamic DBS replaces levodopa

stimulation of the anterior nucleus of thalamus for treatment of refractory in Parkinson’s disease. Neurology. 2002;58:543-8.

epilepsy. Epilepsia. 2010;51(5):899-908. 36. Husted BDS, Shapira NA. A review of the treatment for refractory

23. Witt T, Worth R, Henry TR, Gross RE, Sperling MR, Handforth A et al. obsessive-compulsive disorder: from medicine to deep brain stimulation.

Long-term efficacy and safety of thalamic stimulation for drug-resistant CNS Spectr. 2020;9(11):833-47.

partial epilepsy. Neurology. 2015;84(10):1017-25. 37. Camprodon JA, Rauch SL, Greenberg BD, Dougherty DD. Psychiatric

24. Osborne Shafer P. FDA approval: Medtronic deep brain stimulation Neurotherapeutics. Humana Press, 2016:105-15.

for medically refractory epilepsy. Epilepsy Foundation, 2018. [Internet]. 38. Wilfong A. Seizures and epilepsy in children: refractory seizures and

Available from: https://www.epilepsy.com/article/2018/5/fda-approval prognosis. UpToDate. 2019. [Internet]. Available from:

-medtronic-deep-brain-stimulation-medically-refractory-epilepsy. https://www.uptodate.com/contents/seizures-and-epilepsy-in-children-refr

25. National Health Service UK. Clinical Comissioning Policy: Deep Brain actory-seizures-and-prognosis.

Stimulation for Refractory Epilepsy (all ages). 2018. [Internet]. Available

from: https://www.england.nhs.uk/wp-content/uploads/2018/03/d04-

deep-brain-stimulation-for-refractory-epilepsy.pdf.

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Blue light blocking glasses: should we all be wearing them?

Abstract Blue light ranges from 400 to 490 nanometres on the visible portion of the electromagnetic spectrum and is emitted from common electronic devices such as televisions, smartphones, and computers. With current widespread access to and usage of such devices, concerns regarding exposure to blue light are being increasingly acknowledged. Blue light has been found to be damaging to the eyes and sleep patterns, due to a reduction in the body’s natural production of the hormone melatonin. In response to this potential health problem, blue light blocking glasses have been developed, claiming to protect the eyes from strain and to aid sleep at night. Tiffany Yeretsian Among current published literature, there is conflicting data as to the full extent of the efficacy Gabrielle Sanatani of blue light blocking glasses. While some studies have found blue light blocking glasses to be Bao-Nghi Nguyen effective, others have found no such effect. This paper reviews existing data on this health issue RCSI medical students and the potential benefits of blue light eyewear.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 39-44.

Volume 13: Number 1. 2020 | Page 39 RCSIsmj review

10-12 10-9 10-6 10-3 1 103 �[m] 3.1020 3.1017 3.1014 3.1011 3.108 0.3.106 v[Hz]

300 400 500 600 700 800 �[nm] 1000 750 600 500 428 375 v[THz]

FIGURE 1: The electromagnetic spectrum.30

Background which is responsible for synthesising melatonin.8,9 Melatonin is a Blue light is found on the visible portion of the electromagnetic hormone released in response to darkness that regulates the spectrum, with a wavelength ranging from 400 to 490 nanometres sleep-wake cycle.10 (nm) (Figure 1). Blue light is emitted from the screens of electronic The leading theory is that blue light affects sleep by disrupting the devices, with common devices including televisions, smartphones, function of retinal ganglion cells (RGCs), which are secondary and computers.1,2 Blue light is often utilised in such devices due to the photoreceptors in the retina, and decreasing the expression of fact that it is more efficient, produces less heat, and lasts longer than melanopsin.8 Melanopsin is a photopigment that is sensitive to halogen lights.3 short wavelengths, with maximal sensitivity at wavelengths High-energy short-wavelength blue light between 415 and 455nm is around 480nm, causing a majority of RGCs to be intrinsically the most harmful component of visible light to the eyes.4 Although photosensitive (Figure 2).8 exact numbers are difficult to ascertain, it is estimated that in 2020, These intrinsically photosensitive RGCs produce pituitary adenylate 6.1 billion smartphones will be in use.5 With such widespread use of cyclase-activating polypeptide, an important activator in the RHT. smartphones, the effect of screens and blue light emission on sleep When light is transmitted through the RHT, the SCN is activated to has been increasingly recognised as a health issue. control whole body circadian rhythms, and causes direct suppression Blue light was found to affect circadian rhythms, and therefore sleep of melatonin from the pineal gland (Figure 3).9,11-13 patterns, through the disruption of natural hormonal processes.6 In an This in turn will suppress the sleep-inducing effect of melatonin, as attempt to reduce the ill-effects of increased blue light exposure, blue well as the ability to modify the sleep-wake cycle.9,11-13 Since the light blocking glasses were developed. These glasses are being sold melatonin production is initiated in darkness, the presence of light with the promise of alleviating eyestrain when looking at screens, during and just prior to sleep causes a disruption in the body’s protecting eyes from retinal phototoxicity, and improving sleep circadian rhythm by decreasing melatonin production, therefore quality.7 However, available data is limited and, prior to accepting contributing to marked effects on physiologic functions.14 these claims, it is important to assess all current relevant data on the Blue light-emitting waves are the most crucial component in the efficacy and therapeutic effects of blue light blocking eyewear. synchronisation of the circadian rhythm, especially when compared to green and yellow wavelengths.6,15 Pathophysiology behind blue light: what is the problem? A six-and-a-half-hour exposure to 460nm of blue light was shown to Light has an effect on sleep and circadian rhythms through the photic double the amount of time it takes to initiate the circadian phase input pathways of the retinohypothalamic tract (RHT) to the when compared to 555nm of green light.6,15 Natural blue light is also suprachiasmatic nucleus (SCN). The SCN is the principal circadian critical for increased cognition, alertness, and supressed melatonin pacemaker of bodily functions and mainly acts on the pineal gland, secretion during the day.6 Although blue light is important for

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FIGURE 2: Schematic view of retinal photoreceptors and their specific wavelength sensitivities. a. Cross-sectional view containing rods, cones, and secondary photoreceptors (ipRGCs), which express melanopsin. b. Peak wavelength sensitivities in photoreceptors.8 daytime function, exposure to light-emitting diode (LED) screens, FIGURE 3: Signal pathways that regulate the circadian rhythm and which emit predominantly blue light (approximately 460nm), pineal gland. Signals from the activation of melanopsin in ipRGCs will travel via the RHT pathway (blue) to the SCN (green), which is the contributes to melatonin suppression and reduced fatigue primary regulator of the body’s circadian rhythm. The information is at bedtime.6 then transmitted to the pineal gland through a pathway involving the Blue light, such as that released by screens, has the strongest ability paraventricular nucleus (yellow), the spinal cord, and the superior to inhibit melatonin production.16 A study showed that individuals cervical ganglia.6 who used light-emitting devices, such as a light-emitting e-book, prior to sleep, had decreased melatonin levels, disruption of the start of the circadian clock, and overall required more time to fall asleep.17 Importance of protecting our circadian rhythm Similarly, another study assessed the melatonin levels in collected The detrimental health consequences of blue light lie in its ability to alter blood samples from individuals before and after they were exposed to the circadian rhythm. Disruptions to the body’s natural circadian rhythm various powers of LED blue light at peak wavelengths of 496nm for have been linked to a plethora of health problems, including one and a half hours. The results displayed that increasing the power cardiovascular disease, cancer, mood disorders, metabolic disease, of blue light radiance correlates with increased suppression of diabetes, and cognitive impairments.16,19 Circadian rhythms are melatonin secretion.18 responsible for controlling cardiac repolarisation, and their disruption plays Activation of the RGC pathway by wavelengths in the blue light a pathogenic role in the development of cardiac arrhythmias, including spectrum will suppress the secretion of melatonin and will therefore those responsible for sudden death.20 Critically ill patients in the intensive regulate the body’s circadian rhythm. care unit often suffer from sleep deprivation and sleep disturbances, which This can explain how blue light impacts various physiological cause misaligned circadian rhythms.21 These changes in circadian rhythm functions, including regulation of the circadian clock and sleep-wake lead to metabolic disturbances, such as mitochondrial and endothelial cycles.2,6,8 dysfunction, which hinder recovery in these patients.21 Circadian rhythm is most sensitive to phase delays in the evening; therefore, using artificial A six-and-a-half-hour exposure to light at this time of day delays the timing of the circadian clock and sleep.8 460nm of blue light was shown Using smartphones before bed causes increased insomnia, decreased sleep to double the amount of time it quality, and increased fatigue.22 Overall, disrupted sleep harms multiple takes to initiate the circadian phase organ systems and was clearly associated with detrimental health outcomes.16,19 Blue light blocking glasses attempt to resolve this issue by when compared to 555nm reducing the eyes’ exposure to artificial light, thereby protecting the of green light. body’s natural production of melatonin.19

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A study conducted in 2018 by Perez et al. assessed the efficacy of blue light blocking glasses in 13 university-level students with sleep disorders.26 The results of this study showed that blue light blocking glasses worn at night were effective in reducing sleep disruption caused by screen time, as measured by a sleep diary. Additionally, the glasses were found to be a low-cost intervention, with no associated adverse effects.26 A study conducted by Esaki et al. in patients with delayed sleep phase disorder (DSPD) found that wearing blue light blocking glasses in the evening allowed participants to fall asleep 132 minutes more quickly, on average.23 However, the results of both the Perez et al. and Esaki et al. studies were limited by small sample size, and would therefore need to be replicated with a larger cohort to provide higher quality evidence.23,26 At a slightly larger sample size, a randomised controlled trial completed in 2018 assessed the efficacy of blue light blocking glasses in 76 participants. Results found that the use of blue light blocking glasses at night Evidence behind blue light blocking glasses increased melatonin secretion and improved sleep quality.27 With the rise of screen usage in today’s society, and with the known The aforementioned studies have all confirmed the benefits of blue light effects of blue light on sleep, increasing therapies were developed to blocking glasses; however, as seen in Table 1, the number of studies address this concern. At the forefront of these therapies are blue light and participants remains relatively small. Additionally, publication blocking glasses. Multiple eyewear companies are producing blue light bias may also be a factor, as it can be more challenging to publish a blocking eyewear, with the ability to add this feature to one’s standard negative study.28 prescription. The principle behind these glasses is to stop blue light from As is often the case with novel wearable health technologies, there entering the eyes by using anti-reflection coatings, yellow tinting filters, remains clinical equipoise around the significance and efficacy of blue or a combination of both.7,23 In doing so, these glasses effectively light blocking eyewear. A systematic review that included randomised prevent light from interfering with the sleep-wake cycle.23,24 Multiple controlled trials published prior to May 2017 investigated the effects of studies have assessed the efficacy of blue light blocking glasses blue light blocking glasses in reducing eyestrain, preventing macular in protecting sleep from disruption caused by late night screen degeneration, and improving quality of sleep.7 Contrary to other usage (Table 1). published data, this review found that there is a lack of evidence The earliest study identified in this review was a randomised controlled to support the claim that wearing blue light blocking glasses in the trial conducted in 2009 that compared blue light blocking glasses to general population results in the alleviation of eyestrain or improvement ultraviolet (UV) blocking yellow glasses.24 in sleep quality.7 Overall, the study found that those who were randomised to wear blue This systematic review only assessed three papers, with a total of 136 light blocking glasses for three hours prior to sleep had a statistically participants, indicating a general lack of high-quality data published on significant improvement in self-reported quality of sleep compared to this topic and the need for larger studies.7 those wearing glasses blocking UV light only.24 A similar study, published Finally, a comparison study published in 2019 found that blue light in 2016 by Ayaki et al., assessed the visual quality of participants after blocking glasses do have the potential to protect the eyes from retinal using two different types of eyewear, one blue light shielding and the damage, as well as to protect visual performance and circadian other a control eyewear.25 rhythms.29 The study assessed seven different blue light lens types, This study included 12 participants who wore the eyewear for two hours measuring their efficacy using a spectrophotometer. This study prior to sleep while using an electronic device with a blue light-emitting concluded that blue light blocking glasses were able to reduce blue light screen. Results showed that the secretion of melatonin overnight was emission by 6-43%.29 notably higher after using the blue light shielding eyewear relative to This shows that while blue light blocking glasses may be effective, the the control eyewear, and participants noted an improvement in efficacy of the technology varies, with no existing type of blue light sleep quality.25 shielding glasses being able to block more than 50% of blue light.20

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Finally, a comparison study published sleep. However, with the data published to date, there is conflicting in 2019 found that blue light blocking evidence regarding the extent to which such glasses can protect glasses do have the potential circadian rhythms and, in turn, whether any health benefits will be to protect the eyes from retinal realised. While multiple research articles state that blue light blocking glasses are effective in improving sleep quality, varying measures and damage, as well as to protect methodologies limit the ability to translate this into benefits for visual performance and individuals. Furthermore, despite the increase in literature on blue circadian rhythms. light blocking glasses, many of the trials included very small numbers of participants. Conclusion Overall, the majority of current published literature provides relatively The adverse effects of exposure to blue light on sleep and circadian low-quality evidence, and further studies with larger patient rhythms are consistently reported in a somewhat limited body of cohorts examining the long-term effects of blue light blocking literature. Blue light blocking glasses are being increasingly studied as a glasses are required to fully appreciate the potential scope of their potential intervention to reduce the adverse effects of screen time on therapeutic application.

Table 1: Publications investigating blue light blocking eyewear.

Authors Year Number of Primary outcome Principal findings published participants

Burkhart et al.24 2009 20 Change in overall sleep quality Amber lens users experienced an improvement in sleep quality relative to the control group

Ayaki et al.25 2016 12 Sleep quality and melatonin Participants who wore blue light blocking production glasses had higher secretion of melatonin compared to control group, and improved sleep quality

Esaki et al.23 2016 9 Efficacy of blue light blocking Wearing amber lenses was effective in glasses in patients with delayed patients with DSPD sleep phase disorder (DSPD)

Lawrenson et al.7 2017 136 Efficacy of blue light blocking Lack of evidence to support the use of glasses on sleep quality and blue light blocking glasses to improve eyestrain sleep quality or reduce eyestrain

Perez Algorta 2018 13 Feasibility of blue light blocking Blue light blocking glasses were effective et al.26 glasses at night in students with in enhancing sleep in young adults sleep complaints

Zerbini et al.27 2018 76 Comparison of blue light blocking Blue light blocking glasses are effective glasses and closing curtains in in aiding melatonin secretion and sleep increasing melatonin and having an earlier sleep time

Alzahrani et al.29 2019 N/A Efficacy of blue light blocking Blue light blocking glasses only block glasses on circadian rhythm and blue light to a small extent of less protection from retinal damage than 50%

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References 1. Knufinke M, Fittkau-Koch L, Møst EIS et al. Restricting short-wavelength light 17. Chang AM, Aeschbach D, Duffy JF et al. Evening use of light-emitting

in the evening to improve sleep in recreational athletes – a pilot study. Eur J eReaders negatively affects sleep, circadian timing, and next-morning

Sport Sci. 2019;19(6):728-35. alertness. Proc Natl Acad Sci U S A. 2015;112(4):1232-7.

2. Tosini G, Ferguson I, Tsubota K. Effects of blue light on the circadian system 18. West KE, Jablonski MR, Warfield B et al. Blue light from light-emitting diodes

and eye physiology. Mol Vis. 2016;22:61-72. elicits a dose-dependent suppression of melatonin in humans. J Appl Physiol

3. Hatori M, Gronfier C, Van Gelder RN et al. Global rise of potential health (1985). 2011;110(3):619-26.

hazards caused by blue light-induced circadian disruption in modern aging 19. Touitou Y, Reinberg A, Touitou D. Association between light at night,

societies. NPJ Aging Mech Dis. 2017;3:9. melatonin secretion, sleep deprivation, and the internal clock: health

4. Zhao ZC, Zhou Y, Tan G, Li J. Research progress about the effect and impacts and mechanisms of circadian disruption. Life Sci. 2017;173:94-106.

prevention of blue light on eyes. Int J Ophthalmol. 2018;11(12):1999-2003. 20. Jeyaraj D, Haldar SM, Wan X et al. Circadian rhythms govern cardiac

5. Ericsson. Ericsson Mobility Report, June 2015. 2015. [Internet]. Available repolarization and arrhythmogenesis. Nature. 2012;483(7387):96-9.

from: https://www.ericsson.com/en/news/2015/6/ericsson-mobility-report-june-2015. 21. Brainard J, Gobel M, Scott B et al. Health implications of disrupted circadian

6. Wahl S, Engelhardt M, Schaupp P et al. The inner clock – blue light sets rhythms and the potential for daylight as therapy. Anesthesiology.

the human rhythm. J Biophotonics. 2019;12(12):e201900102. 2015;122(5):1170-5.

7. Lawrenson JG, Hull CC, Downie LE. The effect of blue-light blocking spectacle 22. Exelmans L, Van den Bulck J. Bedtime mobile phone use and sleep in adults.

lenses on visual performance, macular health and the sleep-wake cycle: a Soc Sci Med. 2016;148:93-101.

systematic review of the literature. Ophthalmic Physiol Opt. 2017;37(6):644-54. 23. Esaki Y, Kitajima T, Ito Y et al. Wearing blue light-blocking glasses in the

8. Blume C, Garbazza C, Spitschan M. Effects of light on human circadian evening advances circadian rhythms in the patients with delayed sleep

rhythms, sleep and mood. Somnologie (Berl). 2019;23(3):147-56. phase disorder: an open-label trial. Chronobiol Int. 2016;33(8):1037-44.

9. Moore RY. Suprachiasmatic nucleus in sleep-wake regulation. Sleep Med 24. Burkhart K, Phelps JR. Amber lenses to block blue light and improve sleep: a

2007;8(Suppl. 3):27-33. randomized trial. Chronobiol Int. 2009;26(8):1602-12.

10. Claustrat B, Leston J. Melatonin: physiological effects in humans. 25. Ayaki M, Hattori A, Maruyama Y et al. Protective effect of blue-light shield

Neurochirurgie. 2015;61(2-3):77-84. eyewear for adults against light pollution from self-luminous devices used at

11. Brown GM. Light, melatonin and the sleep-wake cycle. J Psychiatry night. Chronobiol Int. 2016;33(1):134-9.

Neurosci. 1994;19(5):345-53. 26. Perez Algorta G, Van Meter A, Dubicka B et al. Blue blocking glasses worn at

12. Hannibal J, Hindersson P, Knudsen SM et al. The photopigment melanopsin night in first year higher education students with sleep complaints: a

is exclusively present in pituitary adenylate cyclase-activating feasibility study. Pilot Feasibility Stud. 2018;4:166.

polypeptide-containing retinal ganglion cells of the retinohypothalamic 27. Zerbini G, Kantermann T, Merrow M. Strategies to decrease social jetlag:

tract. J Neurosci. 2002;22(1):RC191. reducing evening blue light advances sleep and melatonin. Eur J Neurosci.

13. Ciarleglio CM, Resuehr HE, McMahon DG. Interactions of the serotonin and 2018 doi: 10.1111/ejn.14293. [epub ahead of print]

circadian systems: nature and nurture in rhythms and blues. Neuroscience. 28. Mlinarić A, Horvat M, Šupak Smolčić V. Dealing with the positive publication

2011;197:8-16. bias: why you should really publish your negative results. Biochem Med

14. Stevens RG, Zhu Y. Electric light, particularly at night, disrupts human (Zagreb). 2017;27(3):030201.

circadian rhythmicity: is that a problem? Philos Trans R Soc Lond B Biol Sci. 29. Alzahrani HS, Khuu SK, Roy M. Modelling the effect of commercially

2015;370(1667):pii:20140120. available blue-blocking lenses on visual and non-visual functions. Clin Exp

15. Lockley SW, Brainard GC, Czeisler CA. High sensitivity of the human Optom. 2019 doi: 10.1111/cxo.12959. [epub ahead of print]

circadian melatonin rhythm to resetting by short wavelength light. J Clin 30. Nomanbhay S, Ong MY. A review of microwave-assisted reactions for

Endocrinol Metab. 2003;88(9):4502-5. biodiesel production. Bioengineering (Basel). 2017;4(2) doi:

16. Bonmati-Carrion MA, Arguelles-Prieto R, Martinez-Madrid MJ et al. 10.3390/bioengineering4020057.

Protecting the melatonin rhythm through circadian healthy light exposure.

Int J Mol Sci. 2014;15(12):23448-500.

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The applications and limitations of the Tei index

Abstract The Tei index is a non-invasive Doppler echocardiographic indicator of systolic and diastolic myocardial function. It is calculated as the sum of the isovolumic contraction time and the isovolumic relaxation time divided by the ejection time. It is primarily used to diagnose and determine the prognosis of heart failure, but can also be applied to ischaemic heart disease, valvular heart disease, and other conditions affecting the cardiovascular system. However, it does have limitations, and requires further studies to conclusively determine its clinical significance. Ultimately, the evidence indicates that the Tei index is a promising measure of systolic and diastolic myocardial function.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 45-49.

Introduction The Tei index, or myocardial performance index ejection fraction, which were limited in their ability Traveen Singh (MPI), is a Doppler echocardiographic measure to measure either one or the other.2 Outlined here RCSI medical student that simultaneously assesses systolic and diastolic are the applications and limitations of employing myocardial function.1 This differs from older the Tei index as a clinical tool for the assessment of measures, such as standard echocardiography or myocardial function.

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Calculating the Tei index The Tei index is defined as “the sum of the isovolumic contraction This is an easily measured value, obtained non-invasively, as it is primarily (IVCT) and relaxation (IVRT) times, divided by the ejection time (ET)” a ratio of time intervals: (IVCT + IVRT)/ET.3 It can also be measured by the (Figure 1).1 equivalent formula (a-b)/b, where a represents the time between the termination and subsequent initiation of blood flow across the IVCT + IVRT a - b atrioventricular (mitral or tricuspid) valve, and the value b represents the Tei index = = ventricular ejection time.3 The Tei index is not affected by heart rate, blood ET b pressure, or severity of mitral regurgitation, and therefore does not require specific adjustments for these parameters.2,3 In patients aged older than FIGURE 1: Calculation of the Tei index: IVCT – isovolumic contraction three years, the Tei index is not affected by age. It is more greatly affected time; IVRT – isovolumic relaxation time; ET – ejection time; a – time by age, and has a higher average value, in patients less than three years between termination and initiation of blood flow across mitral valve; old, likely due to ongoing development and maturation of the b – ventricular ejection time.1,3 myocardium.3 The value of the Tei index has a narrow range in normal

Table 1: Applications and results of the Tei index in various pathologies.

Pathology Tei index: increased or decreased? Comments

Heart failure Increased in systolic and diastolic heart failure Higher value indicates more severe disease

Ischaemic heart disease Increased in acute MI; increased in more Increased during positive dobutamine severe vessel disease stress echocardiogram

Valvular heart disease AS with systolic and diastolic dysfunction: increased; May overestimate MR; may AS with isolated diastolic dysfunction: decreased underestimate AS, AR, MS

Pulmonary hypertension Increased Most effective tool for detection and prognosis of pulmonary hypertension

Diabetes mellitus Increased with progressive diastolic dysfunction Resistant to pseudonormalisation

Cardiac amyloidosis Increased Higher value indicates a poorer prognosis

Ebstein’s anomaly Increased Quantitative measure for degree of dysfunction

Cardiotoxicity Increased prior to symptom onset Toxicity from anthracyclines for treatment of paediatric malignancies

Chronic obstructive pulmonary disease Increased Subclinical cardiac dysfunction

Acromegaly Increased Subclinical cardiac dysfunction

Cushing’s syndrome Increased Subclinical cardiac dysfunction

Metabolic syndrome Increased Subclinical cardiac dysfunction

MI – myocardial infarction; AS – aortic stenosis; MR – mitral regurgitation; AR – aortic regurgitation; MS – mitral stenosis.3,6-13

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controls, while in most cardiac pathologies it is increased, due to % Survival based on median Tei index in prolonged IVCT and IVRT, and reduced ET.2-4 heart failure patients 2 100 The normal Tei index value for the left ventricle in adults is <0.39±0.1. Tei index <0.77 90 Tei index >0.77 Mild-to-moderate disease status produces a Tei index of <0.59±0.1, while 80 severe or pre-transplant disease generates a value of <1.06±0.2.2 70 60 50 Clinical applications 40 % Survival 30 The values calculated from the Tei index produce similar results to values 20 obtained via invasive measures such as cardiac catheterisation.5 Therefore, 10 0 the Tei index has been considered a reliable indicator of systolic and 1-year 3-year 5-year diastolic function that may serve as a replacement for more invasive Time to follow-up measurement techniques in heart failure and many other cardiovascular diseases (Table 1).3 FIGURE 2: Clustered bar graph demonstrating the percentage survival in ≤ patients with Tei index 0.77 (n=37), compared to patients with Tei index >0.77 (n=38). 0.77 represents the median Tei index for this Summary of the applications of the Tei index patient population.9 Heart failure In heart failure, the Tei index is positively correlated with New York Heart of acute coronary syndrome.3 Furthermore, in patients who experience Association (NYHA) functional class, and inversely related to left ventricular ischaemia during a dobutamine stress echocardiogram, i.e., have a ejection fraction.3 A higher Tei index is seen in patients with heart failure positive test, Tei index values are higher than in patients who have a compared to normal controls, indicating slower contraction and relaxation negative test.3 of the myocardium (larger isovolumic time intervals), with a shorter interval for ejection of blood.6 This accords with the pathophysiology of Valvular heart disease heart failure, where the myocardial function is compromised leading to an In aortic stenosis, the Tei index is capable of classifying patients into inability to meet tissue requirements of blood flow or pump failure.7 different groups of severity. When aortic stenosis is associated with both There is a strong relationship between the Tei index and the long-term systolic and diastolic dysfunction, the Tei index is elevated in relation to prognosis of heart failure.8 The correlation has been shown to be normal controls. Comparatively, with isolated diastolic dysfunction as a independent of other cardiac functional measurements and well-known result of aortic stenosis, the Tei index is lower than the value in healthy heart failure risk factors.8 A Tei index >0.47 indicates the presence of heart controls.3 However, there is evidence to suggest that the prevalence of failure (86% sensitivity, 82% specificity),3 while a value >0.77 correlates valvular heart disease may be inaccurately detected by the Tei index. The with higher mortality.9 In a retrospective cohort study of 75 patients with presence of aortic stenosis, aortic regurgitation, and mitral stenosis may be heart failure associated with idiopathic dilated cardiomyopathy, the underestimated, while there is a tendency to overestimate the prevalence median Tei index value was 0.77.9 Patients with a Tei index greater than of mitral regurgitation.3 This suggests that the index has poor sensitivity the median value showed substantially higher mortality rates at one, three, and specificity in valvular heart disease. In order to explain these and five years of follow-up (Figure 2).9 tendencies toward inaccurate reporting, further studies of the Tei index in valvular heart disease are required. Ischaemic heart disease The Tei index has been shown to be elevated in patients suffering from Pulmonary hypertension acute myocardial infarction (0.705±0.03; p<<0.05) compared to healthy While the Tei index is classically employed to assess left ventricular controls (0.455±0.023; p<<0.05).3 The elevation arises from a prolonged function, it can be applied to the right ventricle as well. Yeo et al. IVCT and IVRT, while the ET is shortened.3 The index is also capable of demonstrated that the Tei index was the most effective tool for stratifying patients into groups based on severity of coronary artery disease diagnosing primary pulmonary hypertension, as well as assessing (CAD).3 The Tei index is substantially elevated in patients with severe functional status and survival.10 Apart from treatment with calcium coronary disease (three- or four-vessel involvement), compared to patients channel blockers, only the Tei index was predictive of adverse outcomes with mild-to-moderate CAD, defined as one- or two-vessel disease, in these patients.10 A progressive increase in the Tei index of 0.1 was suggesting that the Tei index may have predictive value in the progression associated with a 1.3 times increase in mortality (95% CI: 1.09-1.56).10

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Ogihara et al. performed a study demonstrating that the Tei index was regurgitation, and aortic stenosis.3 This increases the number of false a useful measure in pulmonary hypertension, not only for assessing negative test results and, subsequently, these patients may not receive disease severity, but also to monitor response to treatment.14 The right appropriate treatment. ventricular Tei index was also shown to be effective in making early Studies utilising animal models have demonstrated that the Tei index diagnoses of pulmonary arterial hypertension in patients with appears normal in severe diastolic dysfunction due to pressure left-to-right shunt congenital heart disease.15 overload hypertrophy, while many patient studies have indicated that the Tei index is a reliable indicator in the assessment of Diabetes mellitus diastolic dysfunction.1 Type II diabetes mellitus is associated with progressive diastolic This can likely be explained by the fact that most patients who were dysfunction, which can be demonstrated as an elevated Tei index.11 studied presented with mild-to-moderate diastolic dysfunction, while Typically, as myocardial diastolic function worsens, there is the animal studies were able to produce test subjects with severe pseudonormalisation of the Tei index, due to increasing atrial pressure diastolic dysfunction, leading to pseudonormalisation of the Tei and an increased pressure gradient across the atrioventricular (AV) index.1 To overcome this limitation, larger randomised controlled valve, which leads to altered IVRT and other diastolic measures.12 studies must be conducted, involving patients with more severe However, the Tei index in diabetes mellitus remains abnormally diastolic dysfunction, in order to assess the applicability of the Tei increased despite these changes, likely due to eventual shortening of index in this setting.1 the ET.11 As diastolic dysfunction progresses in patients with diabetes, The Tei index cannot be measured reliably in patients with atrial the Tei index becomes increasingly elevated, with no apparent fibrillation, frequent ventricular ectopic beats, abnormal pseudonormalisation.11 atrioventricular or interventricular conduction pathways, patients with a permanent pacemaker, or if clear Doppler images cannot be Other applications obtained.3 This is largely due to the fact that IVCT, IVRT, and ET are The Tei index can also be employed as a prognostic assessment tool measured in sequence, as opposed to a simultaneous measurement of in cardiac amyloidosis, with a higher value indicating a worse all three parameters during the same heart cycle.13 prognosis in these patients.3 It can also be used as a quantitative herefore, heart rate and rhythm variations from one heart cycle to the measure in congenital heart defects such as Ebstein’s anomaly, to next, such as in the aforementioned conditions, may lead to inaccurate assess the degree of dysfunction.3,16 The index has been used to measurement of variables.13 Tissue Doppler imaging (TDI) can be used monitor adverse outcomes of chemotherapy, particularly the effect to calculate the Tei index, as opposed to standard methods using of anthracyclines, used to treat childhood malignancy, which are pulsed-wave Doppler. TDI is capable of measuring systolic and diastolic known to cause rapidly progressive cardiotoxicity before the onset function (and therefore IVCT, IVRT, and ET) simultaneously, and so of symptoms.3 is less vulnerable to inaccuracies resulting from fluctuations in Wang et al. demonstrated a positive correlation between increased Tei heart rate.13 index and brain natriuretic peptide (BNP) levels in patients with The conventional Tei index was shown to have a close relationship with compensated cirrhosis compared to healthy controls.17 A further the peak rate of pressure change during systole and diastole.5,8 These positive correlation was demonstrated between increased Tei index and values can be affected by altered preload conditions, even if heart BNP in patients with decompensated cirrhosis compared to those with contractility remains constant, potentially leading to a false positive Tei compensated cirrhosis.17 Finally, subclinical cardiac dysfunction, as seen index value.13 in chronic obstructive pulmonary disease (COPD), acromegaly, TDI can also circumvent this issue, as its measurements are relatively Cushing’s syndrome, and metabolic syndrome, can also be detected unaffected by blood volume, and therefore fluctuations in preload.4,13 early by the Tei index.13 However, it should be noted that there is disagreement with regard to the similarity of results obtained from the conventional Tei index Limitations of the Tei Index compared to the TDI-Tei index.18 As mentioned above, the Tei index tends to overestimate the presence Since the majority of studies performed to date have included small of mitral regurgitation, which may lead to some patients being treated patient cohorts, larger studies are required before reliable conclusions unnecessarily for a condition that they do not have.3 Furthermore, the can be drawn.13,18 Systolic intervals are longer, while diastolic intervals index may underestimate the prevalence of mitral stenosis, aortic are shorter when using TDI as opposed to the conventional Tei index.18

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Hence, Rojo et al. have proposed the idea of using the TDI-Tei index as other cardiac pathologies, such as ischaemic and valvular heart disease, a practical but separate measure from the conventional Tei index. It is pulmonary hypertension, cardiac amyloidosis, and subclinical suggested that the TDI-Tei index requires its own set of normal values, cardiac dysfunction. and further studies of its clinical application are necessary, rather than However, a variety of limitations must be considered before its attempting to replace the conventional Tei index with TDI.18 widespread implementation, such as poor sensitivity and specificity in Consequently, the conventional Tei index is used more commonly and valvular heart disease, diastolic dysfunction, arrhythmias, and has been studied in more depth than the TDI-Tei index.3 implanted pacemakers. In states of altered preload, the Tei index tends to display false positive results. Furthermore, the vast majority of Conclusion evidence has been obtained from small-scale studies. Therefore, the Tei The Tei index has yielded promising results with respect to its index requires further studies on a larger scale to determine its application in the diagnosis and prognosis of heart failure and many significance as a reliable measure of myocardial performance.

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2010;11(10):829-33. 11. Goroshi M, Chand D. Myocardial performance index (Tei Index): a simple

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1995;26(6):357-66. mild-to-moderate congestive heart failure. Eur Heart J. 2000;21:1888-95.

3. Lakoumentas JA, Panou FK, Kotseroglou VK, Aggeli KI, Harbis PK. The Tei 13. Correale M, Totaro A, Ieva R, Brunetti ND, Di Biase M. Time intervals and

index of myocardial performance: applications in cardiology. Hellenic J myocardial performance index by tissue Doppler imaging. Intern Emerg

Cardiol. 2005;46:52-8. Med. 2011;6(5):393-402.

4. Tekten T, Onbasili AO, Ceyhan C, Ünal S, Discigil B. Novel approach to 14. Ogihara Y, Yamada N, Dohi K et al. Utility of right ventricular Tei-index for

measure myocardial performance index: pulsed-wave tissue Doppler assessing disease severity and determining response to treatment in patients

echocardiography. Echocardiography. 2003;20(6):503-10. with pulmonary arterial hypertension. J Cardiol. 2014;63:149-53.

5. Tei C, Nishimura RA, Seward JB, Tajik AJ. Noninvasive Doppler-derived 15. Yücel M, Alp H, Yorulmaz A, Karaarslan S, Baysal T. Prediction of the

myocardial performance index: correlation with simultaneous development of pulmonary arterial hypertension with Tei index in

measurements of cardiac catheterization measurements. J Am Soc congenital heart diseases with left-to-right shunt. Turk Kardiyol Dern Ars.

Echocardiogr. 1997;10(2):169-78. 2019;47(6):466-75.

6. Harjai KJ, Scott L, Vivekananthan K, Nunez E, Edupuganti R. The Tei index: 16. Liu D, Hu K, Herrmann S et al. Value of tissue Doppler-derived Tei index and

a new prognostic index for patients with symptomatic heart failure. J Am two-dimensional speckle tracking imaging derived longitudinal strain on

Soc Echocardiogr. 2002;15(9):864-8. predicting outcome of patients with light-chain cardiac amyloidosis. Int J

7. Kemp CD, Conte JV. The pathophysiology of heart failure. Cardiovasc Cardiovasc Imaging. 2017;33(6):837-45.

Pathol. 2012;21(5):365-71. 17. Wang LK, An XF, Wu XL et al. Doppler myocardial performance index

8. Ärnlöv J, Ingelsson E, Risérus U, Andrén B, Lind L. Myocardial performance combined with plasma B-type natriuretic peptide levels as a marker of

index, a Doppler-derived index of global left ventricular function, predicts cardiac function in patients with decompensated cirrhosis. Medicine

congestive heart failure in elderly men. Eur Heart J. 2004;25:2220-5. (Baltimore). 2018;97(48):e13302.

9. Dujardin KS, Tei C, Yeo TC, Hodge DO, Rossi A, Seward JB. Prognostic value 18. Rojo EC, Rodrigo JL, de Isla LP et al. Disagreement between tissue Doppler

of a Doppler index combining systolic and diastolic performance in imaging and conventional pulsed wave Doppler in the measurement of

idiopathic-dilated cardiomyopathy. Am J Cardiol. 1998;82:1071-6. myocardial performance index. Eur J Echocardiogr. 2006;7:356-64.

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In search of an HIV vaccination: failures, successes, and innovations in eliciting humoral and cellular immunity against HIV

Abstract Forty years ago, the human immunodeficiency virus (HIV) pandemic began. It has since claimed the lives of at least 39 million people. In this time, incredible progress has been made in the prevention, diagnosis, and treatment of HIV. However, an effective, economically viable vaccination remains elusive. Most viral vaccinations prompt the creation of neutralising antibodies, which bind surface antigens and prevent the infection of host cells. In the case of HIV-1, there exists only one envelope protein – the trimeric envelope spike. This spike consists of three gp120-gp41 heterodimers. Together, gp120 and gp41 are responsible for attachment and entry into CD4+ T-cells and macrophages. Unfortunately, the trimeric spike is not an ideal target. Neutralisation-sensitive epitopes are recessed and surrounded by host glycans, against which the host will not produce antibodies. The env sequence is highly variable between HIV strains, and undergoes extremely high rates of mutation. Researchers would ideally like to prompt the creation of broadly neutralising antibodies (bNAbs), which bind to, and neutralise, epitopes from different HIV strains. However, an immunogen that stimulates bNAb production to a significant degree has not yet been discovered. Many human trials have explored potential immunogens. For instance, recombinant gp120 with alum adjuvant, HIV-1 gag/pol/nef expressed by an adenovirus vector, and HIV-1 gp120-gp41 expressed by a canarypox vector have all been tested in at-risk populations. Only one – the RV144 vaccination – has been modestly successful in preventing infection. Recently, innovations in the HIV-1 vaccination field have shown great promise. Researchers are attempting to target germline B-cells, which are capable of somatic hypermutation in order to keep pace with the rapid rate of mutation of HIV. They are synthesising ever-improving immunogens that closely resemble the quaternary structure of the envelope protein, exploring the possibility of passive immunisation, and probing the field of gene therapy, in which a viral vector delivers DNA to be incorporated into host cell genomes. All in all, it would seem that a safe and Aidan McKee effective HIV vaccination is a challenging yet attainable goal – one that would prevent countless HIV RCSI medical student infections worldwide and save the lives of millions.

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FIGURE 1: Structure of the trimeric envelope protein of the HIV virus, including transmembrane gp41 and extracellular gp120 regions.7

Introduction HIV trimeric envelope protein The human immunodeficiency virus (HIV) pandemic first began in the HIV-1 and HIV-2 are enveloped retroviruses, with HIV-1 being the 1980s, when an alarming number of people – initially men who had far more common pathogen.4 Their genomes contain three sex with men and injection drug users in the United States – structural genes: pol, gag, and env. In the envelope of each virus, contracted unexplained opportunistic infections, invariably there exists a single viral protein: a trimeric envelope spike succumbing to their illnesses. By the mid 1980s, the Centers for encoded by env.5 Disease Control and Prevention (CDC) recognised HIV infection to be In infected CD4+ T-cells and macrophages, the protein product of the cause of acquired immunodeficiency syndrome (AIDS), which env, gp160, is heavily glycosylated and proteolytically cleaved into renders its victims vulnerable to life-threatening infections and gp120 and gp41. malignancies. Since its discovery, HIV has infected at least 78 million Trimeric envelope spikes are composed of three gp120-gp41 people worldwide and has been directly responsible for 39 million dimers, and are thus a trimer of heterodimers (Figure 1).5,6 Gp120 deaths.1 In Ireland, approximately 8,350 people have been diagnosed mediates attachment to host cells and possesses binding sites for with HIV since the early 1980s.2 CD4, as well as for one co-receptor: either CXCR4 (on CD4+ With the advent of educational campaigns, screening and diagnostic T-cells) or CCR5 (on macrophages). The gp41 protein functions to tests, antiretroviral drug cocktails, and pre- and post-exposure anchor the trimer into the viral envelope.6 prophylaxis (PREP and PEP), HIV incidence and mortality have dropped steadily.3 Despite this progress, practitioners are not Since its discovery, HIV has infected satisfied, citing the issues of late diagnosis, poor access and adherence at least 78 million people worldwide to treatment, and the costliness of treatment and monitoring. HIV and has been directly responsible for 1 incidence remains high, at 5,600 new cases per day worldwide. 39 million deaths. In Ireland, In 2016, 512 new HIV diagnoses were made in Ireland.2 One approximately 8,350 people solution, proposed by concerned clinicians and research scientists, have been diagnosed with is to definitively protect at-risk individuals with a safe and cost-effective vaccination. HIV since the early 1980s.

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FIGURE 2: Structure of the HIV trimeric envelope protein, illustrating potential vaccination epitopes and shielding of these epitopes by host glycans.8

The difficulty of vaccination and 2).4,5,6,10 These epitopes are variably accessible to antibodies Generally speaking, vaccinations elicit the production of neutralising depending on whether the env protein is in a pre-fusion or post-fusion antibodies that bind viral surface antigens and prevent subsequent conformation.10 infection of host cells.6 The trimeric spike is the sole viral protein in the Most antibodies produced endogenously by HIV-1-infected HIV envelope; all other envelope proteins are derived from the host individuals are non neutralising, meaning they do not prevent cell, as is the envelope itself. Thus, the spike protein is a logical target infection of new host cells, although there is some evidence that they for vaccination. reduce viral load via phagocytosis or antibody-dependent cellular Unfortunately, neutralisation-sensitive epitopes on this trimer are cytotoxicity.3 bNAbs are produced endogenously in up to 20-30% of recessed. The envelope protein is heavily glycosylated during its cases, beginning two to four years after infection.4,6,10,11 However, synthesis in host cells, and is therefore surrounded and effectively they are unable to suppress the rapidly dividing and mutating virus.1,5 shielded by host glycans when expressed on the cell surface (Figure 2). Neutralising antibodies produced by the host must either bind to Early efforts towards HIV vaccination these self-glycans, or avoid them.6,9 This is problematic, as the body’s focused on creating immunogens immune tolerance mechanisms limit antibodies that target that mimic the monomeric gp120 5,9 self-glycans. structure, with the intention of Moreover, the envelope protein sequence is highly variable between initiating a humoral response HIV strains.4,5 A worthwhile vaccine candidate would ideally elicit the against CD4bs and V3 regions. creation of broadly neutralising antibodies (bNAbs) that bind epitopes expressed by many different HIV strains. Epitopes of interest include the CD4 binding site (CD4bs) of gp120, the V1 and V2 loops Early human trials: AIDSVax B/E and AIDSVax B/B of gp120, the V3 loop of gp120 (which facilitates binding to CCR5 or Early efforts towards HIV vaccination focused on creating CXCR4 co-receptors), the interface between gp120 and gp41, and immunogens that mimic the monomeric gp120 structure, with the the membrane proximal external region (MPER) of gp41 (Figures 1 intention of initiating a humoral response against CD4bs and V3

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regions.6 This strategy was employed by the first vaccinations to reach C Modified Intention-to-Treat analysis randomised, placebo-controlled Phase III human trials: AIDSVax B/B 1.0 0.9 and AIDSVax B/E.12-14 AIDSVax B/B randomised participants to receive 0.8 Placebo either placebo or repeated intramuscular injections of a bivalent, 0.7 0.6 recombinant gp120 (rgp120) HIV-1 vaccination. Specifically, 0.5 Vaccine researchers administered MN and GNE8 rgp120 from two different 0.4 0.3 HIV-1 subtype B strains (predominant in North America), on alum 0.2 P=0.04 adjuvant. The participants were men who have sex with men and 0.1

Probability of HIV-1 Infection (%) Probability of HIV-1 0.0 high-risk heterosexual women in the Netherlands and North 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

11,13 Time in years America. Similarly, AIDSVax B/E randomised participants to receive No. at Risk Placebo 8198 7775 7643 7441 7325 either placebo or a bivalent rgp120 vaccination. These antigens were Vaccine 8197 7797 7665 7471 7347 derived from CXCR4-dependent subtype B (MN) and Cumulative No. of Infections Placebo 30 50 65 74 CCR5-dependent subtype E (A244) strains on alum adjuvant. The Vaccine 12 32 45 51 participants were injection drug users in Thailand.11,14 FIGURE 3: Modified intention-to-treat analysis of the RV144 trial results; an Promisingly, neutralising antibodies – IgG4 and IgA – were produced attempt to prevent HIV-1 infection in Thailand via administration of ALVAC and AIDSVax vaccinations.15 against tier-1 (typically susceptible) viruses. Unfortunately, there was a weak response against tier-2 (typically resistant) viruses. RV144 trial The vaccine did not provide any protection against HIV-1 infection It was not until 2009 that the first promising progress towards an compared to the control group, and did not reduce viral load or slow effective HIV-1 vaccination in humans was reported. RV144 was a the disease course following infection. The vaccinations were ruled to randomised, double-blinded, placebo-controlled trial that recruited be ineffective.1,5,12-14 16,402 subjects in Thailand, the majority of whom were at increased risk for heterosexual transmission of HIV-1.1,16,17 No human trial to date has demonstrated Participants randomised to the vaccination group received four an HIV vaccination as effective as the ‘priming’ injections with the ALVAC-HIV vaccination, consisting of a modern vaccinations against varicella, recombinant canarypox vector expressing HIV-1 subtype B gag and 17 measles, or polio. However, several pro, and HIV-1 subtype E gp120 linked to gp41. They also received two ‘boost’ injections of the AIDSVax B/E vaccine, consisting revelations have recently occurred that of rgp120 from HIV-1 subtype E and subtype B strains on will rejuvenate efforts to this end. alum adjuvant.1,16,17 At long last, the first positive (albeit, statistically insignificant) results HVTN 502 (STEP) trial were reported. In intention-to-treat analysis, the RV144 vaccination While a substantial humoral immune response was observed in the prevented HIV infection after 42 months of follow-up with an efficacy AIDSVax studies, researchers wondered if they might also be able to of 26.4% (p=0.08; 95% CI: -4.0-47.9).17 elicit cell-mediated immunity (CMI). The Phase II test-of-concept STEP Later, when it was discovered that several participants had HIV-1 study began with this aim. infections at baseline, modified intention-to-treat analysis revealed an Participants were randomised to either a placebo group or a group efficacy of 31.2% (p=0.04; 95% CI: 1.1-52.1) (Figure 3).1,12,17 receiving three doses of a Merck adenovirus serotype 5 (MRKAd5) Vaccination-induced IgG1/IgG3 antibodies against the gp120 V1/V2 HIV-1 gag/pol/nef vaccination.15 Each vaccination consisted of three region were likely responsible for this outcome, eliciting recombinant, replication-defective adenovirus vectors expressing a antibody-dependent cellular cytotoxicity.9,11,12,16 single HIV immunogen – gag, pol, or nef. Participants were HIV These efficacy rates were certainly not sufficient for licensure, and the seronegative and at high risk of infection.11,15 RV144 vaccination regime admittedly did not change disease Promisingly, when the trial concluded in 2008, 75% of vaccinees progression in newly infected participants.1,17 This being said, RV144 displayed a strong CMI response, as measured by IFN-γ ELISPOT provided the first evidence of a correlate of protection from HIV-1 and testing.15 However, as in the AIDSVax trials, no significant protection paved the road to future studies. was offered by vaccination.1,11,15

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HVTN 100 trial V(D)J mutations.19 Only B-cells that express germline precursors, Following the relative success of RV144 in Thailand, a modified rather than mature antibodies, are capable of such somatic version of the RV144 vaccination was created, one that targeted HIV-1 hypermutation in order to optimise antigen specificity and keep subtype C, which is predominant throughout Africa. This vaccination pace with HIV. This process of selection for adequate bNAb consisted of: 1. a canarypox vector, expressing HIV-1 subtype C mutations depends largely on extended and amplified germinal gp120 and subtype B gp41/gag/pro; and, 2. a bivalent subtype C centre activity.1,4,5,9,11 gp120, with squalene adjuvant and an extra ‘boost’ dose compared Unfortunately, HIV-1 is skilled in host mimicry. Germline B-cell-derived to RV144.1,16,18 An initial Phase I/IIa trial, termed HVTN 100 (HIV bNAbs have the potential to neutralise HIV-1 epitopes, but are at least Vaccine Trials Network 100) took place in South Africa, with results partially targeted against host cell elements, and thus are suppressed showing increased antibody binding and a stronger cellular immune via immune tolerance.19 response than RV144.11,16,18 Secondly, scientists are becoming more adept at creating recombinant immunogens that closely resemble the quaternary Ongoing trials: HVTN 702 and HVTN 705 structure of envelope proteins. HVTN 702, also known as Uhambo (English: journey), is the follow-up Frustratingly, the transmembrane domain of gp41 is difficult to Phase IIb/III efficacy trial to HVTN 100.16 It began in South Africa in synthesise and purify.6 2016, with results expected by 2021. This trial will ascertain the This led scientists to create gp140, a recombinant gp120/gp41 efficacy of the HVTN 702 vaccination in preventing HIV-1 subtype C protein that excludes the transmembrane and cytoplasmic gp41 infection in an at-risk population. It will also assess the correlation regions via the introduction of a premature stop codon.6 Further between efficacy and vaccination-induced neutralising antibodies improvements resulted in BG505 SOSIP.664 gp140, a construct against the V1/V2 region of gp120.1,16 with an increasingly truncated gp41, but fewer aberrant Another trial, HVTN 705, will test a prime/boost vaccine that disulphide bonds.6,11,20 depends on a subtype C gp140 construct and an adenovirus vector; Thirdly, researchers have acknowledged the merits of a different it is currently being tested in South Africa, with results expected approach: passive immunisation. It has been found that an infusion of by 2022. ‘second-generation’ bNAbs is capable of protecting macaques from simian-human immunodeficiency virus (SHIV).5,11 One particular The development of a vaccination against infusion, which resulted in a serum titre of 1:100, protected 50% of one of the most aggressive and adaptable macaques from a high-dose intravenous infection.5 viruses in existence would be an Granted, any passive preventive human vaccination would need to be admirable feat, substantially reducing the administered bi-yearly or quarterly, if not more often, and may be expensive to manufacture. 5,600 new HIV infections that occur every However, researchers argue that even a weekly administration of day and, by extension, preventing the antibodies would be more convenient than the current treatment deaths of millions. plan of daily anti-retroviral medications.1 Finally, and perhaps most excitingly, there exists the possibility of Progress and innovations gene therapy. In this technique, researchers implant bNAb-encoding No human trial to date has demonstrated an HIV vaccination as genes into viral vectors whose DNA is incorporated into the host cell effective as the modern vaccinations against varicella, measles, or polio. genome (commonly adeno-associated virus).1 However, several revelations have recently occurred that will rejuvenate After only one intramuscular injection, the bNAb-encoding DNA may efforts to this end. be transferred from viral genomes into host muscle cell genomes, Firstly, it has been noted that the best way to neutralise HIV might be causing bNAbs to be permanently expressed and secreted to sequentially administer a wide variety of immunogens that into circulation.1,9,11 specifically activate germline B-cells.19 The challenge of choosing an appropriate antibody remains, as does The rapid rate of mutation of HIV-1 envelope glycoproteins necessitates the challenge of inducing expression to sufficiently high levels. a similarly rapid rate of mutation in neutralising antibodies. Most Moreover, there is the possibility that hosts possess pre-acquired bNAbs isolated from infected individuals display vast numbers of immunity against the viral vector, preventing uptake.1

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Conclusion Further reading It is clear that a safe and effective HIV vaccination is worthwhile and 1. Abela IA, Kadelka C, Trkola A. Correlates of broadly neutralizing attainable in the years to come. While only one trial (RV144) has put antibody development. Curr Opin HIV AIDS. 2019;14(4):279-85. forward a vaccination that is modestly effective, innovations in 2. Burton S, Spicer LM, Charles TP, Gangadhara S, Reddy PBJ, Styles TM targeting germline B-cells, understanding native env structure, et al. Clade C HIV-1 envelope vaccination regimens differ in their creating native-like immunogens, and administering passive ability to elicit antibodies with moderate neutralization breadth immunisations and bNAb-encoding gene therapies have shown against genetically diverse tier 2 HIV-1 envelope variants. J Virol. great promise. 2019;93(7). The development of a vaccination against one of the most aggressive and adaptable viruses in existence would be an admirable feat, substantially reducing the 5,600 new HIV infections that occur every day and, by extension, preventing the deaths of millions.1

References 1. Ahmad M, Ahmed OM, Schnepp B, Johnson PR. Engineered expression of 13. Flynn NM, Forthal DN, Harro CD, Judson FN, Mayer KH, Para MF; rgp120

broadly neutralizing antibodies against human immunodeficiency virus. HIV Vaccine Study Group. Placebo-controlled phase 3 trial of a recombinant

Annu Rev Virol. 2017;4(1):491-510. glycoprotein 120 vaccine to prevent HIV-1 infection. J Infect Dis.

2. Gardner C, O’Donoghue R, Dermody A. HIV in Ireland. Findings from the 2005;191(5):654-65.

National HIV Knowledge and Attitudes Survey 2017 and People Living with 14. Pitisuttithum P, Gilbert P, Gurwith M, Heyward W, Martin M, Griensven FV

HIV Stigma Survey. Dublin: HIV Ireland, 2017. et al. Randomized, double-blind, placebo-controlled efficacy trial of a

3. Chea LS, Amara RR. Immunogenicity and efficacy of DNA/MVA HIV vaccines bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug

in rhesus macaque models. Expert Rev Vaccines. 2017;16(10):973-85. users in Bangkok, Thailand. J Infect Dis. 2006;194(12):1661-71.

4. Ahmed Y, Tian M, Gao Y. Development of an anti-HIV vaccine eliciting 15. Buchbinder SP, Mehrotra DV, Duerr A, Fitzgerald DW, Mogg R, Li D et al.

broadly neutralizing antibodies. AIDS Res Ther. 2017;14(1):50. Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step

5. Escolano A, Dosenovic P, Nussenzweig MC. Progress toward active or Study): a double-blind, randomised, placebo-controlled, test-of-concept

passive HIV-1 vaccination. J Exp Med. 2017;214(1):3-16. trial. Lancet. 2008;372(9653):1881-93.

6. Sanders RW, Moore JP. Native-like Env trimers as a platform for HIV-1 vaccine 16. Barouch DH. A step forward for HIV vaccines. Lancet HIV. 2018;5(7):338-9.

design. Immunol Rev. 2017;275(1):161-82. 17. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S. Vaccination with ALVAC and

7. Koff WC, Berkley SF. The renaissance in HIV vaccine development – future AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med.

directions. N Engl J Med. 2010;363(5):e7. 2009;361:2209-20.

8. Burton DR, Ahmed R, Barouch DH, Butera ST, Crotty S, Godzik A et al. A 18. Bekker LG, Moodie Z, Grunenberg N, Laher F, Tomaras GD, Cohen KW et al.

blueprint for HIV vaccine discovery. Cell Host Microbe. 2012;12(4):396-407. Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine

9. Haynes BF, Mascola JR. The quest for an antibody-based HIV vaccine. in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial. Lancet

Immunol Rev. 2017;275(1):5-10. HIV. 2018;5(7):e366-78.

10. Pancera M, Changela A, Kwong PD. How HIV-1 entry mechanism and 19. Kelsoe G, Haynes BF. Host controls of HIV broadly neutralizing antibody

broadly neutralizing antibodies guide structure-based vaccine design. Curr development. Immunol Rev. 2017;275(1):79-88.

Opin HIV AIDS. 2017;12(3):229-40. 20. Barouch DH, Tomaka FL, Wegmann F, Stieh DJ, Alter G, Robb ML et al.

11. Hsu DC, O’Connell RJ. Progress in HIV vaccine development. Hum Vaccin Evaluation of a mosaic HIV-1 vaccine in a multicentre, randomised,

Immunother. 2017;13(5):1018-30. double-blind, placebo-controlled, phase 1/2a clinical trial (APPROACH) and

12. Karnasuta C, Akapirat S, Madnote S, Savadsuk H, Puangkaew J, in rhesus monkeys (NHP 13-19). Lancet. 2018;392(10143):232-43.

Rittiroongrad S et al. Comparison of antibody responses induced by RV144,

VAX003, and VAX004 vaccination regimens. AIDS Res Hum Retroviruses.

2017;33(5):410-23.

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Supercentenarians: a look into the lives of the world’s oldest old

Abstract With the trends in global life expectancy being relatively stable, supercentenarians – individuals who live to more than 110 years of age – are a puzzling outlier. Clustered in areas of the world known as the Blue Zones, the reasons for this population’s exceptional longevity are multifactorial. Enrichment of polymorphisms in certain genes (FOX03, APOE4, ACE, KLOTHO, and IL-6) are partially responsible for this longevity; however, equally important are shared lifestyle factors among members of this group (natural movement, plant-based diet, sense of community, and sense of purpose) and a uniquely developed gut microbiota enriched in C. minuta. Additionally, when comparing their life course to the general population, this group has a much lower incidence of common chronic conditions associated with mortality (cardiovascular disease, diabetes, cancer, and dementia). If they do develop these conditions, it appears to be after 100 years of age, leading to the conclusion that they exhibit a compression of morbidity. One theory is that the cause of mortality in this group is organ exhaustion, prompted by the observation that many of them die within one year of becoming ill. Some of them are independent according to the Activities of Daily Living (ADL) scale, and do not represent a significant burden to the healthcare system. As the oldest known Christine Okeefe supercentenarian lived to 122 years of age, there is much debate around whether this RCSI medical student represents the absolute maximum of human lifespan.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 56-61.

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Introduction According to the Tibetan proverb, “the secret to living long is eat half, each gene varies, and collectively they account for around 20-30% of walk double, laugh triple, and love without measure”. The desire to the variance in longevity between individuals.12-14 Out of the 20, there live a long, happy life is rooted deep within the human condition, and are five genes that show a consistently strong association with due to improvements in healthcare over the past century, the average longevity across multiple studies, and these are further explored global life expectancy has risen to 71 years of age, with higher income in Table 1.15 nations being closer to 80 years of age.1 However, this does not Many of these genes are linked to the cardiovascular system, which necessarily mean we are living longer without disease. Current introduces the possibility of developing a polygenic risk score of literature estimates that disorders affecting people over the age of 60 cardiac genes to predict lifespan.16 Additionally, there are other genes contribute almost 25% of the global burden of disease, which begs that show varying levels of association with longevity, including CETP, the question: are we trading gains in years of life for losses in quality SIRT1, TNF-α, HSP 70, and GH.13 It is possible that as more of life?2 Interestingly, there is a growing subset of the population supercentenarians receive full genome sequencing, new genes will be whose lifespan deviates far from the expected, living for a century or added to the list. In addition to genetic profiles, recent literature has more with surprisingly few health issues. They can be divided into proposed that supercentenarians also have a different gut three main groups: centenarians, who live to 100-104 years of age; microbiome, enriched in bacteria such as C. minuta, which has semi-supercentenarians, who live to 105-109; and, been shown to reduce inflammation, lower body mass index, and supercentenarians, who live to 110 or higher.3 How does this happen? promote longevity.17 In traditional ageing models, individuals are healthy until they develop a chronic disease (e.g., diabetes, hypertension, cancer or This review will focus on the fascinating dementia), which, through its associated morbidity, reduces a group of supercentenarians, and will person’s health until they pass away.4 discuss the biological and social reasons Therefore, although the risk of mortality naturally increases as we get for their extended longevity and the older, usually peaking at around 80-85 years of age, the size of the implications this has for healthcare increase is affected by the number of chronic conditions we have.4 systems around the world. Supercentenarians, by way of comparison, are much less likely to develop chronic conditions and, if they do, these generally occur after 105 years of age.5 This means that for most of their life, their risk of Environmental and biopsychosocial mortality, while still rising, remains relatively low.6 Once individuals in Ageing is a complex process involving biological, psychological, and this population become sick, they generally pass away in less than a social components. Therefore, lifestyle factors are an important year, suggesting that their mortality is due to organ exhaustion and consideration for differences in longevity between populations. lack of functional capacity, not necessarily the condition itself.7 This Additionally, these factors play a role in public health policy and the review will focus on the fascinating group of supercentenarians, and promotion of healthy ageing among members of the community.32 will discuss the biological and social reasons for their extended Supercentenarians are still a rarity, with only around 1 in 1,000 longevity and the implications this has for healthcare systems around centenarians reaching this milestone.33 the world. Historically, they have been clustered in five regions of the world termed the Blue Zones: Okinawa, Japan; Ovodda, Sardinia; Loma Factors contributing to longevity Linda, California; Nicoya Peninsula, Costa Rica; and Ikaria, Greece.34 Genetics Careful study of the inhabitants in these areas has shown that there As children and siblings of supercentenarians are more likely to reach are nine lifestyle characteristics common among all the zones, the centenarian category themselves, there is evidence for a potential referred to as the “Power Nine” (Table 2).34 These commonalities genetic component to longevity.8,9 All genes and polymorphisms emphasise that social, environmental, and lifestyle factors can be associated with ageing can be viewed in the GenAge database, with strong determinants of longevity. Additional cohort studies of the most recent update listing 307 polymorphisms.10 Within this individuals who live past the octogenarian stage (ages 80+) have database, there are approximately 20 genes that have been contributed to the finding that subjective well-being, social resources, specifically associated with longevity.10,11 The individual effect size of and physical activity all play a key role in healthy ageing.35-38

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Table 1: Genes associated with longevity.

Gene Function Association with longevity

FOX03 Provides protection from oxidative stress, influences FOX03A variant is positively associated with longevity; however, the metabolic adaptations to caloric restriction, and the exact mechanism has yet to be determined.19 modulates the cell cycle by upregulating proteins involved with apoptosis.18

APOE Plays a key role in fat metabolism (well described Individuals with the E2 allele are more likely to live longer, possibly in relation to the onset of Alzheimer’s disease due to its protective effect against developing neurodegenerative and dementia).20 conditions.21,22 APOE also interacts with other genes such as FOX03 to promote longevity.23

ACE Regulates blood pressure throughout the body.15 The D allele of this gene has been associated with reduced incidence of hypertension and subsequent increases in longevity.24,25 Note: this may only apply to Caucasian populations.26

KLOTHO Control of oxidative stress and insulin sensitivity. The KL-VS gene variant is particularly associated with longevity due Encodes a component of cerebrospinal fluid.15,27 to its ability to suppress insulin signalling throughout the body.27 KL-VS also preserves cognitive function in older age groups, which may also contribute to the longevity effect.28

IL-6 Pro-inflammatory mediator15 Inflammation is a strong predictor of mortality in the elderly. There are decreased levels observed in semi-supercentenarians compared to controls.29 Certain polymorphisms, such as the GG allele, lead to increased production of IL-6 and consequently are less expressed in centenarians compared to controls.30 The effect size of IL-6 in isolation appears to be weaker compared to other longevity-associated genes. Therefore, its observed association may be due to its interaction with other longevity-associated genes.31

Impact on healthcare Impact on medical services One of the challenges facing healthcare systems around the seen with supercentenarians is referred to as “compression of world is the growth of an ageing population. As individuals in this morbidity”, since they tend to spend a much shorter amount of group tend to have multiple noncommunicable diseases that time experiencing health issues before passing away.40 require treatment from a variety of specialties, increased Current estimates put the worldwide population of centenarians at utilisation of medical services and access to quality care become just over 500,000 individuals, and this is predicted to rise to over significant issues.39 three million people by 2050.41 If supercentenarians are to present with chronic conditions, this Therefore, the possibility exists that there could be more occurs late in life and it would appear that the direct burden to the supercentenarians in the future who do not demonstrate a healthcare system is relatively minimal compared to the elderly compression of morbidity pattern, which may result in increased population (ages 65+) as a whole. The specific pattern traditionally dependence on the healthcare system.

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Table 2: “Power Nine” characteristics (adapted from Buettner et al).34

Characteristic Description

Move naturally Movement as a part of daily activities (e.g., gardening, walking) Purpose Having a sense of direction in life Downshift Incorporating stress reduction activities into daily living (e.g., praying, napping, meditation) 80% rule Stop eating when one feels 80% full Plant slant Diets are rich in plant-based foods with little emphasis on meat Wine at 5 Moderate daily alcohol intake Right tribe Having strong positive social ties to others and encouraging healthy behaviours in one another Loved ones first Remaining near one’s family; investing time and love into one’s partner and children Belong Having a community that one can participate in, either faith based or social based

The desire to live a long, happy life is Impact on surgery rooted deep within the human condition, Surgery in the elderly, specifically in those over 80 years of age, is and due to improvements in healthcare associated with several outcomes not seen in younger populations, such as increased incidence of complications, longer hospital stay, over the past century, the average global and increased chance of being admitted to the intensive care unit.46 life expectancy has risen to 71 years of Given their advanced age, these outcomes are likely to be more of an age, with higher income nations being issue in supercentenarians, making this a potentially high-risk group closer to 80 years of age. to send to surgery. That being said, there are several case reports which indicate that it is possible for a supercentenarian to safely Impact on long-term care undergo surgerical procedures that can significantly improve their Regardless of other conditions, frailty and the ability to remain quality of life.47,48 However, given how small this group is, more independent are strongly associated with the risk of dying.42 studies need to be conducted before any claims can be made with a Remaining physically independent at 100 years of age increases the higher degree of confidence. likelihood of living to 110+ years, and based on cohort studies, the Therefore, the effects of supercentenarians on the healthcare system individuals who are living in their own homes at 100 years of age are are relatively small compared to the elderly population as a whole, more likely to become supercentenarians.43 Therefore, having fewer mostly due to the fact that they are a small group. Increased numbers conditions that may place one in a long-term care facility is ideal for in this group may facilitate a push towards more long-term preserving longevity. According to the literature, while having a care facilities. stroke is the strongest predictor of needing long-term care, conditions associated with a wearing out of structures, such as osteoporosis, also Therefore, it is likely that an play an important role.43 As the main health issues in the increase in the number of supercentenarian group are osteoporosis, cataracts, and fractures, it is supercentenarians may lead to a unsurprising that the majority live either in a long-term care facility or corresponding increase in demand with a loved one.3,44 Therefore, it is likely that an increase in the for long-term care facilities. number of supercentenarians may lead to a corresponding increase in demand for long-term care facilities. In places where it is more common for relatives to take care of their elderly, there may not be a Is there a limit to human longevity? rise in long-term care, but instead, an indirect strain on the healthcare With more and more people reaching the centenarian and system via caregiver burnout, especially if the elderly person begins to semisupercentenarian milestone, this question is on the minds of develop multiple illnesses.45 demographers, insurance companies, and healthcare workers alike.

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Currently, there is debate around whether or not there is a maximum Conclusion age that a human being can reach. The compression of morbidity Supercentenarians are a fascinating group to study as they challenge theory would indicate that there is not, which is supported by our ideas of the ageing process and how it can take shape. The historical data of verified supercentenarians demonstrating that the reasons for their exceptional longevity are multifactorial, resulting majority of this population lives to 115 years of age.49-51 from genetic, environmental, microbiota, and community A potential caveat to these statistics is the ability to verify the exact adaptations that promote long life. ages of individuals in the supercentenarian category. The oldest Compared to the general population, they exhibit a compression of verified individual is Jeanne Calment, a French woman who lived to morbidity pattern and often never develop the chronic conditions 122 years of age.52 It has recently been argued that her year of death that significantly impact mortality. was actually that of her daughter, which, if proven true, would put Currently, the oldest confirmed individual died at age 122, and there the longest lived individual at only 119 years of age.53 is much debate about whether this is the limit for human longevity. The question is far from being answered, but it is possible to confirm As more secrets of this population are unlocked, the hope is that the a growing older population that, for some countries, is outstripping lessons learned will be used to promote healthy ageing, thereby the pace of younger generations, making our world look very allowing everyone to live a longer and happier life. different than it did a century ago.

References 1. World Health Organisation. World Health Statistics 2019: Monitoring health for 11. Santos-Lozano A, Santamarina A, Pareja-Galeano H et al. The genetics of

the SDGs. Geneva: WHO, 2019:3-10. exceptional longevity: insights from centenarians. Maturitas. 2016;90:49-57.

2. Prince MJ, Wu F, Guo Y et al. The burden of disease in older people and 12. Christensen K, Johnson TE, Vaupel JW. The quest for genetic determinants of

implications for health policy and practice. Lancet. 2015;385(9967):549-62. human longevity: challenges and insights. Nat Rev Genet. 2006;7(6):436-48.

3. Arai Y, Inagaki H, Takayama M et al. Physical independence and mortality at the 13. Pignolo RJ. Exceptional human longevity. Mayo Clin Proc. 2019;94(1):110-24.

extreme limit of life span: supercentenarians study in Japan. J Gerontol A Biol 14. Herskind AM, McGue M, Holm NV et al. The heritability of human longevity: a

Sci Med Sci. 2014;69(4):486-94. population-based study of 2872 Danish twin pairs born 1870-1900. Hum

4. Horiuchi S, Wilmoth JR. Deceleration in the age pattern of mortality at older Genet. 1996;97(3):319-23. ages. Demography. 1998;35(4):391-412. 15. Revelas M, Thalamuthu A, Oldmeadow C et al. Review and meta-analysis of 5. Ismail K, Nussbaum L, Sebastiani P et al. Compression of morbidity is observed genetic polymorphisms associated with exceptional human longevity. Mech across cohorts with exceptional longevity. J Am Geriatr Soc. Ageing Dev. 2018;175:24-34. 2016;64(8):1583-91. 16. Revelas M, Thalamuthu A, Oldmeadow C et al. Exceptional longevity and 6. Gellert P, von Berenberg P, Oedekoven M et al. Centenarians differ in their polygenic risk for cardiovascular health. Genes (Basel). 2019;10(3):piiE227. comorbidity trends during the 6 years before death compared to individuals 17. Biagi E, Franceschi C, Rampelli S et al. Gut microbiota and extreme longevity. who died in their 80s or 90s. J Gerontol A Biol Sci Med Sci. Curr Biol. 2016;26(11):1480-5. 2018;73(10):1357-62. 18. Sanese P, Forte G, Disciglio V et al. FOXO3 on the road to longevity: lessons 7. Andersen SL, Sebastiani P, Dworkis DA et al. Health span approximates life span from SNPs and chromatin hubs. Comput Struct Biotechnol J. 2019;17:737-45. among many supercentenarians: compression of morbidity at the approximate 19. Davy PMC, Allsopp RC, Donlon TA et al. FOXO3 and exceptional longevity: limit of life span. J Gerontol A Biol Sci Med Sci. 2012;67(4):395-405. insights from hydra to humans. Current Top Dev Biol. 2018;127:193-212. 8. Adams ER, Nolan VG, Andersen SL et al. Centenarian offspring: start healthier 20. Safieh M, Korczyn AD, Michaelson DM. ApoE4: an emerging therapeutic target and stay healthier. J Am Geriatr Soc. 2008;56(11):2089-92. for Alzheimer’s disease. BMC Med. 2019;17(1):64. 9. Perls T, Kohler IV, Andersen S et al. Survival of parents and siblings of 21. Beekman M, Blanché H, Perola M et al. Genome-wide linkage analysis for supercentenarians. J Gerontol A Biol Sci Med Sci. 2007;62(9):1028-34. human longevity: Genetics of Healthy Aging Study. Aging Cell. 10. Tacutu R, Thornton D, Johnson E et al. Human ageing genomic resources: new 2013;12(2):184-93. and updated databases. Nucleic Acids Res. 2018;46(D1):D1083-90.

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22. Schupf N, Barral S, Perls T et al. Apolipoprotein E and familial longevity. 37. Cho J, Martin P, Poon LW, Georgia Centenarian Study. Successful aging and

Neurobiol Aging. 2013;34(4):1287-91. subjective well-being among oldest-old adults. Gerontologist.

23. Fuku N, Diaz-Pena R, Arai Y et al. Epistasis, physical capacity-related genes and 2015;55(1):132-43.

exceptional longevity: FNDC5 gene interactions with candidate genes FOXOA3 38. Andrews RM, Tan EJ, Varma VR et al. Positive aging expectations are associated

and APOE. BMC Genomics. 2017;18(Suppl. 8):803. with physical activity among urban-dwelling older adults. Gerontologist.

24. Kolovou G, Kolovou V, Vasiliadis I et al. The frequency of 4 common gene 2017;57(Suppl_2):S178-86.

polymorphisms in nonagenarians, centenarians, and average life span 39. World Health Organisation. Global health and ageing: WHO; US National

individuals. Angiology. 2014;65(3):210-5. Institute of Aging. 2011.

25. Pereira da Silva A, Matos A, Aguiar L et al. Hypertension and longevity: role of 40. Fries JF. Aging, natural death, and the compression of morbidity. N Engl J Med.

genetic polymorphisms in renin-angiotensin-aldosterone system and 1980;303(3):130-5.

endothelial nitric oxide synthase. Mol Cell Biochem. 2019;455(1-2):61-71. 41. United Nations Department of Economic and Social Affairs. Profiles of Ageing

26. Yang JK, Gong YY, Xie L et al. Lack of genetic association between the 2019: UN, 2019. 42. Gu D, Feng Q. Frailty still matters to health and survival in centenarians: the angiotensin-converting enzyme gene insertion/deletion polymorphism and case of China. BMC Geriatr. 2015;15(1):159. longevity in a Han Chinese population. J Renin Angiotensin Aldosterone Syst. 43. Kiyoshige E, Kabayama M, Gondo Y et al. Association between long-term care 2009;10(2):115-8. and chronic and lifestyle-related disease modified by social profiles in 27. Di Bona D, Accardi G, Virruso C et al. Association of klotho polymorphisms with community-dwelling people aged 80 and 90; SONIC study. Arch Gerontol healthy aging: a systematic review and meta-analysis. Rejuvenation Res. Geriatr. 2019;81:176-81. 2014;17(2):212-6. 44. Schoenhofen EA, Wyszynski DF, Andersen S et al. Characteristics of 32 28. Dubal DB, Yokoyama JS, Zhu L et al. Life extension factor klotho enhances supercentenarians. J Am Geriatr Soc. 2006;54(8):1237-40. cognition. Cell Rep. 2014;7(4):1065-76. 45. Cho J, Nakagawa T, Martin P et al. Caregiving centenarians: cross-national 29. Arai Y, Martin-Ruiz CM, Takayama M et al. Inflammation, but not telomere comparison in caregiver-burden between the United States and Japan. Aging length, predicts successful ageing at extreme old age: a longitudinal study of Ment Health. 2018:1-10. semi-supercentenarians. EBioMedicine. 2015;2(10):1549-58. 46. St-Louis E, Sudarshan M, Al-Habboubi M et al. The outcomes of the elderly in 30. Di Bona D, Vasto S, Capurso C et al. Effect of interleukin-6 polymorphisms on acute care general surgery. Eur J Trauma Emerg Surg. 2016;42(1):107-13. human longevity: a systematic review and meta-analysis. Ageing Res Rev. 47. Dharmarajan TS, Sohagia A. Urgent surgery in a near supercentenarian nursing 2009;8(1):36-42. home resident: possible with favorable outcome! J Am Med Dir Assoc. 31. Soerensen M, Dato S, Tan Q et al. Evidence from case-control and longitudinal 2007;8(8):543-4. studies supports associations of genetic variation in APOE, CETP, and IL6 with 48. Tosun F, Ozen M, Tatar C et al. Unilateral spinal anesthesia experience in a

human longevity. Age (Dordr). 2013;35(2):487-500. supercentenarian. A A Case Rep. 2015;5(7):117-8. ą 32. Sowa A, Tobiasz-Adamczyk B, Topór-M dry R et al. Predictors of healthy ageing: 49. Dong X, Milholland B, Vijg J. Evidence for a limit to human lifespan. Nature

public health policy targets. BMC Health Serv Res. 2016;16(Suppl. 5):289. 2016;538(7624):257-59.

33. Maier H, Gampe J, Jeune B et al. (eds.). Supercentenarians. Demographic 50. Gavrilova NS, Gavrilov LA. Are we approaching a biological limit to human

Research Monographs 07. Springer, Heidelberg, 2010:325. longevity? J Gerontol A Biol Sci Med Sci. 2019.

34. Buettner D, Skemp S. Blue Zones: lessons from the world’s longest lived. Am J 51. Brown NJL, Albers CJ, Ritchie SJ. Contesting the evidence for limited human

Lifestyle Med. 2016;10(5):318-21. lifespan. Nature. 2017;546(7660):E6-7.

35. Sadler ME, Miller CJ, Christensen K et al. Subjective wellbeing and longevity: a 52. Gerontology Research Group. Supercentenarian Research and Database

co-twin control study. Twin Res Hum Genet. 2011;14(3):249-56. Division 2019. [Internet]. [cited 2019 July 17]. Available from:

36. Margrett JA, Daugherty K, Martin P et al. Affect and loneliness among http://www.grg.org/SC/SCindex.html.

centenarians and the oldest old: the role of individual and social resources. 53. Zak N. Evidence that Jeanne Calment died in 1934 – not 1997. Rejuvenation

Aging Ment Health. 2011;15(3):385-96. Res. 2019;22(1):3-12.

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Living in lead: the evolution of interventional radiology

Abstract Since its advent in 1964, the field of interventional radiology (IR) has evolved from a specialty that historically served other physicians to one with the ability to treat a range of diseases and patients on its own. Successful use of percutaneous transluminal angioplasty (PTA) to restore blood flow through stenotic vessels in 1964 demonstrated the ability of IR techniques to treat disease, thereby avoiding open surgical interventions such as endarterectomy and bypass grafting. Since then, IR has further transformed into a specialty with a range of clinical applications, including some that are considered the gold standard in their field today. Percutaneous coronary intervention (PCI) is the first-line treatment for acute myocardial infarctions and similarly has applications in the prevention of coronary artery disease. IR has emerged as a valuable tool in acute settings, including embolisation of upper and lower gastrointestinal bleeds, diverticular diseases, and cases of massive blood loss or haemodynamic instability where both conservative and endoscopic treatments have failed. Furthermore, chemo-, radio-, and bland trans-arterial embolisation have revolutionised hepatocellular carcinoma treatment, offering an additional treatment option for select patients who are deemed inoperable. The impact that IR has had on the field of medicine to date is nothing short of remarkable; however, as one of the ‘youngest’ medical specialties, it is just getting started. Hannah Suchy The possibilities for discovery and invention within this field may yield an ever-expanding role RCSI medical student for IR in the prevention and treatment of numerous disorders.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 62-68.

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Introduction Interventional radiology (IR) is a medical specialty that uses minimally stenotic superficial femoral artery for limb salvage, thereby ‘inventing’ invasive, image-guided procedures for the diagnosis and treatment of percutaneous transluminal angioplasty (PTA).1 Through research and disease. IR is one of the newest medical specialties; it was recognised innovation, IR has grown from a service used to supplement other in 1994 by the American Board of Medical Specialties as a subspecialty specialties, to a specialty with its own fully developed modalities for of radiology.1 Currently, IR is used across many organ systems and treating disease. medical conditions; however, this was not always the case. Prior to its emergence as a specialty in its own right, IR was primarily used as a Traditional surgical procedures are service by other specialties. For example, interventional radiologists associated with a greater risk of adverse were called on to place peripherally inserted central catheter (PICC) events, a longer recovery time, and lines into patients, for administration of total parenteral nutrition, may even result in the amputation chemotherapy, or medications. They were also largely responsible for of a limb, causing a substantial performing biopsies, port insertions, abscess drainages, and other impact on quality of life. similar procedures to aid colleague physicians in their patient care. Although these procedures are still routinely done by IR, the field has expanded to include non-invasive approaches to the treatment Interventional radiology in angioplasty of disease. The advent of IR was rooted in ‘opening up’ occluded or stenotic The concept of IR as its own specialty was first introduced in June arteries of the lower limb through PTA. This procedure involves 1963 by Charles Dotter, who described catheterisation as a treatment inserting a catheter into the common femoral artery, advancing the rather than a diagnostic tool.1 Just seven months later, in January catheter to the site of occlusion or stenosis, and slowly inflating a 1964, Dotter successfully performed percutaneous dilation of a balloon to expand the vascular lumen, thus restoring blood flow

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throughout the vasculature.2 The two main alternatives to PTA are Similarly, there was no difference in the rates of ipsilateral stroke in the endarterectomy or bypass grafting, both of which are open surgical four-year follow-up period (2.0% vs 2.4%, p=0.85).11 Furthermore, procedures that involve general anaesthesia. Open surgical results remained insignificant when stratified by patient factors.10 The treatments are more invasive, expensive, and associated with a longer ambiguity of these results has prompted several additional trials, hospital stay. In addition, traditional surgical procedures are including a CREST-2 trial that is currently ongoing.12 The controversy associated with a greater risk of adverse events, a longer recovery surrounding this topic demonstrates the need for further research; time, and may even result in the amputation of a limb, causing a angioplasty may soon be the preferred treatment for carotid stenosis substantial impact on quality of life (QoL).3 Infra-popliteal PTA has given that the outcomes appear to be as good as those for surgical been shown to be safe and effective in patients facing limb salvage intervention, while the technique is less invasive. surgery, providing an advantage in QoL compared to traditional As the use of angioplasty migrated from pathologies in the lower limb management.4 In 1981, the effectiveness of PTA was demonstrated in to those in the carotid artery, the now most commonly used form of the treatment of carotid artery stenosis, a significant risk factor for angioplasty was born: percutaneous coronary intervention (PCI). PCI stroke and neurological deficits.5 As in the lower limb, the alternative is used in both the acute treatment of MI and in the preventive to PTA is endarterectomy with surgical removal of the endoluminal setting, and has proved to be a life-saving technique by restoring atheromatous plaque or, less often, an open arteriotomy dilation.6 blood flow to ischaemic cardiac tissue. It is now routinely used as the The ability to perform PTA under conscious sedation with local preferred treatment of coronary artery disease when fewer than three anaesthesia, rather than general anaesthesia as is required for coronary arteries are involved with significant atheromatous disease.13 endarterectomy, allows for intraoperative visualisation of the upper Thus, it was the evolution of IR, beginning with lower limb limit of stenosis using fluoroscopy.6 This enables specific targeting of angioplasty, that has led to significant reductions in mortality and affected areas only, and avoids further damage to the vessel.7 complications, and an improvement in QoL.

Having transitioned from a IR in the acute setting service for other specialties Following the introduction of IR in the setting of elective procedures to a field with its own treatments to symptomatically treat peripheral vascular disease, it was soon for disease, interventional discovered that interventional procedures were effective in the acute management of bleeding, specifically within the gastrointestinal (GI) radiologists have gone from being tract. Initially, this was done with local infusion of a vasoactive drug, ‘a doctor’s doctor’ to such as epinephrine or norepinephrine, to induce vasoconstriction ‘a patient’s doctor’. and reduce bleeding.14 The procedure was then modified to treat GI bleeding from both arterial and oesophageal varices via injection of The topic of carotid endarterectomy versus angioplasty remains hotly vasopressin.15 Ultimately, the most effective method for arterial bleeds debated and, though many studies indicate endarterectomy to be the was shown to be embolisation, a technique in which a catheter is preferred treatment, more recent randomised controlled trials (RCTs) threaded through the vasculature and deposits an embolic agent such suggest otherwise.8-10 as Gelfoam, coils, or ‘glue’ within the vessel to artificially plug the The Carotid Revascularization Endarterectomy versus Stenting Trial bleeding site.16 This method has proven to be highly effective and has (CREST), an RCT involving 2,502 patients, showed no significant been widely used, particularly in cases where the patient is a poor difference in the two treatment strategies.11 In the study, patients with surgical candidate.17 evidence of carotid artery stenosis, as demonstrated by angiography, Embolisation has been demonstrated to be particularly effective in ultrasound, or computed tomography/magnetic resonanace imaging patients with massive blood loss or haemodynamic instability who (CT/MRI) angiography, were randomised to receive preventive have failed both conservative and endoscopic treatment.18 Additional treatment with either endarterectomy or angioplasty with stenting. studies have shown that embolisation and surgery are equally The primary endpoints were evidence of periprocedural stroke, effective in the treatment of upper GI bleeds, defined as those myocardial infarction (MI), death, or ipsilateral stroke within four proximal to the ligament of Treitz at the fourth part of the years of the procedure.12 The trial found no significant difference in duodenum.19,20 Although embolisation for lower GI bleeding carries a the incidence of primary endpoints in the periprocedural period. higher risk of bowel infarction due to limited collateral blood supply,

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studies have shown a similar success profile over surgical methods to and associated with fewer complications and shorter hospital stays.28,29 that seen in upper GI bleeds.21 For example, a meta-analysis As with many medical procedures, the use of RFA for HCC carries some conducted at the University of Rochester School of Medicine, New challenges. Although RFA is equally effective in prolonging survival, some York, found that embolisation for diverticular bleeds was successful in studies have shown that RFA possesses a higher incidence of local 85% of patients and therefore concluded that lower GI embolisation recurrence compared to surgical resection.30,31 Additionally, larger is an effective treatment for diverticular bleeding.22 These results tumours (>5cm) may be difficult to treat with single probe ablation, and illustrate the critical role that IR can play in the acute setting, may require additional probes and more complex procedures.30 Larger particularly for those patients whose lives are at risk from significant tumours have also been demonstrated to carry a higher local recurrence GI bleeding. rate than those measuring less than 3cm.32 Finally, tumour location may serve as a contraindication to RFA due to increased risk of bleeding, Thus, it was the evolution of IR, peritoneal seeding, or injury to adjacent structures such as local beginning with lower limb angioplasty, vasculature or bile ducts.31 that has led to significant reductions Alternative approaches for the treatment of HCC include embolisation in mortality and complications, and both with and without chemotherapeutic agents. These approaches are particularly effective in treating HCC as the cancer typically receives its an improvement in QoL. blood supply exclusively from the hepatic artery, as opposed to the rest of the liver parenchyma, which receives dual blood supply from the IR as standalone treatment hepatic artery as well as the portal vein.24 The vasculature directly Once established as a treatment in the acute setting, and with the supplying the tumour can thus be used to deliver therapeutic agents development of smaller devices that could be used percutaneously, the such as chemotherapy or radioactive substances to the tumour cells, or practice of IR expanded to a be definitive treatment for certain chronic it can be therapeutically blocked to stop nutrient flow to the tumour.33 disorders, such as cancer. Minimally invasive interventional techniques Figure 1 shows axial CT and CT angiography images of HCC before and have drastically altered available treatments for hepatocellular carcinoma after treatment with embolisation. (HCC). HCC is the most common primary liver tumour in adults and is the third most common cause of cancer-related death worldwide.23 HCC RFA involves percutaneous placement occurs in up to 90% of patients with cirrhosis, and is thus linked to of an electrode into the tumour using either chronic hepatitis and alcohol use, two incredibly common health CT or ultrasound guidance, 24 problems worldwide. with subsequent application Traditionally, surgical approaches such as local resection and liver of an electrical current. transplantation have been regarded as the standard of care in the treatment of HCC.25 However, surgery is often deemed unsafe or These three techniques have been termed chemo-, radio-, and bland impossible due to the tumour’s location or other comorbidities that trans-arterial embolisation, and all involve intra-arterial placement of render the cancer unresectable from a surgical perspective. IR offers embolic material such as Gelfoam or beads.34 The material may be alternative approaches for the treatment of HCC, such as percutaneous packed with a chemotherapeutic agent, such as doxorubicin, which is radiofrequency ablation (RFA), other methods of thermal ablation, or then delivered locally rather than systemically to the tumour.35 Similarly, embolic approaches. this can be done with application of Yttrium-90 (Y-90), a radiation RFA involves percutaneous placement of an electrode into the tumour therapy used to treat HCC. However, when the embolic material is used using either CT or ultrasound guidance, with subsequent application of alone to cut off blood supply to the tumour, this is termed bland an electrical current. This causes frictional heating of the tissue embolisation; this has been proposed to be as effective as surrounding the electrode, killing the tumour cells along with a margin chemo-embolisation, but with a reduced number of adverse effects of normal hepatic tissue by heating to above 60°C.26 Microwave and compared to chemotherapy.36 There is some debate over which form of laser can also be used for thermal ablation; however, the body of embolisation is most effective, with different physicians in support of literature assessing RFA is most extensive.27 Several studies in patients each one. Regardless, this wide range of IR techniques used to treat HCC with HCC have demonstrated RFA to be as effective as surgical resection is crucial given the number of patients who are deemed unsuitable in prolonging survival, with the added advantage of being less invasive for surgery.

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FIGURE 1: 1a. Non-contrast CT from 25/7/16 demonstrating localised HCC in the right lobe of the liver. 1b. Venous phase CT from 15/11/16, demonstrating tumour shrinkage post emoblisation. 1c. CT angiography with evidence of tumour blood supply. 1d. CT angiography after selective embolisation of tumour vascular supply with maintained parent vessels to preserve liver tissue.

The future of IR As IR has become an established specialty on its own, recognised by to transition directly into IR training after two years of diagnostic colleagues and organisations within medicine, it is critical to look to its radiology (DR) residency. Such a scheme differs from the previous future growth and development. As of April 2019, IR has established an system where individuals wanting to practise IR would be required to integrated residency programme in the United States that allows trainees apply to an IR fellowship after their DR residency. This alone will allow

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the specialty to further set itself apart from its ancestry in DR, and allow trainees to gain specialisation and expertise in the field. Furthermore, having transitioned from a service for other specialties to a field with its own treatments for disease, interventional radiologists have gone from being a ‘doctor’s doctor’ to a ‘patient’s doctor’.37 However, few people are aware of IR, and may only encounter this specialty once they require one of these minimally invasive procedures.37 The introduction of IR to a patient’s care team earlier in their disease course may allow patients to better understand the field and its role in diagnosis and treatment, which can therefore provide more comfort once faced with an interventional procedure. As healthcare systems evolve with the advent of new technology and an ever-changing climate for physicians, interventional radiologists will need to further establish their role. With the skills of a surgeon, the keen eyes of a radiologist, and the standard of treatment for numerous diseases, both acute and chronic, compassion of a clinician, interventional radiologists have the unique and have reduced complication rates, length of hospital stay, and the opportunity to flourish in an environment with new tools for medical costs associated with prolonged hospital stay. Minimally evaluation, advances in treatments and innovation, and a patient invasive, image-guided procedures are also less costly compared to their population that understands the value of good practitioners.38 surgical equivalents. Additionally, interventional radiology allows for less-invasive procedures with faster recovery times, potentially improving Conclusion QoL. Going forward, IR will continue to play an ever-expanding role in IR has evolved from a support service for other medical specialties to a the definitive treatment of many disorders, reducing the need for specialty in its own right. The advancements within IR have altered the invasive approaches.

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interventional radiology. J Vasc Interv Radiol. 2003;14(7):841-53. light of ICSS and CREST studies. Acta Neurochir Suppl. 2018;129:95-9.

2. Gruntzig A, Kumpe DA. Technique of percutaneous transluminal angioplasty 9. Brooks WH, McClure RR, Jones MR, Coleman TC, Breathitt L. Carotid

with the Gruntzig ballon catheter. AJR Am J Roentgenol. 1979;132(4):547-52. angioplasty and stenting versus carotid endarterectomy: randomized trial in a

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extremity bypass surgery, endovascular interventions, and major amputations. 10. Mantese VA, Timaran CH, Chiu D, Begg RJ, Brott TG. The carotid

J Vasc Surg. 2009;50(1):54-60. revascularization endarterectomy versus stenting trial (CREST): stenting versus

4. Brown KT, Schoenberg N, Moore E, Saddekni S. Percutaneous transluminal carotid endarterectomy for carotid disease. Stroke. 2010;41(10 Suppl):S31-4.

angioplasty of infrapopliteal vessels: preliminary results and technical 11. Brott TG, Hobson RW, Howard G, Roubin GS, Clark WM, Brooks W et al.

considerations. Radiology. 1988;169(1):75-8. Stenting versus endarterectomy for treatment of carotid-artery stenosis. N Engl

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an update. Eur Neurol. 2015;73(1-2):51-6. 12. Rosenfield K, Matsumura JS, Chaturvedi S, Riles T, Ansel GM, Metzger DC et al.

6. Noiphithak R, Liengudom A. Recent update on carotid endarterectomy versus Randomized trial of stent versus surgery for asymptomatic carotid stenosis. N

carotid artery stenting. Cerebrovasc Dis. 2017;43(1-2):68-75. Engl J Med. 2016;374(11):1011-20.

7. Hasso AN, Bird CR, Zinke DE, Thompson JR. Fibromuscular dysplasia of the 13. King SB, Smith SC, Hirshfeld JW, Morrison DA, Williams DO, Jacobs AK. 2007

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Coll Cardiol. 2008;51(2):172. 27. Chen L, Sun J, Yang X. Radiofrequency ablation-combined multimodel

14. Rösch J, Gray R, Grollman J, Ross G, Steckel R, Weiner M. Selective therapies for hepatocellular carcinoma: current status. Cancer Lett.

arterial drug infusions in the treatment of acute gastrointestinal 2016;370(1):78-84.

bleeding. A preliminary report. Gastroenterology. 1970;59(3):341-9. 28. Fang Y, Chen W, Liang X, Li D, Lou H, Chen R et al. Comparison of

15. Baum S, Nusbaum M. The control of gastrointestinal hemorrhage by long-term effectiveness and complications of radiofrequency ablation

selective mesenteric arterial infusion of vasopressin. Radiology. with hepatectomy for small hepatocellular carcinoma. J Gastroenterol

1971;98(3):497-505. Hepatol. 2014;29(1):193-200.

16. Masada T, Tanaka T, Sakaguchi H, Nakagomi M, Miura Y, Hidaka T et 29. Sun W-C, Chen IS, Liang H-L, Tsai C-C, Chen Y-C, Wang B-W et al.

al. Coils versus gelatin particles with or without intraarterial antibiotics Comparison of repeated surgical resection and radiofrequency ablation

for partial splenic embolization: a comparative evaluation. J Vasc Interv for small recurrent hepatocellular carcinoma after primary resection.

Radiol. 2014;25(6):852-8. Oncotarget. 2017;8(61):104571-81.

17. Krämer SC, Görich J, Rilinger N, Siech M, Aschoff AJ, Vogel J et al. 30. Elnekave E, Erinjeri JP, Brown KT, Thornton RH, Petre EN, Maybody M et

Embolization for gastrointestinal hemorrhages. Eur Radiol. al. Long-term outcomes comparing surgery to embolization-ablation for

2000;10(5):802-5. treatment of solitary HCC <7cm. Ann Surg Oncol. 2013;20(9):2881-6.

18. Loffroy R, Guiu B, d’Athis P, Mezzetta L, Gagnaire A, Jouve JL et al. 31. Peng Z-W, Lin X-J, Zhang Y-J, Liang H-H, Guo R-P, Shi M et al.

Arterial embolotherapy for endoscopically unmanageable acute Radiofrequency ablation versus hepatic resection for the treatment of

gastroduodenal hemorrhage: predictors of early rebleeding. Clin hepatocellular carcinomas 2cm or smaller: a retrospective comparative

Gastroenterol Hepatol. 2009;7(5):515-23. study. Radiology. 2012;262(3):1022-33.

19. Ripoll C, Bañares R, Beceiro I, Menchén P, Catalina M-V, Echenagusia A 32. Zhang W, Luo E, Gan J, Song X, Bao Z, Zhang H et al. Long-term survival

et al. Comparison of transcatheter arterial embolization and surgery for of hepatocellular carcinoma after percutaneous radiofrequency ablation

treatment of bleeding peptic ulcer after endoscopic treatment failure. guided by ultrasound. World J Surg Oncol. 2017;15(1):122.

J Vasc Interv Radiol. 2004;15(5):447-50. 33. Pesapane F, Nezami N, Patella F, Geschwind JF. New concepts in

20. Gralnek IM. Upper GI bleeding. Gastroenterol Clin North Am. embolotherapy of HCC. Med Oncol. 2017;34(4):58.

2014;43(4):xv-xvi. 34. Kishore S, Friedman T, Madoff DC. Update on embolization therapies for

21. Patel TH, Cordts PR, Abcarian P, Sawyer MA. Will transcatheter hepatocellular carcinoma. Curr Oncol Rep. 2017;19(6):40.

embolotherapy replace surgery in the treatment of gastrointestinal 35. Kis B, El-Haddad G, Sheth RA, Parikh NS, Ganguli S, Shyn PB et al.

bleeding?(2)(2) Curr Surg. 2001;58(3):323-7. Liver-directed therapies for hepatocellular carcinoma and intrahepatic

22. Khanna A, Ognibene SJ, Koniaris LG. Embolization as first-line therapy cholangiocarcinoma. Cancer Control. 2017;24(3):1073274817729244.

for diverticulosis-related massive lower gastrointestinal bleeding: 36. Brown KT, Do RK, Gonen M, Covey AM, Getrajdman GI, Sofocleous CT et al.

Evidence from a meta-analysis. J Gastrointest Surg. 2005;9(3):343-52. Randomized trial of hepatic artery embolization for hepatocellular carcinoma

23. Ghouri YA, Mian I, Rowe JH. Review of hepatocellular carcinoma: using doxorubicin-eluting microspheres compared with embolization with

epidemiology, etiology, and carcinogenesis. J Carcinog. 2017;16:1. microspheres alone. J Clin Oncol. 2016;34(17):2046-53.

24. Boyvat F. Interventional radiologic treatment of hepatocellular 37. Keller EJ, Vogelzang RL. Who we are and what we can become: the

carcinoma. Exp Clin Transplant. 2017;15(Suppl. 2):25-30. anthropology of IR and challenges of forming a new specialty. J Vasc

25. Bruix J, Sherman M. Management of hepatocellular carcinoma: an Interv Radiol. 2018;29(12):1703-4.e2.

update. Hepatology. 2011;53(3):1020-2. 38. Matsumoto AH. The 2019 Dotter Lecture: Patients and patience: why

26. Zhang B, Moser M, Zhang E, Zhang WJ. Radiofrequency ablation interventional radiologists need both. J Vasc Interv Radiol.

technique in the treatment of liver tumours: review and future issues. 2018;30(10):1581-5.

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3D models lead a revolution

Abstract Three-dimensional (3D) printing is revolutionising healthcare as we know it. The technology involves taking a digital model of a subject and printing it in consecutive layers to create a fully formed object in the form of a 3D model. Diseased organs can be modelled and reproduced, allowing surgeons to handle and examine them before, during, or after an operation. The ability to prepare for surgery with this direct, hands-on approach has improved outcomes around cost, speed, and precision. In addition, the ability to view pathological diseases tangibly is invaluable for patients’ understanding of diseases, thereby improving the overall patient-doctor relationship. Likewise, medical students can further their understanding of complex human anatomy and deepen their knowledge of pathology. The technology is also a large contributor to precision medicine, through its ability to create prosthetic designs suitable for patients’ unique aesthetic and functional needs. Furthermore, the ‘polypill’, a product of 3D printing, can package multiple complex medications into a single tablet – a promising tool for addressing the challenges of polypharmacy. Despite the notable applications developed thus far, 3D printing has not yet reached the limit of its vast capabilities. With the increased Carol Rizkalla implementation of the technology within the healthcare sector, additional efforts and research RCSI medical student towards enhancements will allow us to realise the full potential of 3D models.

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Introduction Uses of 3D printing Each year, the healthcare industry continues to make leaps and Optimising surgical planning bounds towards greater achievements. Three-dimensional (3D) Even before a surgery takes place, 3D printing technology is making printing, an up-and-coming technology with highly versatile significant changes in the way surgeons think about procedures and societal applications, has captivated the medical community as a the technical challenges that they may encounter. There have been rapidly expanding medical tool with the potential to revolutionise many publications regarding tissue replicas being used as a healthcare. supplement to scans from traditional imaging modalities in Though it is called 3D ‘printing’, the technology itself does not preoperative surgical planning.7-10 This has been particularly helpful in involve any ink, but rather utilises materials such as plastics or living patients with unique anatomies where the 3D print can be used as a cells.1 This is done through the process of additive manufacturing, visual aid and a printed record of the original anatomy, such as in where a software directs hardware to deposit material in successive children who require complex surgeries due to anatomic anomalies.8,9 layers until a fully formed 3D model has been created. The first step in generating a 3D object is acquiring the image data Although one may think of 3D printing as a recent technology, its from traditional imaging modalities. The quality of the image is history begins in 1981 with a Japanese doctor’s patent application for important as low-resolution images can result in discrepancies a 3D printer. Unfortunately, Dr Hideo Kodama’s application was not between the generated model and the patient’s actual anatomy.11 successful and, as such, it was not until 1986 that the first patent was Following this, the region of interest is extracted through a process granted to an American inventor named Charles Hull. This led to the called ‘segmentation’. The data is then transformed into a format creation of the first 3D printing company: 3D Systems. Today, 3D recognised by the 3D printer, and is subsequently printed.12,13 Systems is one of the largest 3D printing companies and a leader in These patient-specific organ replicas can allow surgeons and trainees 3D printing innovation. Even Hull himself admits that he to familiarise themselves with the patient’s unique anatomy, underestimated the impact and potential of this technology.2 contributing to the emerging model of personalised medicine. This Since then, there have been major improvements in both imaging has the potential benefit of reducing operating time and risk of and printing that have led to further reductions in cost, making 3D trauma to the patient.11 The reduction in operative times is important printing technology attractive to multiple fields.3 to note as this has led to overall cost reduction attributed to using the Its impact on medicine has been compared with the revolutionary technology.14 In a study examining the use of 3D printing in role of computerised tomography (CT) scans in the 1970s, which orthopaedic surgical planning, the researchers observed a decrease in served as a ground-breaking substitute for exploratory invasive bleeding (average decrease of 50%) and a decrease in surgical time procedures.4 While a CT scan will produce hundreds of images at in all cases (mean time decreased by 43%), which consequently once that subsequently need to be reviewed, 3D technology allows resulted in a reduction in the amount of anaesthesia required. cross-sectional slices to be combined into a concise 3D representation Furthermore, once the models were examined by the surgeons, of the area being scanned, allowing for greater accuracy compared to decisions were made to opt for a different surgical strategy for some the commercially available two-dimensional displays.5 patients than what is normally done to reduce the risk and the 3D printing in healthcare is allowing medical professionals to offer number of operations.6 patients new diagnostic and management strategies, especially when The models used for preoperative planning can also be used used concurrently with medical imaging.6 intraoperatively. 3D models can be colour coded to highlight certain areas of pathology that a surgeon may want to either excise or avoid Three-dimensional (3D) printing, during surgery.15 This function may help to orient surgeons during the an up-and-coming technology with operation, thereby minimising damage to surrounding healthy tissues highly versatile societal applications, and reducing error.5 has captivated the medical community In conjunction with the aforementioned advantages to the surgeons, patients themselves can also benefit directly from 3D printing. The as a rapidly expanding medical use of pre- and postoperative surgical models can increase patients’ tool with the potential to understanding of their upcoming procedures.11 Studies have shown revolutionise healthcare. that when physicians used a 3D model to explain a procedure, patients and their families had an increased understanding of the aims

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and possible complications, resulting in greater patient however, 3D models may prove to be more advantageous due to satisfaction.15,16 superior cost–benefit ratios, easier storage, and the ability to display The list of surgical specialties that have been enhanced by 3D printing rare diseases through intricate 3D replications.20 Furthermore, the is an expanding one. In 2012, surgeons from the Cardiovascular specific organ positioning displayed through this technology is a Division of the University of Wisconsin School of Medicine turned to closer representation of what may be encountered in the operating 3D printing to print out a scaled replica of a heart containing a left room compared to the fixed tissue of cadavers, and would facilitate ventricle pseudoaneurysm, a complication of myocardial infarction the depiction of structures that could have been damaged during carrying an increased risk of mortality.17 Using the 3D model, cadaver preparation.21 surgeons were able to determine the best approach to cannulate the aneurysm, and select the appropriate shape and size of the catheter There have been many publications and occlusion device to be used specifically for this patient’s regarding tissue replicas being used as a dimensions. With guidance from the 3D model, percutaneous closure supplement to scans from traditional of the pseudoaneurysm was successful. imaging modalities in preoperative In 2015, surgeons from the Children’s Hospital of Fudan University in surgical planning. Shanghai used 3D printing to create a scaled replica of conjoined twins with a shared digestive tract.18 The model served as an accurate A randomised controlled trial examined medical students’ representation of the complicated anatomical structures and understanding of complex spinal anatomy using teaching modules anomalies that would be encountered during the operative across three different formats: CT images, 3D images, or 3D-printed separation. This allowed surgeons to practice alternative techniques models.22 The result of the chi-squared analysis showed that those to determine the safest way to proceed.18 with exposure to 3D-printed models were more confident with the material and had a deeper understanding of the mechanisms Educating future doctors of disease compared to students trained using the other two mediums Understanding gross anatomy requires complex spatial awareness. A (p<0.05). The ability to manipulate physical models allowed for thorough understanding of 3D anatomic relationships is vital to the a more wholesome understanding of anatomic relationships interpretation of imaging studies, the safe and effective execution of and showed superior educational benefit compared to surgical procedures, and the prompt arrival at accurate diagnoses.19 cadaver dissections.13,23,24 Human anatomy has traditionally been taught using cadaver Additionally, medical students can ease their way into their clerkship dissection, where students gain understanding through direct years by practicing invasive procedures on 3D models rather than the visualisation and manipulation of the 3D structures of their cadavers; traditional method of ‘see one, do one’. By providing a 3D model for

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to a long-standing blockade. Dr Loubani’s solution included utilising 3D printing technology to create supplies such as stethoscopes, for as little as 30 cents.31 Having almost immediate access to scarce medical supplies in war-ridden regions can help to ensure that victims receive a level of care that is not limited by a lack of basic supplies. Additionally, the 3D printing technology facilitates the creation of artificial tissue with the use of living cells, as opposed to traditional synthetic agents.32 These tissues may be used for medical research, as they are miniature replicas of organs, or as cheaper alternatives to human organ transplants.33 The use of 3D printing in transplant surgery addresses most moral and ethical issues that may be tied to traditional transplant methods. teaching and practicing a complicated spinal procedure, such as a Additionally, 3D printing decreases the risk of tissue rejection, as lumbar puncture, the risk of injury to actual patients can be customised organ development utilises the patients’ cells; however, reduced.25 In a study examining the impact of 3D models on the the revascularisation of tissue remains a challenge.34 NASA is offering understanding of congenital heart disease within residents, there was a $500,000 prize for the first research team that can establish 1cm added benefit among those in the interventional group, particularly thick human vascularised organ tissue in an in-vitro environment, that regarding complex anatomical conditions such as Tetralogy of can maintain metabolic function similar to their in-vivo native cells Fallot.26 3D models appear to be an efficacious adjunct to traditional throughout a 30-calendar-day survival period.35 cadaveric teaching and a valuable tool for medical students in both Moreover, 3D printing has the potential to change the their lecture-based and early clinical years.27 pharmaceutical world and simplify daily life for patients with multiple ailments and complex drug regimens through the creation of a Innovations unique pill that can hold multiple drugs at once, each one with 3D printing has influenced many aspects of healthcare, providing different release times.36 novel opportunities to create or enhance the function of various This has already been done with the so-called ‘polypill’, which innovations across multiple fields. With the introduction of 3D demonstrates that complex medication regimes can be combined printing, prosthetic limbs have gained increased symbiosis with into a single personalised tablet.36 The pill is designed in such a way patient uniqueness. 3D printing allows for the design of comfortable that there are several compartments, each one with a drug that and cost-effective prostheses that can suit a patient’s specific body requires a specific release time. Distinct release profiles were made type.28 Importantly, the advantages of such technology are not bound possible by utilising various material compositions that altered drug by borders or socioeconomic status. Low-cost 3D printers are being distribution and diffusion when placed in solutions.37 In addition to used in war-torn developing countries to make prosthetics for enhanced pharmacokinetics and pharmacodynamics, 3D-printed pills amputees, such as in Sudan where there are an estimated 50,000 in the polypill concept can be highly cost effective, thereby making patients in need.29 The United States Army also aims to implement 3D the technology accessible to poorer developing countries and printing by first imaging all their soldiers in a healthy state, so that in applicable to health programmes at an affordable price. the case of an amputation, they can reconstruct the prosthesis in the field.30 The future of 3D printing Areas that are under blockade often have trouble accessing basic Dr Frank Rybicki, a leading American expert in the applications of 3D medical supplies and likely depend on overseas shipments for their printing in medicine, has been recruited as chief of medical imaging materials. Obtaining medical devices with 3D printing or placing a at The Ottawa Hospital to direct the hospital’s implementation of 3D 3D printer directly in the area of need can provide immediate access printing technology. to critical supplies. Dr Tarek Loubani, an Associate Professor at the Part of his role is to speak out publicly to share the realities and University of Western Ontario, was working in the Gaza Strip during potentials of such technology with members of the public and times of hostility when there was a shortage of medical supplies due healthcare workers. As he is from the United States, where 3D

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printing has been expanding most, he is certain that the widespread anaesthetics to antibiotics, and these advancements have made acceptance of this “ultimate form of personalised medicine” is significant improvements to the practice of medicine. 3D printing currently underway, and it is merely a matter of time before it is a technological innovation that is transforming healthcare by becomes the standard in radiology departments across the country.38 assisting medical students, residents, physicians, and surgeons in a As 3D printing becomes more widely available, opportunities for variety of ways. Medical training programmes could avail of 3D innovation will continue to arise. In the field of orthopaedics, modelling to improve anatomy teaching and allow students to 3D-printed casts are being developed. The aim is to create an have a more hands-on approach. injury-localised exoskeleton, with denser material focused on the Physicians can utilise these models to explain disease fractured area for more support and a well-ventilated, lightweight pathophysiology to patients, and this enhanced understanding structure designed for patient comfort.39 In addition, further may empower patients to ask specific questions about their health. innovations are being considered as scientists are developing Additionally, surgeons can use 3D-printed patient-specific organ four-dimensional (4D) printing methods derived from 3D-printed replicas to simulate procedures as part of postgraduate surgical models, with the added ability to change shape once printed.40 training and preoperative complex surgical planning. Interestingly, such technology would have applications in wound We have also seen that this technology is not confined to treatment, as the 4D-printed structures can be seeded in with living developed countries. cells. The future of this technology depends on further research, The applications of 3D printing in the field of medicine are nearly awareness of the boundless potential, and leadership dedicated to limitless, and it is indeed a promising field that mandates further implementing programmes within a clinical setting. exploration. 3D printing is paving the way for a universally enhanced approach to healthcare due to improved patient Conclusion satisfaction and comprehension, enhanced surgical planning, and Technology drives innovation in healthcare, from CT scans to greater savings to the healthcare system.

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2017;189(29):E973-E4. 9. Olivieri LJ, Krieger A, Loke YH, Nath DS, Kim PC, Sable CA. Three-dimensional

2. Lengua CAG. History of rapid prototyping. In: Farooqi KM (ed.). Rapid printing of intracardiac defects from three-dimensional echocardiographic

Prototyping in Cardiac Disease: 3D Printing the Heart. Cham: Springer images: feasibility and relative accuracy. J Am Soc Echocardiogr.

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3. O’Connor J. Tissue engineering. Plastic surgery (4th ed). Elsevier, 10. Marro A, Bandukwala T, Mak W. Three-dimensional printing and medical

2018:231-60. imaging: a review of the methods and applications. Curr Probl Diagn Radiol.

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5. Sun Z. 3D printing in medicine: current applications and future directions. Unterhinninghofen R, Kauczor HU et al. 3D printing based on imaging data:

Quant Imaging Med Surg. 2018;8(11):1069-77. review of medical applications. Int J Comput Assist Radiol Surg.

6. Galvez M, Asahi T, Baar A, Carcuro G, Cuchacovich N, Fuentes JA et al. Use of 2010;5(4):335-41.

three-dimensional printing in orthopaedic surgical planning. J Am Acad 12. Cignoni P, Callieri M, Corsini M, Dellepiane M, Ganovelli F, Ranzuglia G.

Orthop Surg Glob Res Rev. 2018;2(5):e071. MeshLab: an open-source mesh processing tool. Computing. 2008;1:129-36.

7. Matsumoto JS, Morris JM, Foley TA, Williamson EE, Leng S, McGee KP et al. 13. Torres K, Staskiewicz G, Sniezynski M, Drop A, Maciejewski R. Application of

Three-dimensional physical modeling: applications and experience at Mayo rapid prototyping techniques for modelling of anatomical structures in

Clinic. Radiographics. 2015;35(7):1989-2006. medical training and education. Folia Morphol. 2011;70(1):1-4.

8. Costello JP, Olivieri LJ, Su L, Krieger A, Alfares F, Thabit O et al. Incorporating 14. Ballard DH, Trace AP, Ali S, Hodgdon T, Zygmont ME, DeBenedectis CM et al.

three-dimensional printing into a simulation-based congenital heart disease Clinical applications of 3D printing: primer for radiologists. Acad Radiol.

and critical care training curriculum for resident physicians. Congenit Heart 2018;25(1):52-65.

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15. Malik HH, Darwood AR, Shaunak S, Kulatilake P, El-Hilly AA, Mulki O et al. 29. Heater BH. Inexpensive limbs could bring new hope to Sudan’s 50,000

Three-dimensional printing in surgery: a review of current surgical amputees. 2014. [Internet]. [cited 2019 June 29]. Available from:

applications. J Surg Res. 2015;199(2):512-22. https://finance.yahoo.com/news/inexpensive-3d-limbs-could-bring-ne

16. Wurm G, Lehner M, Tomancok B, Kleiser R, Nussbaumer K. Cerebrovascular w-hope-to-sudans-75055744752.html.

biomodeling for aneurysm surgery: simulation-based training by means of 30. Krassenstein EK. Military may soon be able to copy & 3D print

rapid prototyping technologies. Surg Innov. 2011;18(3):294-306. exact replicas of bones & limbs for injured soldiers. 2015.

17. Mohamed E, Telila T, Osaki S, Jacobson K. Percutaneous closure of left [Internet]. [cited 2019 June 29]. Available from:

ventricle pseudoaneurysm using 3D printed heart model for procedure https://3dprint.com/44793/copy-and-3d-print-bones/?utm_source=Da

planning: a novel approach. Catheter Cardiovasc Interv. 2019;94(6):874-7. ily+3D+Printing+News&utm_campaign=fbd7b68c1e-Latest_3D_Printi

18. Simon. Chinese doctors use 3D printed replicas to practice separating ng_News_02_17_2015_2_16_2015&utm_medium=email&utm_term=

conjoined twins. 2015. [Internet]. [cited 2019 August 25]. Available from: 0_861dc04374-fbd7b68c1e-226645849. 31. Scott CS. 3D Printed, open source glia stethoscope receives clinical http://www.3ders.org/articles/20150608-chinese-doctors-use-3d-printed-re validation. 2018. [Internet]. [cited 2019 June 29]. Available from: plicas-to-practice-separating-conjoined-twins.html. https://3dprint.com/206934/glia-stethoscope-validation/. 19. Pujol S, Baldwin M, Nassiri J, Kikinis R, Shaffer K. Using 3D modeling 32. Correia Carreira S, Begum R, Perriman AW. 3D Bioprinting: The techniques to enhance teaching of difficult anatomical concepts. Acad Emergence of Programmable Biodesign. Advanced Healthcare Radiol. 2016;23(4):507-16. Materials. 2019:e1900554. 20. O’Reilly MK, Reese S, Herlihy T, Geoghegan T, Cantwell CP, Feeney RN et al. 33. Luo Y, Lin X, Huang P. 3D bioprinting of artificial tissues: construction Fabrication and assessment of 3D printed anatomical models of the lower of biomimetic microstructures. Macromol Biosci. limb for anatomical teaching and femoral vessel access training in medicine. 2018;18(6):e1800034. Anat Sci Educ. 2016;9(1):71-9. 34. Leberfinger AN, Dinda S, Wu Y, Koduru SV, Ozbolat V, Ravnic DJ et al. 21. Grillo FW, Souza VH, Matsuda RH, Rondinoni C, Pavan TZ, Baffa O et al. Bioprinting functional tissues. Acta Biomater. 2019;95:32-49. Patient-specific neurosurgical phantom: assessment of visual quality, 35. Lewis T. Could 3D printing solve the organ transplant shortage? 2017. accuracy, and scaling effects. 3D Print Med. 2018;4(1):3. [Internet]. [cited 2019 Oct 14]. Available from:

22. Li Z, Li Z, Xu R, Li M, Li J, Liu Y et al. Three-dimensional printing models https://www.theguardian.com/technology/2017/jul/30/will-3d-printin

improve understanding of spinal fracture – a randomized controlled study in g-solve-the-organ-transplant-shortage.

China. Sci Rep. 2015;5:11570. 36. Khaled SA, Burley JC, Alexander MR, Yang J, Roberts CJ. 3D printing of

23. Huang W, Zhang X. 3D printing: print the future of ophthalmology. Invest five-in-one dose combination polypill with defined immediate and

Ophthalmol Vis Sci. 2014;55(8):5380-1. sustained release profiles. J Control Release. 2015;217:308-14.

24. Abla AA, Lawton MT. Three-dimensional hollow intracranial aneurysm 37. Robles-Martinez P, Xu X, Trenfield SJ, Awad A, Goyanes A, Telford R et

models and their potential role for teaching, simulation, and training. World al. 3D printing of a multi-layered polypill containing six drugs using a

Neurosurg. 2015;83(1):35-6. novel stereolithographic method. Pharmaceutics. 2019;11(6).

25. Odom M, Gomez JR, Danelson KA, Sarwal A. Development of a homemade 38. Duffy A. Superstar doctor brings medicine’s new dimension to Ottawa. 2015.

spinal model for simulation to teach ultrasound guidance for lumbar [Internet] [cited 2019 Oct 13]. Available from:

puncture. Neurocrit Care. 2019;31(3):550-8. https://ottawacitizen.com/news/local-news/the-3d-dreams-of-dr-frank-rybicki.

26. White SC, Sedler J, Jones TW, Seckeler M. Utility of three-dimensional 39. Dodziuk H. Applications of 3D printing in healthcare. Kardiochir Torakochirurgia Pol. 2016;13(3):283-93. models in resident education on simple and complex intracardiac congenital 40. Choi CQ. ‘4D-printed’ objects change shape after they’re made. 2016. heart defects. Congenit Heart Dis. 2018;13(6):1045-9. [Internet]. [cited 2019 September 1]. Available from: 27. McLachlan JC, Bligh J, Bradley P, Searle J. Teaching anatomy without http://www.livescience.com/53477-shape-shifting-4d-printed-objects. cadavers. Med Educ. 2004;38(4):418-24. html?li_source=LI&li_medium=more-from-livescience. 28. Vujaklija I, Farina D. 3D printed upper limb prosthetics. Expert Rev Med

Devices. 2018;15(7):505-12.

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Precision psychiatry: made-to-measure medicine

Abstract As medical technology advances and new medical treatments become more sophisticated, research has begun to focus on individual patient characteristics rather than the overall disease process. Precision medicine has emerged in all medical specialties and aims to tailor medical treatments to patient-specific genetic and environmental characteristics. Psychiatry is an area of medicine that has been slow to adopt the precision medicine approach. Mental illness and psychiatric disorders are a leading cause of disability worldwide and treatment options for patients are limited by a lack of understanding of disease mechanisms. The emerging field of precision psychiatry aims to delineate the underlying neuropsychobiology of common psychiatric disorders and develop patient-centred treatments, which target the underlying Katie Nolan cause rather than just treating the presenting symptoms. This review aims to give an overview RCSI medical student of the current research and advances in precision psychiatry.

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Introduction pharmaceutical companies are decreasing drug development for Modern medical advances are moving away from a ‘one size fits all’ psychiatry, but the incidence of mental illness is increasing in the model and embracing the importance of approaching each patient as population, a new therapeutic approach is needed.13 a unique case. These advances combine genetics, environmental Schizophrenia is a prime example of an illness that has benefited exposures, and lifestyle choices to develop robust treatment greatly from the precision medicine approach. Numerous studies paradigms tailored to the individual.1 Precision medicine identifies have identified the heritability of schizophrenia; risk of developing this and harnesses the uniqueness of each patient and their illness to mental illness has repeatedly been shown to be higher in first- and deliver targeted diagnostic, prognostic, and therapeutic approaches.2 second-degree relatives, with an underlying genetic cause in familial Precision medicine has gained extensive ground in areas such as cases.14,15 Genome-wide association study (GWAS) results have oncology, where the identification of tumour biomarkers has led to identified a major histocompatibility complex (MHC) on chromosome targeted therapy.3,4 In the past, cell lines were analysed to test novel 6 as a locus of importance for schizophrenia.16 This locus has been molecular therapies and targets; however, newer patient-centred linked to immunoregulatory genes and supports the multifactorial models use patient-derived cells and tumour models to ensure more mechanism of schizophrenia development.17 Despite this clear precise treatment targets and reliable outcomes.5 In neurology, correlation, the disorder’s heterogeneity has prevented the discovery precision medicine is being used to target heterogeneous diseases of a causative gene and, to date, research has not yielded any such as Alzheimer’s disease and dementia, to both understand the substantial therapeutic targets. With precision medicine advances multimodal processes at play, and develop new, targeted leading to genetically guided immunotherapy treatments in other therapeutics.6,7 The combination of targeted biomarkers and systems fields of medicine, it is hoped that focused precision medicine in biology, in addition to rapid advances in imaging and scientific psychiatry will alter the therapeutic landscape.18 technology, has ensured the expansion of precision medicine into all medical fields. Scientists and clinicians are now identifying a need for Precision medicine has gained extensive precision therapy for mental illness and psychiatric disorders. ground in areas such as oncology, where the identification of tumour biomarkers Precision medicine in the field of psychiatry has led to targeted therapy. Figures from the World Health Organisation (WHO) in 2019 estimate that 44.3 million people in Europe are suffering from major depression and 37.3 million people are suffering from major anxiety.8 Impact of precision psychiatry on diagnostics In addition to being a leading cause of disability, the WHO identified When examining progress in medical diagnostics and therapeutics in mental illness as the most significant public health challenge in the the last 20 years, it is apparent that psychiatry has taken a back seat. European Union.8 Currently, diagnosing a mental illness or psychiatric disorder relies on Innovations in both screening and diagnostics have resulted in key identifying clusters of signs and symptoms that fit the Diagnostic and medical advances within the last two decades.9,10 Many areas of Statistical Manual of Mental Disorders (DSM) and the International medicine now focus on personalised treatment models tailored to Classification of Diseases (ICD) criteria.19 However, these diagnostic the individual patient. Advances in precision medicine observed classification tools do not utilise evidence from emerging in other medical fields serve to emphasise the need for psychiatry neurobiological or behavioural systems research and, therefore, are to adopt similar approaches and therapies for individualised not evolving with the current theories in psychiatry.20 patient management. Currently, patients and their doctors must work together in a Contemporary scientific techniques such as genomics, therapeutic alliance using a trial and error system to identify therapies transcriptomics, proteomics, and metabolomics are leading scientists that may or may not alleviate psychiatric symptoms. For many and clinicians to investigate the neurobiology of psychiatric diseases, patients, this process can be a long and drawn out search for with the aim of identifying novel biomarkers and gene targets for symptomatic relief, and even trials of multiple or combination multiple psychiatric disorders.11 Proponents of this emerging field treatments may not provide adequate resolution. Examples of this can describe the potential for a paradigm shift within psychiatry and a be seen in patients treated for depression who, despite multiple narrowing of the gap between illness pathophysiology and symptom antidepressants, do not make a full return to psychosocial functioning variability among patients.12 In the current climate, where and remain at high risk for relapse.21 A new Korean longitudinal study,

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the MAKE Biomarker Discovery for Enhancing anTidepressant metabolic dysregulation in patients who develop AN that can affect Treatment Effect and Response (MAKE BETTER) study, aims to create their treatment and recovery, and there is a call for further research a treatment–response prediction index by combining genetic, focused on AN as a metabo-psychiatric disorder.29 Prioritising genes demographic, clinical, and blood-marker data.22 The study aims to for further follow-up will require more input from scientists, clinicians, use integrated biological markers from the patient to predict and systems biologists to model the genetic architecture.30 antidepressant treatment response on a patient-specific basis.22 As with schizophrenia and other psychiatric illnesses, disease A new Korean longitudinal study, the heterogeneity means that identifying specific risk factors and MAKE Biomarker Discovery for biomarkers remains difficult and requires precision medicine Enhancing anTidepressant Treatment 23 techniques to elucidate important targets. Effect and Response (MAKE BETTER)

study, aims to create a treatment– Genetic targets and novel biomarkers response prediction index by combining Heterogeneity refers to the differences and diversity that occur in humans and in cellular systems.24 Heterogeneity within patients and genetic, demographic, clinical, and illness mechanisms accounts for the differences in treatment blood-marker data. response, which is well documented in the literature.25,26 The Psychiatric Genomics Consortium, which began in 2009, is an Metabolomics is an area of research that analyses the global international GWAS that aims to identify the genomic basis for metabolite profile of a given system, be that cell or organism, under common psychiatric disorders.27 defined conditions.31 Metabolomics employs precise quantitative Eight hundred investigators across 36 countries have analysed data methods such as nuclear magnetic resonance and mass spectrometry from more than 400,000 patients.28 This worldwide large-scale to examine the ‘metabolic fingerprints’ of a disease.32 genetic analysis of psychiatric disorders aims to overcome the Examination of a system at the molecular level can provide key heterogeneity that has hampered smaller study samples and evidence for the role of particular molecules in a disease process or prevented investigators from drawing conclusions from data samples. signalling pathway and, thus, provide insight into treatment design. Further research will be needed to link these highlighted genomic Patients with schizophrenia were found to have differential expression regions to underlying biological disease processes, and it is this of gamma aminobutryic acid (GABA), 3-methyl-2-oxobutanoic acid multi-system approach for which precision medicine is renowned and (MAO), and p-aminobenzoic acid (PABA) when compared to celebrated. A recent GWAS analysis of genetic loci across 16,992 non-schizophrenic control patients.33 A systematic review of the patients with anorexia nervosa (AN) identified a metabolic current literature has also identified dysregulation of inflammatory mechanism for the disease. Authors pointed to a fundamental markers such as essential polyunsaturated fatty acids (EPUFAs), lipid

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peroxidation metabolites, and glutamate in patients with nucleotide polymorphism (SNP) on chromosome 4p15 that is schizophrenia.34 In one study, analysis of lipids identified significant associated with a favourable response to antipsychotic treatment in differences in serum lipid profiles between patients with bipolar patients with schizophrenia.46 The DRD2 gene locus was identified as disorder and those with schizophrenia.35 Metabolomic analysis of this a risk locus for schizophrenia, and SNPs in this locus are significant nature could provide precise biomarker profiles – biosignatures – for predictors of response to risperidone, an antipsychotic.47,48 Genetic specific psychiatric disorders, which could, in turn, be used to screen analysis such as this helps clinicians to determine which patients may patients to provide more accurate diagnoses. A corresponding area of be suitable for treatment and reduces the need for trial and error in a interest at the molecular level is the role of food and the vulnerable patient cohort. gastrointestinal microbiome in depression. In recent years, the role of C-reactive protein (CRP), an inflammatory The microbiota and the gut–brain axis have been assessed in animal marker, has been investigated for major depressive disorder. Levels of models with evidence that dysregulation of the microbiome can lead CRP were shown to predict better treatment response to nortriptyline, to anxiety and stress behaviours in animals.36 When rats born without a norepinephrine reuptake inhibitor, compared to escitalopram, an their own microbiome were given faecal microbiota transplants from SSRI.49 Low CRP levels were shown to correlate with greater patients with depression, they began to exhibit anxiety behaviours reductions in disease severity with SSRI treatment.50 This research and anhedonia.37 identifies the important role for biomarker analysis in patient The role of dysbiosis in the gastrointestinal tract is well represented in treatment, and points to further investigation of antibodies against schizophrenia, which has demonstrated a high correlation with pro-inflammatory cytokines as a novel antidepressant treatment for inflammatory bowel disorders.38,39 Patients with schizophrenia patients with an inflammatory profile.51 demonstrate pro-inflammatory gut microbiomes, which have been Pharmacogenomics can be applied to nearly any psychiatric disorder linked to breakdown of the gastrointestinal barrier.40 This evolving and can be used to predict treatment response to commonly used area of research has prompted investigation of the role of therapeutic psychiatric medications. In the future, this genetic information can be probiotics as adjuvant therapies in patients with psychiatric and combined with other clinical data, such as neuroimaging and a neurodevelopmental disorders.41 Further elucidation of the structure patient’s specific physiology, to deliver tailored drug regimens for of our microbiome and its role in psychiatric disorders may contribute each patient. to direct and adjuvant therapies, and increased understanding of the link between psychiatric conditions and body system dysfunction. Further elucidation of the structure of The emerging research into novel genetic targets and biomarker our microbiome and its role in psychiatric profiles of psychiatric disease provides insight into future therapeutics disorders may contribute to direct in the field of precision psychiatry. and adjuvant therapies, and increased

understanding of the link between Genes for variable drug response psychiatric conditions and body The growing popularity of pharmacogenomics has aided the advancement of precision medicine in many fields. Through the system dysfunction. identification of biomarkers from GWAS and other genomic studies, the therapeutic value of new drugs can be monitored and assessed. Computational psychiatry For example, in major depressive disorder, first-line treatment is a At the forefront of combining new data from neuroscience research selective serotonin reuptake inhibitor (SSRI), yet only 50-60% of with what is known about psychiatry is the field of ‘computational patients respond to these drugs and treatment effect can take weeks psychiatry’. This combines both theory and systems biology data to to become evident.42 help classify disease and predict treatment outcomes for patients.52 This is an example of how data analysis from GWAS, imaging, and Computational psychiatry aims to improve mental illness clinical trials could help to overcome the ‘trial and error’ method of classifications and treatment by combining neurobiology, many psychiatric treatments.43 In patients with bipolar disorder who neuroscience, and symptomatology using refined computational respond well to the first-line treatment lithium, researchers were able systems. It allows for more rigorous descriptions and mapping than to identify specific genetic loci with strong association to lithium the biopsychosocial model.53 Systems biology in psychiatry uses response.44,45 Similarly, GWAS analysis was able to identify a single algorithms to stratify psychiatric illnesses and clinical populations into

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clusters or subgroups, which can overcome the heterogeneity seen in significant improvement in depressive symptoms in patients using clinical research. It can incorporate neuroimaging data, symptom smartphone apps compared to control patients, but could not data, and biological data into specialised in silico models.54 With identify significant improvements with cognitive training or further refinement, these ‘machine learning analyses’ may help to mindfulness apps.59 These results suggest a need for further research predict, diagnose, and provide specific treatments for patients on an on the specific aspects of these apps that improve depression. Online individual basis.55 messaging and telephone services can also allow clinicians to offer treatment and support to patients in remote areas who might not As new research dissolves the long-held otherwise have access to treatment.60 belief in psychiatric illness as simply a While smartphone apps and online platforms hold promise for constellation of mood symptoms, improving modern psychiatry, research has also shown that some precision medicine aims to give a mental health apps make unsubstantiated claims about their effectiveness. One study of 73 apps found that most used scientific pathophysiologic mechanism for language, were not validated, and provided low-quality evidence of individual disorders and provide targeted effectiveness.61 Studies such as these highlight the need for combined treatments based on a patient’s specific research between psychiatry and app manufacturers to ensure that physiology, genetic factors, mental health apps and smartphone technology provide effective and environment. treatment and benefit to patients.

Advanced diagnostics and emerging therapies Conclusion Clinicians and researchers are utilising modern wearable technology In an era of fast-paced medical and scientific advances, when CRISPR such as smartphones, smartwatches, and portable technology to technology is promising precision genetic alterations and precision analyse circadian rhythms, heart rate, mood, sleep, and appetite for medicine is offering a personalised treatment plan for multiple illnesses, more immediate and affordable patient analysis.56,57 One study used it is important for psychiatry to make similar strides in both diagnosis wrist-worn technology to predict depression by identifying and treatment. Mental illness is a rapidly increasing worldwide parameters such as repetitive fine motor movements or reduced problem. As new research dissolves the long-held belief in psychiatric movements at specific times of day.58 illness as simply a constellation of mood symptoms, precision medicine Clinicians with access to data collected by these devices could aims to give a pathophysiologic mechanism for individual disorders and monitor patients’ progress in real time and provide assistance or provide targeted treatments based on a patient’s specific physiology, changes in treatment prior to relapses or in cases of poor drug genetic factors, and environment. While further advances are needed, tolerance. The first meta-analysis of smartphone applications for current research demonstrates that new ground is being broken and treating depressive symptoms identified 18 randomised controlled provides hope for treatment strides in this underdeveloped area of trials (RCTs) incorporating 3,414 participants.59 The analysis showed a medical treatment.

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Pharmacogenomics. 2008;9(10):1437-43. 61. Larsen ME, Huckvale K, Nicholas J, Torous J, Birrell L, Li E et al. Using science

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Marijuana in medicine: wonder drug or ‘I wonder if it really works’ drug?

Abstract There have recently been significant changes surrounding the legalisation of marijuana in numerous countries worldwide. Considering its legalisation, as well as its continued usage in the field of medicine, it is crucial to familiarise oneself with different aspects of the drug. These aspects include cannabinoid bioavailability, evidence-based research demonstrating its clinical effectiveness, the long-term impacts on the human body, and physicians’ opinions surrounding the general use of cannabinoids. The human body has an endocannabinoid system that plays a role in homeostatic functions. When synthetic cannabinoids are introduced into the body, they interact with the endocannabinoid receptors and disrupt homeostasis. These disruptions can present as euphoria, changes to sensorimotor function, or altered sleep patterns. There are two main components to cannabis: the psychoactive delta-9-tetrahydrocannabinol (THC); and, the non-psychoactive cannabidiol (CBD). Treatment methods revolve around maximising the impact of CBD while minimising that of THC. Currently, studies have shown effective use of cannabinoid-based products in the treatment of multiple sclerosis, epilepsy, glaucoma, pain modulation, and symptom management for oncology patients experiencing negative effects from chemotherapy. However, the current treatment of some conditions, such as anxiety-related disorders, remains controversial. As with any new medication, it is important to educate those who will be prescribing it. With evidence from several surveys, the current standpoint is that further education is required before this medication can be comfortably prescribed, as some of the long-term impacts of the drug can outweigh the short-term benefits. Some long-term impacts potentially include lung disease if the medication is Deena Shah taken via inhalation, changes to fertility, and schizophrenia-related disorders. Overall, the effective use RCSI medical student of cannabinoids in modern-day medicine relies on further concrete research to support its regular use in clinical practice.

Royal College of Surgeons in Ireland Student Medical Journal 2020; 1: 82-89.

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Introduction Marijuana is made from shredded and dried components of the The medicalisation of marijuana requires a full understanding of its Cannabis sativa or Cannabis indica plant, and was initially discovered impact on the body and the development of evidence-based in Central Asia where it was burned for religious ceremonial recommendations for its effectiveness in treating disease. The purposes.1-3 In 1836, cannabis was introduced to European countries; pharmacological impact of cannabis on the endocannabinoid system, however, shortly after its introduction into the United Kingdom, the an outline of its studied risks and benefits, and a discussion of British colonies banned the usage of cannabis in 1840 due to its physicians’ opinions on the integration of marijuana into the world of negative psychoactive effects on their workers.3-4 The United States medicine are all crucial aspects to understanding its role in banned the sale of cannabis in 1906 and Canada followed suit in modern-day medicine. 1923.5 Arguably one of the most controversial drugs on the market, marijuana is now legal in more than 30 countries worldwide and has Effects of marijuana on the body recently gained momentum in the realm of medical treatment.1 Over The body contains an endogenous cannabinoid system comprised of the last 20 years, the legality of medicinal and recreational marijuana two G protein-coupled receptors: cannabinoid 1 (CB1); and, use has been debated, culminating in its current decriminalised status cannabinoid 2 (CB2). These receptors regulate various functions in in Canada and many parts of Australia and the United States.6 The inflammation, neural development, pain, immune function, and legalisation of marijuana allows for safer methods of obtaining the memory.9-14 When these receptors are activated via drug and introduces a new industry that provides additional jobs and endocannabinoids, there is a subsequent release of acetylcholine, revenue for the economy.7 dopamine, and glutamine neurotransmitters, along with the There are, however, many important questions surrounding its inhibition of γ-aminobutyric acid, N-methyl-D-aspartate, opioid, and legalisation such as the direct, long-term effects of cannabis use and serotonin receptors.15 The CB1 receptors are concentrated in the whether physicians are comfortable prescribing a drug that still central nervous system (basal ganglia, cerebellum, and spinal cord) requires more scientific investigation. This is evident in Ireland and the while the CB2 receptors are located in the immune system.15-17 United Kingdom where marijuana use is legal for limited medicinal Marijuana is made of more than 60 pharmacologically purposes only.8 active cannabinoids that act on these CB receptors.18-19 The

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fashion to that of highly lipid-soluble drugs.23-24 A single marijuana cigarette, with a mass of 0.5-1 grams, can increase venous blood levels of THC to 75-150 nanograms per ml of plasma; however, these levels of THC decrease within minutes and can drop to 5-10% of their peak within one hour.21-23 The rapid drop in plasma THC levels is not due to clearance from the body, but rather a redistribution to other tissues. Once in the tissue, metabolism is relatively slow, resulting in a half-life ranging from 20 hours to 13 days.23 Comparatively, oral ingestion of cannabis has a delayed onset of action, whereby maximum THC venous blood levels are reached one to six hours after ingestion.25 The liver metabolises cannabis through hydroxylation and oxidation, resulting in the creation of psychoactive metabolites. These metabolites result in a greater level of sedation compared to those from inhaled cannabis. In terms of elimination, most THC passes through the faeces and approximately 33% is eliminated in the urine. Furthermore, when cannabis is administered in either form it has the ability to partially inhibit drugs metabolised by cytochrome P450 and compete with drugs that are bound to primary active cannabinoids contained in marijuana include delta plasma proteins.25-29 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is the psychoactive component, contributing to feelings of euphoria, A single marijuana cigarette, with a psychosis, impaired memory, reduced locomotor and cognitive mass of 0.5-1 grams, can increase venous function, increased appetite, and drowsiness.16 The blood levels of THC to 75-150 nanograms non-psychoactive component, CBD, does not interact with the per ml of plasma; however, these levels CB receptors, but rather with a multitude of ion channels of THC decrease within minutes and and endogenous enzymes exerting anti-epileptic, anti-inflammatory, can drop to 5-10% of their and anti-emetic effects.20 When marijuana is taken, it over-activates these receptors and subsequently changes the body’s normal peak within one hour. homeostatic processes. Use and uptake in medicine In 1836, cannabis was introduced to Multiple sclerosis European countries; however, shortly In the treatment of multiple sclerosis, marijuana is taken either orally after its introduction into the United as CBD oil or via inhalation as a combination of THC and CBD. It has Kingdom, the British colonies banned the been found to aid in sleep, deterioration of continence, spasticity, and mood derangements.30 usage of cannabis in 1840 due to its A randomised placebo-controlled trial, which enrolled 667 patients negative psychoactive effects on with stable multiple sclerosis, assessed the efficacy of treating these their workers. patients with oral cannabis extract, THC, or placebo.30 The primary outcome was measured using the Ashworth spasticity scale. This Routes of administration and bioavailability study demonstrated an improvement in spasticity (p=0.003) in 61%, Cannabis is usually inhaled or taken orally, and the method used 60%, and 46% of participants on cannabis extract, THC, and placebo, dictates the bioavailability of the drug. Smoked or inhaled cannabis respectively.30 has an increased rate of bioavailability and allows for easier dose Another randomised controlled trial assessed the efficacy of oral titration.21-22 Additionally, cannabinoids in the form of aerosolised cannabis extract versus placebo on walking ability and muscle particles are rapidly absorbed and delivered to the brain in a similar stiffness.31 Treatment of muscle stiffness was twice as high in the

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group treated with cannabis extract as compared to placebo (29.4% vs 15.7%; p=0.004). It is from these and similar studies that cannabis has been shown to be an effective form of symptom mitigation in patients with multiple sclerosis.32

Treatment of muscle stiffness was twice as high in the group treated with cannabis extract as compared to placebo (29.4% vs. 15.7%; p=0.004).

Epilepsy Evidence has demonstrated that use of marijuana is effective for seizure mitigation as a primary or adjunctive form of treatment in patients who have failed to respond to other first-line medications.33 However, further research is required to demonstrate if this form of medication is superior to current standard anti-seizure medications. Marijuana is taken either topically as CBD oil or orally as a combination of CBD and THC for epileptic seizure mitigation. Currently, the Epilepsy Foundation is undertaking research on an oral oil-based CBD extract reduced breakdown of naturally occurring endocannabinoids, thus called Epidiolex.33 This product was Food and Drug Administration prolonging duration of action due to inhibited monoacylglycerol (FDA) approved in the United States in December 2018 and is currently lipase (MAGL).35-36 undergoing phase three clinical trials. Epidiolex has been involved in a While research supports the use of topical CBD oil, inhalation of multicentre, double-blind, placebo-controlled trial whereby patients marijuana for glaucoma treatment is not supported by diagnosed with Lennox-Gastaut syndrome, a severe childhood-onset ophthalmology societies worldwide due to the short duration of epilepsy syndrome, between the ages of two and 55 years, were action and psychotropic effects with smoking (risks of use outweigh assigned to a cannabinoid (Epidiolex) group or a placebo group. short-term benefits of treatment).34 A total of 225 patients were enrolled and administered a daily dose of the medication for 14 weeks. The cannabinoid group was further divided Pain modulation into a 10mg or a 20mg daily dose. Symptomatically, the medication Nabilone, an oral CBD that has been FDA approved for the treatment resulted in a 41.9% decrease in seizures for the 20mg cannabinoid of nausea and vomiting, has also been effectively used for pain group, a 37.2% decrease in the 10mg cannabinoid group, and a 17.2% manangment.37 A systematic review identified nine randomised decrease in the placebo group. Common adverse effects in the controlled trials whereby cancer-related pain, chronic non-malignant cannabinoid group included somnolence, decreased appetite, and pain, and acute postoperative pain were treated using diarrhoea. Overall, the addition of cannabis to the medication regime for cannabinoid-based substances or codeine.37 these patients was shown to reduce seizure frequency.33 This review found that a combination of oral THC (20mg), oral synthetic nitrogen analogue of THC (1mg), and intramuscular Overall, the addition of cannabis to levonantradol (1.5-3mg) was almost as effective as codeine the medication regime for these (50-120mg).37 Despite effectiveness, the psychotropic adverse effects patients was shown to reduce from THC emphasise the potential negative side effects impacting the central nervous system.38 Controversy arises in attempts to determine seizure frequency. if the psychotropic effects outweigh the benefits of pain modulation Glaucoma when taking THC, specifically when the ratio of THC:CBD favours For the treatment of glaucoma, topical CBD is preferred over inhaled THC. Additionally, a risk–benefit ratio must be established on a combinations of CBD and THC.34 Topical CBD reduces intraocular case-by-case basis to determine the beneficence of cannabis for pressure by increased activation of the CB1 receptors and pain management.39

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Groups were compared using statistical determine if cannabis use results in symptom reduction, or if it further parametric brain mapping, as well as a contributes to anxiety associated with cannabis use disorder.40 subjective change in anxiety-related symptoms. Results from this study Despite these results, a more recent found that CBD use was associated systematic review of the literature with a significant decrease in in March 2013 outlined 31 studies subjective anxiety (p<0.0001). with cross-sectional and prospective cohort designs, whereby anxiety

was positively associated with Anti-anxiety There have been numerous studies to determine the impact of CBD cannabis use or cannabis on anxiety-related disorders. As of now, there is low-quality evidence use disorder. supporting the use of CBD due to the contradictive evidence linking cannabis use with anxiety-related symptoms and cannabis When marijuana meets cancer abuse disorder.40 The use of cannabis has been suggested as a treatment for the side In 2011, a multi-session study assessed the impact of cannabis on effects of chemotherapy, namely anxiety, lack of appetite, depression, patients with generalised social anxiety disorder in an attempt to disturbed sleep, fatigue, nausea, pain, and vomiting.44 Therefore, ascertain the direct relationship between anxiety and cannabis.41 In marijuana acts to aid in the overall well-being of the patient as the first session of this study, 10 treatment-naive patients were either opposed to treating the cancer itself. given an oral dose of CBD at 400mg, or a placebo. In the second In Israel, a study was conducted from 2015 to 2017 analysing 2,970 session, both groups of patients were given the medication they had cancer patients treated for six months with 16 different strains of not received in the first session. Groups were compared using cannabis with varying THC:CBD concentrations that were statistical parametric brain mapping, as well as a subjective change administered either topically or orally via oil extracts.45 in anxiety-related symptoms. Results from this study found that CBD Of the remaining 1,211 patients, 95.9% use was associated with a significant decrease in subjective reported an improvement in their anxiety (p<0.0001).41 Despite these results, a more recent systematic review of the literature symptoms regardless of the particular in March 2013 outlined 31 studies with cross-sectional and cannabis strain and concentration, as prospective cohort designs, whereby anxiety was positively associated most patients (72.1%) consumed a with cannabis use or cannabis use disorder.42 combination of the two strains Anxiety as a result of cannabis use can manifest as symptoms of a (sativa and indica). cannabis abuse disorder or withdrawal, typically present one to three days after cessation, and can last for up to 28 days.43 The main symptoms treated were sleep disturbances (78.4%), pain A survey-based study conducted in Canada analysed the impact of (77.7%), weakness (72.7%), nausea (64.6%), and lack of appetite cannabis for medicinal purposes in the treatment of anxiety and (48.9%). Throughout the course of this study, over 900 patients died depression.40 Of the 2,032 consumers that were verified with a and 600 terminated treatment. Of the remaining 1,211 patients, Canadian licensed producer, 92% reported that cannabis improved 95.9% reported an improvement in their symptoms regardless of the their anxiety symptoms despite standardised anxiety and depression particular cannabis strain and concentration, as most patients scales indicating no change to disease during the study course.40 (72.1%) consumed a combination of the two strains (sativa and Nevertheless, the possibility of cannabis use disorder as well as indica). Therefore, the study concluded that cannabis is an effective confounding non-psychiatric factors contributing to improvements in and safe method of symptomatic treatment for patients alongside anxiety cannot be ruled out. other active cancer treatments or while in palliative care. However Overall, due to the contradictive nature of the current evidence to further research is required to determine effective dosages to support CBD usage in anxiety patients, further research is required to maximise symptom relief.45

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Currently, two cannabinoids (dronabinol and nabilone) have been FDA approved for the treatment of chemotherapy-induced nausea and vomiting. They act to reduce the release of serotonin from enterochromaffin cells in the small intestine, which initiate the vomiting reflex.37,46,47

The long-term impacts of marijuana inhalation are associated with damage to bronchial passages resulting in ongoing productive cough and wheeze. This can lead to both acute and chronic conditions such as pneumothorax, chronic obstructive pulmonary disease, and lung cancer.

Long-term impacts of marijuana The long-term impacts of marijuana inhalation are associated with damage to bronchial passages resulting in ongoing productive cough Often, first-time users can have a and wheeze. This can lead to both acute and chronic conditions such negative reaction in the form of as pneumothorax, chronic obstructive pulmonary disease, and lung disorientation and gastrointestinal 1 cancer. Paradoxically, long-term marijuana use may also lead to cyclic upset; however, this is more common vomiting syndrome, despite the drug’s well known anti-emetic in older patients. properties. This syndrome is a chronic condition characterised by recurring attacks of nausea and vomiting with associated abdominal pain and migraines.48 The role of the physician From a cardiovascular perspective, marijuana has the ability to Pertaining to the ethical principle of non-maleficence, a physician increase the heart rate for up to three hours, which can be fatal to should be well versed in the risks and benefits of any medication or patients with ongoing arrhythmias, electrocardiogram abnormalities, substance prior to recommending, prescribing, or administering it to or coronary artery disease.1,49 Additionally, marijuana use is suspected a patient. The medical use of cannabis-based products should be no to impact fertility in both male and female populations through different. A study conducted in Colorado, USA, assessed family alterations in the stimulation of CB1 and CB2 receptors.50-51 It has physicians’ comfort levels in prescribing marijuana through been postulated that cannabis causes a reduction in the synthesis of questionnaires containing various situations in which medicinal both testosterone and luteinising hormone by disrupting the marijuana may or may not be warranted.53 Results showed that 64% hypothalamic-pituitary-gonadal axis; however, more research is of family physicians were not convinced that the use of marijuana required to provide definitive proof of changes in fertility.50-51 outweighed the long-term risks, and nearly all physicians in the study From a mental health perspective, long-term use of marijuana from a agreed that formal education with respect to the use of medicinal young age has been linked to schizophrenia and memory marijuana would be necessary if there were plans to move forward.53 difficulties.52 This occurs when marijuana is inhaled due to the Current guidelines in Canada are based on the idea of prescribing increased amount of psychoactive THC in comparison to smaller amounts at a lower potency, and state that the use of medical non-psychoactive CBD that enters the body. With this in mind, the marijuana is exclusive to cases where patients have failed to respond therapeutic effect of marijuana is dictated by the higher ratio of CBD to other forms of therapy.54 Often, first-time users can have a negative to THC to minimise the psychoactive effects of THC and maximise the reaction in the form of disorientation and gastrointestinal upset; therapeutic impact of CBD.19 however, this is more common in older patients.19

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Conclusion The effective use of medicinal marijuana is not black and white, as The future use of marijuana as a medicinal source lies within the engineering the ideal combination of CBD to THC lies in reducing the domains of physician education, risk-versus-benefit analysis, ethical prevalent psychotropic effects associated with drug use. Given the rise concerns, and side effect profile. in legality of cannabinoid-based products worldwide, for medicinal or Further research and education is required to establish concrete recreational use, more rigorous research can begin and hopefully guidelines and comfort in the physician community surrounding bring about a new family of user-friendly medications. medicinal cannabis use.

References 1. The National Academies of Sciences, Engineering, and Medicine. The Health system and migraine pain: an update. Front Neurosci. 2018;12:172.

Effects of Cannabis and Cannabinoids: Current State of Evidence and 14. Howlett AC. Efficacy in CB1 receptor-mediated signal transduction. Br J

Recommendations for Research. Washington, DC: The National Academies Pharmacol. 2004;142:1209-1218.

Press, 2017. 15. Pertwee RG. Pharmacological actions of cannabinoids. Handb Exp Pharmacol.

2. Knezevich E, Wu Y. Marijuana for the treatment of seizure disorders. US Pharm. 2005;(168):1-51.

2015;40(1):24-28. 16. Koppel BS, Brust JC, Fife T et al. Systematic review: efficacy and safety of

3. Iversen, Leslie L. The Science of Marijuana. Oxford University Press, 2018:110. medical marijuana in selected neurologic disorders: report of the Guideline

4. European Monitoring Centre for Drugs and Drug Addiction. A Cannabis Development Subcommittee of the American Academy of Neurology.

Reader: Global Issues and Local Experiences. Luxembourg: Office for Official Neurology. 2014;82(17):1556-63.

Publications of the European Communities, 2008. 17. Bhattacharyya S, Morrison PD, Fusar-Poli P et al. Opposite effects of

5. Musto DF. The American Disease: Origins of Narcotic Control (3rd ed.). New delta-9-tetrahydrocannabinol and cannabidiol on human brain

York: Oxford University Press, 1999. function and psychopathology. Neuropsychopharmacology.

6. U.S. Food and Drug Administration. FDA Regulation of Cannabis and 2010;35(3):764-74.

Cannabis-Derived Products, including Cannabidiol (CBD). 2019. [Internet]. 18. Aymerich MS, Aso E, Abellanas MA, Tolon RM, Ramos JA et al. Cannabinoid

[cited 2019 October 16]. Available from: https://www.fda.gov/news-events/ pharmacology/therapeutics in chronic degenerative disorders affecting the

public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-in central nervous system. Biochem Pharmacol. 2018;157:67-84.

cluding-cannabidiol-cbd. 19. Joy JE, Watson SR Jr, Benson JA Jr et al. Marijuana and medicine: assessing the

7. Krishna M. The Economic Benefits of Legalizing Weed. Investopedia Economy science base. Division of Neuroscience and Behavioral Health, Washington, DC:

Government and Policy. 2019. Available from: https://www.investopedia.com National Academy Press, 1999.

/articles/insights/110916/economic-benefits-legalizing-weed.asp. 20. Haüser W, Petzke F, Fitzcharles MA. Efficacy, tolerability and safety of

8. Baker N, Petkar S. Medical marijuana in the UK – is it legal and how much does cannabis-based medicines for chronic pain management – an overview of

Sativex cost? The Sun. 2019. [Internet]. Available from: https://www.thesun. systematic reviews. Eur J Pain. October 2018;22(3):455-70.

co.uk/news/6559385/medical-marijuana-uk-legal-treatment-sativex/. 21. Huestis MA, Henningfield JE, Cone EJ. Blood cannabinoids. 1. Absorption of

9. Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: THC and formation of 11-OH-THC and THCCOOH during and after smoking

signalling and function in the central nervous system. Int J Mol Sci. marijuana. J Anal Toxicol. 1992;16(5):276-82.

2018;19(3):E833. 22. Huestis MA, Sampson AH, Holicky BJ, Henningfield JE, Cone EJ. Characterization

10. Huang WJ, Chen WW, Zhang X. Endocannabinoid system: role in depression, of the absorption phase of marijuana smoking. Clin Pharmacol Ther.

reward and pain control (review). Mol Med Rep. 2016;14(4):2899-903. 1992;52(1):31-41.

11. Kaur R, Ambwani SR, Singh S. Endocannabinoid system: a multi-facet 23. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H et al.

therapeutic target. Curr Clin Pharmacol. 2016;11(2):110-7. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other

12. Di Marzo V. New approaches and challenges to targeting the endocannabinoid cannabinoids with emphasis on man. Pharmacol Rev. 1986;38(1):21-43.

system. Nat Rev Drug Discov. 2018;17:623-39. 24. Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medical Cannabis: Rational

13. Greco R, Demartini C, Zanaboni AM, Piomelli D, Tassorelli C. Endocannabinoid Guidelines for Dosing. IDrugs. 2004:7(5):464-70.

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25. Kelly P, Jones RT. Metabolism of tetrahydrocannabinol in frequent and 40. Turna J, Simpson W, Patterson B, Lucas P, Van Ameringen M. Cannabis use

infrequent marijuana users. J Anal Toxicol. 1992;16(4):228-35. behaviours and prevalence of anxiety and depressive symptoms in a cohort of

26. Kosel BW, Aweeka FT, Benowitz NL, Shade SB, Hilton JF, Lizak PS et al. The Canadian medicinal cannabis users. J Psychiatr Res. 2019;111:134-9.

effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. 41. Crippa JAS, Derenusson GN, Ferrari TB. Neural basis of anxiolytic effects of

AIDS. 2002;16(4):543-50. cannabidiol (CBD) in generalized anxiety disorder: a preliminary report. J

27. Benowitz NL, Jones RT. Effect of delta-9-tetrahydrocannabinol on drug Psychopharmacol. 2010;25(1):121-30.

distribution and metabolism. Antipyrine, pentobarbital and ethanol. Clin 42. Walsh Z, Gonzalez R, Crosby K, Thiessen MS, Carroll C, Bonn-Miller MO.

Pharmacol Ther. 1977;22(3):259-68. Medical cannabis and mental health: a guided systematic review. Clin Psychol

28. Gustafson RA, Levine B, Stout PR, Klette KL, George MP, Moolchan ET et al. Rev. 2017;28:15-29.

Urinary cannabinoid detection times after controlled oral administration of 43. Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and significance

delta9-tetrahydrocannabinol to humans. Clin Chem. 2003;49(7):1114-24. of cannabis withdrawal. J Abnorm Psychol. 2003;112(3):393-402.

29. Benowitz NL, Nguyen T, Jones RT, Herning RI, Bachman J. Metabolic and 44. Anderson SP, Zylla DM, McGriff DM, Arneson TJ. Impact of medical cannabis

psychophysiologic studies of cannabidiol-hexobarbital interaction. Clin on patient-reported symptoms for patients with cancer enrolled in Minnesota’s

Pharmacol Ther. 1980;28(1):115-20. medical cannabis program. J Oncol Pract. 2019;15(4):e338-45.

30. Zajicek JP, Fox PJ, Sanders PH et al. Cannabinoids for treatment of spasticity and 45. Schleider LBL, Mechoulam R, Lederman V, Hilou M, Lencovsky O et al.

other symptoms related to multiple sclerosis (CAMS study): multicenter Prospective analysis of safety and efficacy of medical cannabis in large

randomized placebo-controlled trial. Lancet. 2003;362:1517-26. unselected population of patients with cancer. Eur J Intern Med.

31. Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG. Multiple sclerosis and 2018;49:37-43.

extract of cannabis: results of the MUSEC trail. J Neurol Neurosurg Psychiatry. 46. Mortimer TL, Mabin T, Engelbrecht AM. Cannabinoids: the lows and the highs

2012;83(11):1125-32. of chemotherapy-induced nausea and vomiting. Future Oncol.

32. Weinkle LJ, Shelton I, Sillau SH, Domen C, Nair KV et al. Exploring cannabis use 2019;15(9):1035-49.

by patients with multiple sclerosis in a state where cannabis is legal. Mult Scler 47. Marinol [product information]. Marietta, GA: Solvay Pharmaceuticals, 2008.

Relat Disord. 2018;27:383-90. 48. Galli JA, Sawaya RA, Friedenberg FK. Cannabinoid hyperemesis syndrome. Curr

33. Kerr A, Walston V, Wong VSS, Kellogg M, Ernst L. Marijuana use among patients Drug Abuse Rev. 2011;4(4):241-9.

with epilepsy at a tertiary care center. Epilepsy Behav. 2019;97:144-8. 49. Franz CA, Frishman WH. Marijuana use and cardiovascular disease. Cardiol Rev.

34. Rafuse P, Buys YM. Medical use of cannabis for glaucoma. Canadian Journal of 2016;24(4):158-62.

Ophthalmology. 2019;54(1):7-8. 50. Du Plessis SS, Agarwal A, Syriac A. Marijuana, phytocannabinoids, the

35. Miller S, Daily L, Leishman E, Bradshaw H, Straiker A. Δ9-tetrahydrocannabinol endocannabinoid system, and male fertility. J Assist Reprod Genet.

and cannabidiol differentially regulate intraocular pressure. Invest Ophthalmol 2015;32(11):1575-88.

Vis Sci. 2018;59(15):5904-11. 51. Brents LK. Marijuana, the endocannabinoid system and the female reproductive

36. Miller S, Kulkarni S, Ciesielski A, Nikas SP, Mackie K et al. system. Yale J Biol Med. 2016;89(2):175-91.

Controlled-deactivation CB1 receptor ligands as a novel strategy to lower 52. Vaucher J, Keating BJ, Lasserre AM, Gan W, Lyall DM et al. Cannabis use and risk

intraocular pressure. Pharmaceuticals (Basel). 2018;11(2). of schizophrenia: a Mendelian randomization study. Mol Psychiatry.

37. Cesamet [product information]. Aliso Viejo, CA: Valeant Pharmaceuticals, 2008. 2018;23(5):1287-92.

38. Campbell FA, Tramer MR, Carroll D, Reynolds DJM, Moore RA, McQuay HJ. Are 53. Kondrad E, Reid A. Colorado family physicians’ attitudes toward medical

cannabinoids an effective and safe treatment option in the management of marijuana. J Am Board Fam Med. 2013;26(1):52-60.

pain? A qualitative systematic review. BMJ. 2001:323(7303):13. 54. Allan GM, Ramji J, Perry D, Ton J, Beahm NP, Crisp N et al. Simplified guideline

39. Russo EB. Cannabinoids in the management of difficult to treat pain. Ther Clin for prescribing medical cannabinoids in primary care. Can Fam Physician.

Risk Manag. 2008;4(1):245-59. 2018;64(2):111-20.

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Remembering the Great War: figures of the First World War ANIRUDH GAUTAM and BONNIE YAM discuss major figures of World War I, whose achievements laid the foundations of modern medicine and nursing.

FIGURE 1: Christmas Day in hospital ward. Watercolour by Nurse Dakin (?), 1917-18.

In June 2019, we celebrated the 100th anniversary of the treaty that of the modern era. In Ireland, over 100,000 men volunteered to serve ended one of the most brutal conflicts ever to face humanity. The First in the British Army, Navy, and Royal Air Force, and over 60 million World War, fought from 1914-1918 between the Central Powers and people served in armed forces worldwide.1,2 The war was fought from the Entente Cordiale, was arguably the conflict that marked the start the banks of the river Seine to the far reaches of Tsingtao on the other

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side of the world. The ‘War to End All Wars’ saw many advances, from the Schlieffen-Moltke plan to the Hundred Days Offensive. However, born from the grit, mud, blood, and suffering of this struggle, advances were also made on another great front: medicine (Figure 1). Outlined is a panorama of the lives of certain legendary figures who came to prominence during the Great War, who were integral to the practice of modern medicine in the fields of plastic surgery, anaesthesia, wound care, and psychiatric nursing.

While plastic surgery is an ancient field stretching back centuries, the First World War spurred the need for reconstructive surgery. The advances made in plastics during the Great War were intimately related to maxillofacial surgery, which did not become a fully fledged specialty until after the Second World War.

Plastic surgery While plastic surgery is an ancient field stretching back centuries, the First World War spurred the need for reconstructive surgery. The advances made in plastics during the Great War were intimately related to maxillofacial surgery, which did not become a fully fledged specialty until after the Second World War.3 Sir Harold Delf Gillies, an otolaryngologist from New Zealand, was especially prolific in advances around repairing jaw defects and using skin flaps for reconstruction of the eyes, ears, mouth, and eyelids FIGURE 2: Sir Harold Delf Gillies. (Figure 2).4 On the first day of the Battle of the Somme, which was the single bloodiest day in the entire war, over 2,000 patients surgery in America.3,6 Their counterparts in the Central Powers, arrived at his new unit in the Cambridge Military Hospital at including August Lindemann, Christian Bruhn, and Johannes Esser, Aldershot for reconstructive work.3 In the words of Andrew Bamji, also attempted to relieve those suffering on the opposite side of the historian of Sidcup Hospital: “There is no doubt whatever that the field, and their work was especially important in establishing the casualties of the Western Front were the vital experimental the importance of revascularisation.6 subjects who enabled the modern specialty of plastic surgery to develop”.3 Gillies subsequently played a prominent role in the Anaesthesia creation of the American Association of Plastic Surgeons.4 His One great in the history of anaesthesia that Ireland can claim as its successes spurred a flurry of activity in other Commonwealth own is Sir Ivan Magill, an Ulsterman from Larne and a colleague of countries, including Canada, New Zealand, and Australia. Henry Gillies.7 Having graduated from Queen’s University in Belfast with Pickerell, a leading figure in plastic surgery advancement efforts in an MB BCh BAO in 1913, he joined the Royal Army Medical Corps New Zealand, described several procedures, including bone grafts at the onset of the war. While serving as a Captain in the Irish from the tibia and the treatment of gunshot wounds, in his work Guards, he joked about being an anaesthetist, even though he had Facial Surgery.5 Contemporaneously across the globe, Vilray Blair little prior exposure to the field.8 However, this eventually placed from the United States helped to establish plastic and maxillofacial him at Queen’s Hospital in Sidcup immediately after the War,

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FIGURE 3: Queen Elisabeth of Belgium and Dr Antoine Depage in the military FIGURE 4: Caricature of Georges Villa (1913) produced with reference to his stay in hospital in Vinkem (Alfred Bastien, 1918). New York. where he met individuals such as Dr Gillies.8 Being primarily a maxillofacial practice, injuries to the facial regions presented Nurses were as important as medical unique challenges. In order to maintain a stable airway, Magill personnel to the war effort. Particularly introduced a mainstay of modern medicine, the endotracheal (ET) of note are certain Australian nurses 7 tube, and his eponymous forceps with which the tube is placed. who would prove instrumental in While he described his successes in endotracheal insufflation, many advancing nursing in mental health, difficulties still arose with the device, including anaesthetic including Ellen Julia Gould and Dame compounds being expelled back to the anaesthetist with each breath.8-10 He went on to be hailed as one of the founding fathers Maud McCarthy. of modern anaesthetics, continuing to make advances in Wound care intubation, thoracic surgery, and anaesthetic agents and Wound treatment, a relatively more established field, was a techniques until the 1970s.9 Magill’s legacy also remains in the necessary prerequisite for eventual transport to and treatment in foundation of the Association of Anaesthetics of Great Britain and hospitals like the one at Sidcup. Ireland, where he was the honorary Secretary of the Section of Debridement and antiseptic use, followed by immediate primary Anaesthetics of the Royal Society of Medicine.10 closure, was the standard of wound care prior to the Great War.11

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Dr Antoine Depage, a renowned Belgian surgeon with experience While the remainder of Dakin’s life was uneventful, his solution treating the Turkish in the prior Balkan wars, was a key figure in continued to be used even without Carrel’s method for decades improving effective wound management. after the war.16 Carrel, on the other hand, went on to make During the War, he at first organised the Belgian Red Cross advances in transplant medicine (Figure 4). in Brussels; after the Germans took Brussels, he developed While he was awarded numerous decorations from several several advanced war-oriented surgical hospitals across the countries for his service during the War, including the Belgian Northern Front (Figure 3).12 Officier de l’Ordre de Leopold, the American Distinguished Service Depage, participating in the Allied Front since 1915, described his Medal, and the British Cross of the Knight Commander of St successes in removal of dead tissue (debridement, in its literal Michael and St George,14 his name was tarnished by ambivalent sense, simply involves the opening of the wound), in delayed associations with the eugenic ideas embraced by the National primary closure to prevent bacterial infection, and in treating these Socialist movement of Germany and by his friendship with Charles infections with hypochlorite of soda in the fallout of the war.11,13 Lindbergh, who himself had Nazi affiliations.18 He also described his advances in the care of open fractures and amputations.12 Later in his life, Depage founded the first Carrel, having established funding from cancer institute in Belgium alongside a certain Jules Bordet of the Rockefeller Foundation, utilised Bordetella fame.12 this antiseptic effectively in

establishing the Carrel-Dakin In order to maintain a stable method of wound care. airway, Magill introduced

a mainstay of modern medicine, Psychiatric nursing the endotracheal (ET) tube, Nurses were as important as medical personnel to the war effort. and his eponymous Particularly of note are certain Australian nurses who would prove forceps with which instrumental in advancing nursing in mental health, including Ellen the tube is placed. Julia Gould and Dame Maud McCarthy. During the Great War, a phenomenon of ‘shell shock’ was noticed in active military personnel after combat, with signs and symptoms The solution of hypochlorite, essential for Depage, would not have including disordered gait, tremors, headaches, and vivid, existed without the English chemist Dr Richard Drysdale Dakin and terrifying dreams.19 his partner, the French physician Dr Alexis Carrel. In the trenches of France, soldiers were exposed to several species Dr Antoine Depage, a renowned Belgian of bacteria, including B. tetani, B. perfringens, and staphylococci.14 surgeon with experience treating While innocuous on their own, they could become important the Turkish in the prior Balkan wars, pathogens in war wounds, with over 90% of wounds containing was a key figure in improving microorganisms that had a serious impact on treatment.15 It was effective wound management. on this background that Dr Dakin joined Dr Carrel, prior to 1915, at Hôpital Complémentaire 21 to develop his famous solution of hypochlorite.14,16,17 Dame Maud McCarthy, born in Sydney and trained as a military Carrel, having established funding from the Rockefeller nurse before participating in the South African War in the late Foundation, utilised this antiseptic effectively in establishing the 1800s, was made the Matron-in-Chief of France and Flanders on Carrel-Dakin method of wound care. Though labour intensive, this the bulk of the Western Front. process, in which Dakin’s solution is used to irrigate rubber tubing Being one of the first to notice shell shock affecting soldiers, she dressings regularly, was nonetheless a breakthrough that would be founded a special psychiatric nursing service to alleviate their the most important advance until the advent of sulfa antibiotics suffering.20 Another nurse leader, particularly trained as a ‘mental two decades later.16 nurse’, was Ellen ‘Nellie’ Julia Gould, who worked with several

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senior physicians to codify the diagnosis and initiate rudimentary Conclusion treatment for shell shock.21 While this diagnosis would be refined We do not stumble into modernity, blind and without precedent, over decades and would eventually be classified in the Diagnostic but instead are moulded by those who came before us, through and Statistical Manual (DSM) as post-traumatic stress disorder the light of the tunnel of history. Modern medicine is no exception (PTSD),19 both McCarthy and Gould were instrumental in the – figures such as Gillies, Depage, Dakin, Carrel, Magill, McCarthy, nascent practice of nursing in Australia and were thus highly and Gould are integral to our understanding of saving and decorated by the British Empire.20,22 improving lives. Institutions, instruments, and techniques that we find omnipresent in healthcare settings had a historic beginning. Understanding this history Understanding this history is of importance to any student of is of importance to any student of medicine. From the ancient Greeks to the Mayo Clinic, medicine medicine. From the ancient Greeks to continues to evolve around us, and the relics of the past continue the Mayo Clinic, medicine continues to surround us, from medical journal articles to physical objects. Indeed, in the basement at the Royal College of Surgeons in to evolve around us, and the relics of Ireland (RCSI), an exhibition of antique equipment is displayed, the past continue to surround us, and students attending Cappagh National Orthopaedic Hospital from medical journal articles to will find displayed an authentic Esmarch tourniquet. When one physical objects. explores deeper, one learns that these people and instruments arose from a time of immense suffering and atrocity; an examination of these lives reveals the substance of legends.

References 1. Winter JM. Britain’s ‘Lost generation’ of the First World War. Popul Stud. 13. Depage A. General considerations as to the treatment of war wounds. Ann 1977;31(3):449-66. Surg. 1919;69(6):575-88. 2. Tucker S, Roberts PM. World War I: A Student Encyclopedia. Vol. 1. ABC-CLIO, 14. Limjoco UR, Landon CW, Ragland JJ. The contributions of Alexis Carrel to the 2005:273. management of contaminated wounds. Can J Surg. 1995;38(2):183-7. 3. Simpson DA, David DJ. World War I: the genesis of craniomaxillofacial surgery? 15. Murray CK, Hinkle MK, Yun HC. History of infections associated with ANZ J Surg. 2004;74(1-2):71-7. combat-related injuries. J Trauma. 2008;64(3 Suppl.):S221-31. 4. Backstein R, Hinek A. War and medicine: the origins of plastic surgery. Univ 16. King M. Our historical roots: Dr Richard Drysdale Dakin, DSc, and his solution. Toronto Med J. 2005;82(3):217-9. J Wound Ostomy Cont Nurs. 2008;35(3):289-92. 5. Pickerill HP. Facial Surgery. Edinburgh: Livingstone, 1924. 17. Schutze H. Iodine and sodium hypochlorite as wound disinfectants. Br Med J. 6. Stathopoulos P. Maxillofacial surgery: the impact of the Great War on both sides 1915;2(2869):921-2. of the trenches. Oral Maxillofac Surg. 2018;22(1):21-4. 18. Dutkowski P, De Rougemont O, Clavien P. Alexis Carrel: genius, innovator and 7. Dundee JW. Anaesthetics. With special reference to Ivan Magill. Ulster Med J. ideologist. Am J Transplant. 2008;8(10):1998-2003. 1987;56(Suppl.):S87-90. 19. Ray SL. Evolutions of posttraumatic stress disorder and future directions. Arch 8. Nosker GS, Swan KG. Sir Ivan Magill: the right physician in the right place at Psychiatr Nurs. 2008;22(4):217-25. the right time. J Trauma. 2007;62(4):1056-9. 20. Shields L, Magee D. A leading nurse in World War One: Dame Maud McCarthy. 9. Thomas KB. Sir Ivan Whiteside Magill, KCVO, DSc, MB, BCh, BAO, FRCS, Working Papers in the Health Sciences. 2015;1:14. FFARCS (Hon), FFARCSI (Hon), DA. Anaesthesia. 2018;33(7):628-34. 21. Rae R. An historical account of shell shock during the First World War and 10. McLachlan G. Sir Ivan Magill KCVO, DSc, MB, BCh, BAO, FRCS, FFARCS (Hon), reforms in mental health in Australia 1914-1939. Int J Ment Health Nurs. FFARCSI (Hon), DA, (1888-1986). Ulster Med J. 2008;77(3):146-52. 2007;16:266-73. 11. Hardaway RM. 200 years of military surgery. Injury. 1999;30(6):387-97. 22. Rae R. Ellen Julia Gould: a civilan nurse and founder of the military nursing 12. Van Hee R. History of the ISS/SIC: Antoine Depage, one of the founders of the tradition in Australia (1860-1941). J R Aust Hist Soc. 2006;92(2):165-82.

ISS/SIC. World J Surg. 2002;26(10):1195-201.

Page 94 | Volume 13: Number 1. 2020 RCSIsmj persepctive Breaking the cycle of condescension: the medical hierarchy

The practice of intimidating and humiliating medical students in order to ‘toughen them up’ is coming under increasing criticism, says CANDICE PARMAR.

Introduction As medical students enter their clinical years of education and begin physicians.1 This cross-examination has a tendency to result in the to apply their knowledge and interact with patients, there is a greater belittlement and humiliation of the learner if they respond incorrectly pressure to prove their competence. During these years, those lower to questions.1 Seen as a rite of passage in the culture of medicine down in the medical hierarchy may experience what has come to be worldwide, those that experience this demeaning behaviour often known as ‘pimping’, a process in which medical students, interns, and end up becoming perpetrators later on, and act to preserve the cycle residents are inundated with difficult questions from senior of condescension.1 Seemingly contradictive to the goals of medicine

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to train compassionate, tolerant, respectful, and professional The key factor contributing to medical students not speaking up is physicians, this behaviour nonetheless persists, and has been fear: fear that if they report their superiors, it could poorly impact increasingly associated with detrimental effects on trainees’ their grades, influence whether or not they receive references to well-being and patient care alike.2-4 Increasing numbers of physicians further their careers, disrupt their positive image, or encourage and students are leaving medicine or regretting the decision further mistreatment.3-5,12 Additionally, there is a general lack to pursue this career path due to this negative and stressful of confidence in the medical system to act even if incidents learning environment.1,4-7 are reported.4 In some countries, such as Pakistan, students believe that they do not The key factor contributing to medical have access to adequate support when mistreatment occurs.7 students not speaking up is fear: fear that However, in Australia, even with access to support, 54.8% of junior if they report their superiors, it could medical officers do not make use of it.6 Instead, students commonly poorly impact their grades, influence avoid the perpetrator or that area of medicine altogether; they may isolate themselves, or even quit medical school.4 While some students whether or not they receive references to are unaware of how to report these situations to perpetrators or further their careers, disrupt their positive senior administrators, some also rationalise humiliation as an image, or encourage further educational tool.5

mistreatment. Alternatively, many believe that it The prevalence of belittlement motivates students to study harder, Students have the highest risk of experiencing various forms of allows them to recognise their harassment, including racism and verbal, physical, and sexual abuse, weaknesses, and prepares them during the clinical years of medical school.8 Among these, verbal for the demands of a abuse and the abuse of power are the most widespread.8 In particular, medical career. humiliation is found to have the greatest impact on students, and is only possible where there is a difference in power.4 Wilkinson et al. found the experience of humiliation and degradation to be highly Accepting the status quo prevalent among 49% of medical students across New Zealand.4 The four main factors that contribute to the continued mistreatment Similarly, 45% of Canadian family medicine residents,5 52% of of students are: the medical institution; the nature of the work; the Pakistani students,7 50% of Saudi Arabian students,9 and 84% of US perpetrator; and, the victim.8 Doctors with greater hierarchical power students10 all endured some form of humiliation during their medical who perpetuate ‘pimping’ or belittlement do not acknowledge that it training, including belittlement, intimidation, unjustified criticism, is a problem. Alternatively, many believe that it motivates students to exclusion, and demoralisation. Humiliation is also a common study harder, allows them to recognise their weaknesses, and occurrence for medical students in Ireland, South Australia, and other prepares them for the demands of a medical career.3 Ultimately, many parts of the world.5 of these doctors believe that since they themselves became successful Although there is a consensus that humiliation as a method of after experiencing these same approaches, this method of teaching teaching is ineffective for those experiencing it, one of the main must be ideal for students or is a form of ‘good intimidation’.13 Some reasons it persists is because students generally remain silent and do doctors are hesitant to label the rite of passage as harassment since not report incidents.5 Since humiliation occurs rather often, it may not they believe the behaviour is intended to push students to improve.13 be considered worth reporting despite its negative consequences.4 One surgical resident went as far as to say “some people need to One study compared the difference in reporting of mistreatment be scared into doing things” as a means to justify belittling between nursing and medical students. Nursing students were more teaching techniques.13 likely to confront or report their clinical supervisors, while medical The concept behind this type of learning is negative reinforcement, students were prone to avoiding their supervisors.11 Despite the where students will study and prepare more to remove the negative majority of medical students experiencing some type of humiliation consequence of being humiliated for not knowing the answers to during their education, these incidents are not commonly reported.12 questions. Regardless of the perpetrators’ intentions, only 25% of

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New Zealander students found this technique motivational,4 and only 2% of doctors who experienced harassment agreed that it made them more eager to learn medicine.5 Despite the impact on their well-being, many of those who experience harassment end up becoming perpetrators as they move up the medical hierarchy.1 According to social learning theory, successful behaviours depend on differential reinforcement.14 In this case, since the majority of students do not report incidents of harassment, the perpetrator’s behaviour endures without consequence. The infrequency of reporting has likely contributed to ‘pimping’ becoming widespread and largely normalised. In clinical years, medical students look to physicians as role models of how they should act when they gain their own professional identities as doctors.15 Even for students who do not necessarily agree with these teaching methods, if they are sufficiently rewarded for acting similarly to their superiors, they will likely become perpetrators of this demeaning teaching method in the future.14 This valuable resource that allows prospective students to determine is also known as anticipatory socialisation, where peers will exhibit which school they should attend.16 However, many students traits to match the ‘in-group’, even if the behaviour is seen as become desensitised to cadavers due to the overwhelming concern undesirable outside of that group.15 The students that do not become of avoiding embarrassment during their next anatomy questioning perpetrators may become uninterested in or even avoid specialties period.16 Methods of teaching or ‘pimping’, where students are that highlight this behaviour.15 compelled to focus on appearances and grades rather than fuelling a true passion for medicine, should be a concern, especially as this Even for students who do not necessarily relates to the care of future patients. agree with these teaching methods, It is the high-risk nature of certain medical specialties that allows if they are sufficiently rewarded little liberty for error when it comes to caring for patients.13 In these for acting similarly to their superiors, high-stakes scenarios, there may be a sense of urgency or impatience evoked from those higher up in the medical hierarchy, they will likely become perpetrators and this attitude may be perceived by junior trainees as blunt or of this demeaning teaching method rude behaviour. While this behaviour might allow for a patient’s in the future. care to continue efficiently, conversely, the presence of a hostile environment with poor communication could lead to increased Changing the system medical errors, and patient morbidity or mortality.17 This tense Even though the practice of medicine evolves with new research environment often discourages entry into specialties such as and technological developments, the educational framework general surgery, urology, gynaecology, paediatrics, plastic surgery, utilised by medical institutions is more resistant to change.16 While and interventional radiology.1,10,13,17 This then perpetuates a cycle medical school curriculums are always adapting to incorporate the wherein those who do not believe there is a systemic problem will latest best practice guidelines and new evidence-based medicine, continue entering these specialties with little or no desire for these reforms often do not consider the preferred teaching change, thus allowing the intimidating behaviour to persist. methods of different educators.16 Instead, there is a greater emphasis on the corporate structures required to maintain schools, Long-term implications such as tuition and competitive programmes, rather than on Intimidating ‘teaching’ methods, such as ‘pimping’, have many promoting humanistic and compassionate educational negative long-term consequences for those lower down in the behaviours.16 Medicine can become dehumanised when the medical hierarchy, as well as indirect effects on patient care. This scholarly aspect of medical education takes prominence.16 For method of teaching negatively affects students’ and junior trainees’ instance, anatomy laboratories at medical schools are seen as a mental health, with increased levels of depression, anxiety, burnout,

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and suicidal ideation, and many individuals cope by abusing alcohol Conclusion and drugs.1-5,7-12,13,18,19 Additionally, students who have experienced The harassment and humiliation of medical students is being this type of humiliation have lower self-esteem and confidence in increasingly recognised as an issue rather than accepted as a rite of their clinical abilities.1-3,5,8,11,13 Being humiliated can translate into passage. The justifications by perpetrators for mistreatment during medical errors, because students either do not want to disagree training are severely outweighed by its negative consequences on with their superiors when it comes to treatment plans, or students’ and patients’ well-being. develop decreased empathy and compassion due to burnout and Contrary to the beliefs of some perpetrators, medical students do not desensitisation.1-3,5,8,11,18 One study examining physician behaviour in need to ‘toughen up’ and submit to a cycle of condescension in order an emergency department found that 71% of medical errors were to become competent doctors. Instead, deep systemic change is due to poor communication and collaboration.19 Ironically, the required to foster safe, positive learning environments that respect presence and persistence of this negative learning environment are and support trainees. Ultimately, this will allow patients to receive a accepted in a profession that advocates for considerate, empathic, higher standard of care by supporting and promoting the and respectful behaviour towards others. fundamental tenets of medicine.

References

1. Green WM, Durbin JM, Prior IC. Investigating the prevalence and impact 10. Frank E, Carrera JS, Stratton T, Bickel J, Nora LM. Experiences of belittlement

of incivility in medical schools: a review of the literature. Conference: and harassment and their correlates among medical students in the United

Adult Education Research 2019. [Internet]. Available from: States: longitudinal survey. BMJ. 2006;333(7570):682.

https://www.researchgate.net/publication/333641547_Investigating_the_preva 11. Timm A. ‘It would not be tolerated in any other profession except medicine’:

lence_and_impact_of_incivility_in_medical_schools_A_review_of_the_literature. survey reporting on undergraduates’ exposure to bullying and harassment in

2. Scott KM, Caldwell PH, Barnes EH, Barrett J. “Teaching by humiliation” and their first placement year. BMJ Open. 2014;4(7):e005140.

mistreatment of medical students in clinical rotations: a pilot study. Med J Aust. 12. Szubert AK, Gibberd A, Buisson E, Hooker C, Ivory K. Mistreatment in

2015;203(4):185e.1-6. Australian medical education: a student-led scoping of experiences. Australian

3. Seabrook M. Intimidation in medical education: students’ and teachers’ Medical Student Journal 2018.

perspectives. Studies in Higher Education. 2004;29(1):59-74. 13. Musselman LJ, MacRae HM, Reznick RK, Lingard LA. ‘You learn better under

4. Wilkinson, TJ, Gill DJ, Fitzjohn J, Palmer CL, Mulder RT. The impact on students the gun’: intimidation and harassment in surgical education. Med Educ. 2005;39(9):926-34. of adverse experiences during medical school. Med Teach. 2006;28(2):129-35. 14. Bandura A. Social Learning Theory. Englewood Cliffs, NJ: Prentice Hall, 1977. 5. Leisy HB, Ahmad M. Altering workplace attitudes for resident education 15. Burford B. Group processes in medical education: learning from social identity (A.W.A.R.E.): discovering solutions for medical resident bullying through theory. Med Educ. 2012;46(2):143-52. literature review. BMC Med Educ. 2016;127(16):1-10. 16. Bloom SW. The medical school as a social organization: the source of 6. Lau MW, Li WE, Llewellyn A, Cyna AM. Prevalence and associations of resistance to change. Med Educ. 1989;23(3):228-41. psychological distress in Australian junior medical officers. Intern Med J. 17. Lazarus JL, Hosseini M, Kamangar F, Levien DH, Rowland PA, Kowdley GC et 2017;47(10):1190-6. al. Verbal aggressiveness among physicians and trainees. J Surg Educ. 7. Ahmer S, Yousafzai AW, Bhutto N, Alam S, Sarangzai AK, Iqbal A. Bullying of 2016;73(4):756-60. medical students in Pakistan: a cross-sectional questionnaire survey. PLoS One. 18. Haglund MEM, aan het Rot M, Cooper NS, Nestadt PS, Muller D, Southwick 2008;12(3):e3889. SM et al. Resilience in the third year of medical school: a prospective study of 8. Fried JM, Vermillion M, Parker NH, Uijtdehaage S. Eradicating medical student the associations between stressful events occurring during clinical rotations mistreatment: a longitudinal study of one institution’s efforts. Acad Med. and student well-being. Acad Med. 2009;84(2):258-68. 2012;87(9):1191-8. 19. Klingber K, Gadelhak K, Jegerlehner SN, Brown AD, Exadaktylos AK, Srivastava 9. AlMulhim AA, Nasir M, AlThukair A, AlNasser M, Pikard J, Ahmer S et al. Bullying DS. Bad manners in the emergency department: incivility among doctors. among medical and nonmedical students at a university in Eastern Saudi PLoS One. 2018;13(3):e0194933. Arabia. J Family Community Med. 2018;25(3):211-6.

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The story of

narrative medicine BRIAN LI discusses how narrative medicine can improve both patient care and physician well-being.

Introduction Narrative medicine was first introduced in the 1980s by Dr Arthur narrative-based therapies to patients themselves, or to indirectly Kleinman, a medical anthropology professor at Harvard University, improve patient care by developing physicians’ soft skills. Narrative who proposed that in the management of the chronically ill, there medicine humanises the clinical process and draws from the art of was value in understanding the patient’s story of their illness.1 The medicine, without minimising the importance of empirical, modern definition, established in 2014 by a committee of evidence-based science.3 international experts in narrative medicine, states that narrative medicine is both a tool to comprehend and integrate the different Narrative medicine in practice perspectives of all participants in the illness experience, and a clinical Two anecdotes may be helpful in highlighting ways in which a intervention based on a communicative competence.2 In other words, narrative medicine approach can enhance the patient-doctor narrative medicine aims to directly improve care by offering various interaction, offering greater insight into patients’ disease experience

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Columbia University, wrote about a middle-aged patient with a long history of hospitalisations due to uncontrolled diabetes.5 After allowing the patient to freely vent about her illness, her unhelpful doctors, and her lost livelihood, the patient then disclosed what she really wanted: a new set of dentures (her diabetes had caused severe gum disease, which led to significant tooth loss). Three months later, after writing letters to Medicaid and calling in favours from dental clinics, Dr Charon met the patient again, who returned in high spirits. Typically, a physician would have simply focused on the patient’s uncontrolled glucose levels. In this situation, Dr Charon recognised that it was only through re-establishing the patient’s confidence and sense of self – in this case, restoring the patient’s smile – that a path towards healing was most likely.

By simply listening, Dr Divinsky discovered the root cause of her patient’s habit, allowing her to offer supportive counselling aimed at the patient’s social circumstances rather than solely focusing on medically to better aid management planning. Dr Miriam Divinsky, a treating her addiction. Canadian family physician, describes how exercising silence during a consultation allowed her to learn the true underlying cause of her Narrative medicine in physician training patient’s extensive chainsmoking: not merely a physical addiction, A narrative-based approach to medicine begins with developing but rather loneliness.4 the foundational clinical skills and attitudes taught to all medical The patient described smoking as one of her best friends, and that trainees: from gaining a biopsychosocial understanding of the while quitting might be an achievement, it would also feel like whole patient, to building rapport and allowing patients ample a loss. opportunity to describe their disease experience. Evidence has shown that the simple act of using open-ended questions at the A systematic review conducted on the start of a consultation can significantly increase patient effects of reflection on health satisfaction.6 professional education and practice This satisfaction has been shown to be associated with highlighted its utility in helping improvements in physical functioning, adherence to management plans, and fewer malpractice litigations.7-9 Narrative medicine, of healthcare providers to understand course, does not hold ownership of open-ended questioning or and learn from situations, most many other established techniques. Rather, it develops our often those that are complex. appreciation for these processes, which can heighten our clinical intuition about what to do with the open-ended answers that By simply listening, Dr Divinsky discovered the root cause of her we receive.5 patient’s habit, allowing her to offer supportive counselling aimed at the patient’s social circumstances rather than solely focusing on Honing clinical skills medically treating her addiction. The key to developing a narrative-based approach to clinical Dr Rita Charon, a physician, professor, and literary scholar from medicine first lies in exercising effective communication skills,

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INITIATING THE SESSION

Preparation

Establishing initial rapport

Identifying the reason(s) for the consultation

Providing Building the Structure GATHERING INFORMATION relationship

Making Exploration of the patient’s problem to discover: Using organisation appropriate ■ ■ overt Biomedical perspective The patient’s perspective non-verbal ■ Background information – context behaviour Attending to Developing flow rapport PHYSICAL EXAMINATION Involving the patient EXPLANATION AND PLANNING

Providing the correct amount and type of information

Aiding accurate recall and understanding

Achieving a shared understanding: incorporating the patient’s illness framework

Planning: Shared decision making

CLOSING THE SESSION

Ensuring appropriate point of closure

Forward planning

FIGURE 1: Calgary-Cambridge Communication Skills Guideline.19

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which is easier said than done, considering how complex the patients (Table 2).14,18,19 Almost all models share the common patient-doctor interaction can be. Physicians must be well thread of active listening, which is one of the most important skills acquainted with a litany of verbal and non-verbal abilities that can of narrative-based medicine. easily be forgotten or undervalued, but are essential to building rapport with patients. These abilites include, but are not limited to, Encouraging reflective practice active listening, appropriate eye contact, quality of information There are many broad definitions of ‘reflection’ found in the given, language, and empathy.10,11 It is unsurprising to hear reports literature, but most emphasise a purposeful appraisal of one’s and of patients still complaining about doctors who seem uninterested others’ knowledge and experience, in order to derive greater and unable to address their concerns, while physicians counter meaning and understanding.20,21 Reflective practice is often cited with complaints of difficult patients and the pressures of managing as an important part of developing professional competence that their practice.12 can improve empathy, emotional self-awareness, and understanding of past clinical interactions.21 This is not limited to Almost all models share the common students; many medical institutions now include reflective practice thread of active listening, which is one as part of the physician licensing and revalidation processes.22,23 of the most important skills of A systematic review conducted on the effects of reflection on narrative-based medicine. health professional education and practice highlighted its utility in helping healthcare providers to understand and learn from

There is no shortage of evidence-based models and guidelines situations, most often those that are complex.21 Due to the nature focusing on developing clinical communication skills.13-16 Many of reflection, it is difficult to ascertain true improvements in aspects guides provide step-by-step instructions from the initial patient such as self-understanding or professional practice, since most data greeting to the conclusion of the interview (Figure 1), do not go beyond self-reports. Research on the effects of reflective supplementing each section with clinical techniques and practice is relatively new; most studies have been qualitative and recommendations.10,13,17 One guide delineates seven guiding have contributed to developing theoretical models.21 Creative principles for a narrative-based approach to medicine (Table 1) writing classes and reflective writing are two different methods and includes specific phrases to be used when interviewing that have been hypothesised to facilitate the development of

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Table 1: An outline of Launer’s 7 principles or the 7 Cs.14

Launer’s 7 principles

Conversations Allowing patients to express their story fully without judgement or interference, but facilitating the conversation in a way that is most conducive to understanding

Curiosity Having a genuine interest while being aware of one’s emotional reactions to patients’ stories

Context Exploring the reason behind why the patient is presenting their problem at that moment in the context of family, work, community, spirituality, beliefs, values, and personal expectations

Complexity Having an awareness of the intricacies of patients’ lives and their health so as not to be fixated on singular solutions to problems

Challenge Being willing to challenge patients and oneself with new ideas and new management plans

Caution Being aware of one’s limitations and being understanding of patients’ needs and their ability to cope with change

Care Being non-judgmental and accepting of patients

Table 2: Exploratory phrases and questions.18

Exploratory Inviting change

Tell me about it How else might you explain…?

Tell me more Suppose...

What is worrying you most? Are there any other possibilities?

What does this mean for you? What needs to happen to change the situation?

What do you think might be causing…? If the situation changed, what would happen?

How would you describe…? What will happen if nothing changes?

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Other narrative-based approaches have demonstrated improvement in psychological symptoms such as depression, but also in more complex areas of psychosocial burden, such as a sense of life purpose, a sense of well-being, or a feeling of suffering.

reflective skills.24,25 Classes allow for the exchange of ideas in an patients when applied as a clinical intervention.30 These environment where participants are encouraged to think broadly.24 interventions, which borrow techniques from psychotherapy, are Reflective writing, which is notably different from creative writing, centred around forms of artistic expression such as writing, is more targeted to the writer’s specific experiences.25 Although speaking, or applied theatre.2 These techniques provide patients there are no ‘ground rules’ for reflective writing, it typically with different platforms through which to share the story of their involves examining the thoughts, feelings, reactions, and questions illness; they can give healthcare providers more knowledge of that arose from an encounter.17 Reflection, in the context of patients’ symptomatology, but can also be therapeutic in and narrative medicine, goes beyond just recall, review, and analysis, of themselves.2,21 and is more focused on the interpretation of lived events.26 A systematic review was conducted on randomised controlled trials investigating the effects of expressive writing (EW) as an Consuming literature intervention on the health outcomes of patients with breast Reading and analysis of literature, both medical and non-medical, cancer.31 Researchers found that patients with breast cancer who has also been proposed as a powerful way to learn narrative engaged in EW experienced a significant improvement in physical skills.17,27 Much like literary texts, patient stories can either be symptoms, although these effects were only observed within a straightforward or complex. They encourage us to be open to new three month follow-up. Similar to this study, a meta-analysis of ideas and possibilities, while ultimately pursuing the goal of experimental studies on clinical populations demonstrated that EW heightened understanding, particularly with regard to stories was associated with significant relief of physical rather about relationships and human nature.17 The application of literary than psychological symptoms (p<0.05).32 One randomised analysis in the field of medicine is not so dissimilar to history, law, controlled trial investigated the effects of storytelling on health and other humanities; there is simply less recognition for the promotion and found that the experimental group, patients with interpretive and more emphasis on empirical science.28 Consuming baseline uncontrolled hypertension, experienced significantly literature can also be therapeutic for medical students reduced systolic and diastolic blood pressures after three and physicians, providing catharsis, personal insights, and a months (p=0.012).33 vehicle for reflection.29 These results are surprising since these techniques, which stem from the field of psychiatry and are intended for psychological Narrative medicine as a therapeutic intervention symptom management, appeared to mitigate physical symptoms Narrative medicine has been shown to have therapeutic effects on in non-psychiatric patients.

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Other narrative-based approaches have demonstrated patients’ health. Specifically, it was noted that narrative-based improvement in psychological symptoms such as depression, but therapies helped patients to manage their pain, improve their also in more complex areas of psychosocial burden, such as sense sense of well-being, and improve communication with their family of life purpose, sense of well-being, or feeling of suffering. members. Despite the current shortage of robust scientific studies Dignity therapy, an evidence-based and clinically effective on narrative-based approaches, it is difficult to dismiss the psychotherapeutic technique, was studied in 100 end-of-life potential benefits patients may experience. Researchers are patients in Canada and Australia over a two-year period.34 This encouraged to use interventions that are built upon existing type of intervention offers patients an opportunity to openly reflect narrative medicine frameworks and develop standardised protocols on issues that matter most to them and discuss aspects of their in future studies to achieve the highest quality of evidence. lives that they cherish the most. A test-retest analysis demonstrated that patients who engaged in Sometimes, medicine does not have dignity therapy experienced a significantly improved sense of an answer, and all we as healthcare purpose, an increased will to live, and reduced depressive providers have left to offer our patients 34 symptoms (p<0.05). is a kind reminder that they have Although there is now more discussion on narrative medicine, the been listened to, that they are number of studies investigating its clinical benefits is still relatively important, and that they are sparse. The majority of published literature on this topic consists largely of theoretical articles, editorials, and reviews.2 In order to not alone. bridge the gap between theory and evidence-based practice, there is a need to demonstrate the clinical benefits of narrative-based Conclusion therapies in robust, experimental studies. Fioretti et al. conducted There is certainly room for, if not a need for, narrative-based a systematic review on the scientific value of narrative medicine’s medicine in the field of healthcare. The ideals of narrative medicine role in patients’ and/or their caregivers’ experiences with disease.2 can provide guidance for improving physicians’ clinical skills, In all ten studies included in the review, with interventions ranging attitudes, and well-being, and can also be implemented as an from writing, storytelling, and drawing therapy to applied theatre, intervention for patients through artistic pursuits. It would be a narrative-based approach was found to be beneficial to both unreasonable to deny the absolute importance of data, logical delivering patient-centred care and directly improving aspects of reasoning, and biomedical knowledge. However, it is equally

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unwise to reduce the field of healthcare to just symptom providers have left to offer our patients is a kind reminder that they management and identification of disease processes. Sometimes, have been listened to, that they are important, and that they are medicine does not have an answer, and all we as healthcare not alone.

References 1. Kleinman, A. Illness Narratives: Suffering, Healing and the Human Condition. 18. Zaharias G. Narrative-based medicine and the general practice consultation:

New York, USA: Basic Books, 1988. Narrative-based medicine 2. Can Fam Physician. 2018;64(4):286-90.

2. Fioretti C, Mazzocco K, Riva S, Oliveri S, Masiero M, Pravettoni G. Research 19. Launer J. Narrative-based Primary Care: a practical guide. CRC Press, 2017.

studies on patients’ illness experience using the narrative medicine approach: a 20. Aukes LC, Geertsma J, Cohen-Schotanus J, Zwierstra RP, Slaets JP. The

systematic review. BMJ Open. 2016;6(7):e011220. development of a scale to measure personal reflection in medical practice and

3. Greenhalgh T. Narrative based medicine: narrative based medicine in an education. Med Teach. 2007;29(2-3):177-82.

evidence based world. BMJ. 1999;318(7179):323-5. 21. Mann K, Gordon J, MacLeod A. Reflection and reflective practice in health

4. Divinsky M. Stories for life: introduction to narrative medicine. Canadian Family professions education: a systematic review. Adv Health Sci Educ Theory Pract.

Physician. 2007;53(2):203-5. 2009;14(4):595-621.

5. Charon R, Marcus ER. The Principles and Practice of Narrative Medicine. Oxford 22. Catto G. GMC and the future of revalidation: building on the GMC’s

University Press, 2017. achievements. BMJ. 2005;330(7503):1293.

6. Robinson JD, Heritage J. Physicians’ opening questions and patients’ 23. College of Family Physicians of Canada. Eligibility requirements and general

satisfaction. Patient Educ Couns. 2006;60(3):279-85. information. 2007. [Internet]. [Retrieved October]. Available from:

7. Langer EJ, Janis IL, Wolfer JA. Reduction of psychological stress in surgical https://www.cfpc.ca/eligibility/.

patients. Journal of Experimental Social Psychology. 1975;11(2):155-65. 24. Koppe H. A road to humanity. Aust Fam Physician. 2008;37(7):563-5.

8. Kaplan SH, Greenfield S, Ware JE. Impact of the doctor-patient relationship on 25. Hatton N, Smith D. Reflection in teacher education: towards definition and

the outcomes of chronic disease. Communicating with Medical Patients. implementation. Teaching and Teacher Education. 1995;11(1):33-49.

1989:228-45. 26. Murphy JW, Franz BA, Schlaerth C. The role of reflection in narrative medicine.

9. Frankel RM. Emotion and the physician-patient relationship. Motivation and J Med Educ Curric Dev. 2018;5:2382120518785301.

Emotion. 1995;19(3):163-73. 27. Charon R. Narrative Medicine: Honoring the Stories of Illness. Oxford University

10. Kurtz, S., Silverman, J., Benson, J. and Draper, J. Marrying content and process Press, 2008.

in clinical method teaching: enhancing the Calgary-Cambridge guides. Acad 28. Hunter K. “Don’t think zebras”: Uncertainty, interpretation, and the place of

Med. 2001;78(8):802-9. paradox in clinical education. Theor Med. 1996;17(3):225-41.

11. Kee JW, Khoo HS, Lim I, Koh MY. Communication skills in patient-doctor 29. Stone J. In the Country of Hearts: Journeys in the Art of Medicine:[Excerpt].

interactions: learning from patient complaints. Health Professions Education. Acad Med. 2016;91(4):510.

2018;4(2):97-106. 30. Morris DB. Narrative medicines: challenge and resistance. Perm J. 2008;12:88-96.

12. Tallis RC. Hippocratic oaths: medicine and its discontents. Clin Med (Lond). 31. Zhou C, Wu Y, An S, Li X. Effect of expressive writing intervention on health

2005;5(2):186. outcomes in breast cancer patients: a systematic review and meta-analysis of

13. Silverman J, Kurtz S, Draper J. Skills for Communicating with Patients. CRC randomized controlled trials. PloS One. 2015;10(7):e0131802.

Press, 2016. 32. Frisina PG, Borod JC, Lepore SJ. A meta-analysis of the effects of written

14. Launer J. Narrative-Based Primary Care: a practical guide. Abington, UK: emotional disclosure on the health outcomes of clinical populations. J Nerv

Radcliffe Medical Press, 2002. Ment Dis. 2004;192(9):629-34.

15. Brown RF, Bylund CL. Communication skills training: describing a new 33. Houston TK, Allison JJ, Sussman M, Horn W, Holt CL, Trobaugh J et al. Culturally

conceptual model. Acad Med. 2008;83(1):37-44. appropriate storytelling to improve blood pressure: a randomized trial. Ann

16. Zaharias G. What is narrative-based medicine? Narrative-based medicine 1. Can Intern Med. 2011;154(2):77-84.

Fam Physician. 2018 Mar 1;64(3):176-80. 34. Chochinov HM, Hack T, Hassard T, Kristjanson LJ, McClement S, Harlos M.

17. Zaharias G. Learning narrative-based medicine skills: Narrative-based medicine Dignity therapy: a novel psychotherapeutic intervention for patients near the

3. Canadian Family Physician. 2018;64(3):176-80. end of life. J Clin Oncol. 2005;23(24):5520-5.

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Gender identity and stigma

EMILY HUTCHINGS looks at the impact of stigma on quality of life and healthcare in the transgender population.

Introduction The transgender community is heavily marginalised, with barriers to care.2 To improve healthcare delivery to transgender individuals facing stigmatisation and discrimination in social and individuals, it is crucial to understand the challenges they face healthcare settings. The violence and psychological harm when accessing healthcare, and the role that healthcare experienced by transgender people severely impacts on their professionals have in breaking down these barriers. quality of life, and is a direct breach of fundamental human rights. The WHO’s universal health coverage Twenty-five million people, approximately 0.5% of the world’s goals for 2030 address improving population, identify as being transgender.1 The World Health health equity, which should ideally Organisation (WHO) defines universal health coverage as “ensuring that all people have access to needed health services”, include access to gender but globally, members of the LGBTQ+ community face significant affirmation therapies.

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The most significant predictor of positive mental health in transgender youth is family connectedness; those with greater social support have more favourable mental health outcomes. Implementing programmes to promote safe and supportive communities for transgender people is imperative.

Unique healthcare needs of the transgender These guidelines, last updated in 2012, include information on population available hormonal and surgical gender affirmation treatments, as A transgender individual is defined as someone whose biological or well as psychological support and care for paediatric patients with assigned sex does not match their experienced gender.3 The WHO gender incongruence.8 International Classification of Disease revision 11 renamed gender Social, psychological, and behavioural counselling are extremely identity disorder and transsexualism to gender incongruence in important in supporting these patients, and should be included as 2019.4 It now classifies gender incongruence as a sexual health part of gender-affirming care.9 disorder, representing a shift away from what was previously Despite the existence of such guidelines, evidence suggests that considered a psychological diagnosis.5 physicians are not appropriately applying them to benefit their The new diagnostic criteria aim to provide transgender individuals transgender patients. with greater access to gender-affirming treatments, including A survey conducted in Ireland found that 58 out of 64 general hormonal therapy, surgery, and psychological counselling services. practitioners (GPs) who participated in the study did not follow The WHO’s universal health coverage goals for 2030 address any guidelines for LGBTQ+ care, with some GPs even stating that improving health equity, which should ideally include access to the practice guidelines were unnecessary.10 gender affirmation therapies.6 Physicians need to ensure that they are providing optimal care to The transgender population has been identified to be at increased their transgender patients. This can be achieved, in part, by being risk of substance abuse, mental health disorders, sexually aware of and following established guidelines. transmitted infections (STI), and physical and psychological The healthcare needs of transgender individuals differ from those violence.7 Therefore, healthcare professionals should ensure that of the general population. Increased health risks to transgender special considerations are made when delivering standard care patients are multifactorial, relating to behavioural patterns, social practices to transgender patients. This may include increased determinants of health, stigma, and poor healthcare access.7,11,12 attention to and frequency of mental health assessments, Increasing patient access to gender-affirming therapies, screening for STIs and violence, and assessing the patient’s transgender counselling services and opportunistic screening, and available social supports and barriers to care. care that follows transgender guidelines, may help to address The World Professional Association for Transgender Health has health risks and support equitable health access and support for created reference guidelines outlining the gold standards of care.8 transgender patients.

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Stigma and discrimination: their effects on mental a negative healthcare experience, and 69% specifically had a health negative healthcare experience in gender identity clinics. These The stigma faced by transgender individuals can be debilitating negative encounters included inappropriate responses, inadequate and can significantly affect quality of life.7 Someone who is training and knowledge, and unclear treatment paths provided by transgender is more likely to suffer from abuse, discrimination, and physicians. This affirms the need for increased awareness among violence.7 Difficulty obtaining employment secondary to health practitioners of the importance of non-discriminatory discrimination has been linked to transgender individuals being care and gender-affirming care pathways for transgender people more likely to engage in commercial sex work.5 The Human Rights in Ireland. Campaign Foundation reported 26 violence-related deaths among A paediatric study conducted in the US found that over 30% of transgender persons in the United States, and over 60 transgender adolescents reported having attempted suicide, a rate violence-related transgender deaths in Pakistan in 2018.11 They four times greater than the general youth population.14 By also reported that 84% of transgender youth have felt unsafe in US adulthood, 52% of American transgender individuals will have schools, and over 30% of transgender employees reported being attempted suicide.15 The Irish Health Service Executive (HSE) denied equal opportunity in the workplace due to their gender identified isolation, family rejection, violence, and stigma as identity in the US.11 contributors to depression, anxiety, substance abuse, self-harm, and suicide in the transgender population.16 The most significant A paediatric study conducted in the US predictor of positive mental health in transgender youth is family found that over 30% of transgender connectedness; those with greater social support have more adolescents reported having attempted favourable mental health outcomes.17 Implementing programmes suicide, a rate four times greater than to promote safe and supportive communities for transgender people is imperative. the general youth population.

Effect of stigma on access to healthcare In 2013, Transgender Equality Network Ireland (TENI) evaluated Healthcare providers have unfortunately contributed to the the mental health and well-being of 164 transgender people in stigmatisation, discrimination, and health inequality faced by Ireland.13 They reported that 74% of transgender people have had transgender populations.2 The “heteronormative attitude of

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care by their practitioner, or had to educate their own care provider on appropriate care.19 Discrimination in the form of harassment or refusal of care due to an individual’s sexual identity is both a violation of human rights, and a violation of justice under the Hippocratic Oath.20

Role of healthcare professionals in improving quality of life for transgender patients Breaking down the barriers experienced by transgender patients plays a significant role in improving quality of life and access to healthcare. As patient advocates, physicians have a fundamental role to play in both identifying and eliminating these barriers.12 Lack of education among healthcare practitioners can result in a poorer quality of care, as well as increased discrimination against transgender patients.13 Ireland has acknowledged a crucial need to change the approach to transgender care throughout the country. In 2015, a systematic review was carried out by the HSE identifying the need to further healthcare providers” has been shown to impact the LGBTQ+ explore the specific healthcare requirements of transgender population’s access to safe and ethical care.2 Lack of education, patients.10 In 2019, the HSE partnered with TENI to implement an confounded by a cultural, moral, and institutional ‘transphobia’ intensive training programme aimed at developing physicians’ may explain some of the barriers to appropriate transgender skills in providing care for transgender individuals and their care.12 For example, transgender patients are less likely to access communities.21 healthcare screening such as cervical checks, breast screening, and Currently, there is no formal training on transgender care for other preventive and routine testing.12 In addition, these patients medical students in Ireland, and thus the European Medical often postpone seeking medical care, compared to the general Students’ Association is now advocating for gender education to population.12 Transgender patients also frequently choose not to be included in medical school curriculums. Education on disclose their gender identity to their physician due to a fear of transgender health, especially during medical training, can discrimination.12 Surveys conducted in the US found that 22% of improve the knowledge, skills, and attitudes of physicians transgender adults avoid seeking healthcare due to anticipated providing care to transgender patients.13,22 These interventions discrimination.18 must address medical care needs, social determinants of health, and cultural awareness in relation to transgender care. Improved Lack of education among healthcare clinical education would help to ensure that transgender patients practitioners can result in a receive equitable access to culturally competent care with respect poorer quality of care, as well as and dignity, in safe environments. increased discrimination against Conclusion transgender patients. The marginalisation, stigmatisation, and discrimination faced by transgender people results in violence, psychological harm, In 2015, the National Centre for Transgender Equity (NCTE) in the inadequate access to health services, and overall poorer quality of US conducted a survey of 28,000 transgender patients and life. This must change. To provide universal health coverage as identified that 9% of respondents had been directly refused care outlined by the WHO, the quality of healthcare received by the for routine or gender-related issues by a healthcare provider due to transgender population needs to improve significantly. Educational their identification as transgender.19 Some 33% of respondents had programmes on the healthcare needs of transgender individuals been verbally harassed, physically or sexually assaulted, refused aimed at healthcare providers, and improved psychological and

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social supports for transgender patients, will improve access to with freedom from discrimination. De-stigmatisation, through care and lessen the degree of stigma faced by transgender people. education and advocacy, would not only be a meaningful step Receiving culturally competent care, regardless of gender identity, towards addressing the human rights and healthcare needs of should be considered a human right, and must go hand in hand transgender people, but is fundamentally a necessary step.

References

[Internet]. Available from: https://assets2.hrc.org/files/assets/resources 1. World Health Organization. Growing recognition of transgender health. /2018AntiTransViolenceReportSHORTENED.pdf. Bulletin of the World Health Organization. 2016;94(11):790-1. 12. Cruz T. Assessing access to care for transgender and gender nonconforming 2. World Health Organization. Universal health coverage. 2020. [Internet]. [cited people: a consideration of diversity in combating discrimination. Soc Sci Med. 2020 January 6]. Available from: https://www.who.int/health-topics/universal- 2014;110:65-73. health-coverage#tab=tab_1. 13. Dubin SN, Nolan IT, Streed CG, Jr., Greene RE, Radix AE, Morrison SD. 3. Merriam-Webster. Definition of transgender. 2020. [Internet]. [cited 2020 Transgender health care: improving medical students’ and residents’ training January 16]. Available from: https://www.merriam-webster.com/dictionary and awareness. Adv Med Educ Pract. 2018;9:377-91. /transgender. 14. McNeil J, Bailey L, Ellis S, Regan M. Speaking from the margins: trans mental 4. World Health Organization. WHO/Europe brief – transgender health in the health and well-being in Ireland. 2015. [Internet]. Available from: context of ICD-11. 2020 [Internet]. [cited 2020 January 6]. Available from: https://www.researchgate.net/publication/281453128_Speaking_from_the_m http://www.euro.who.int/en/health-topics/health-determinants/gender/gende argins_Trans_mental_health_and_well-being_in_Ireland. r-definitions/whoeurope-brief-transgender-health-in-the-context-of-icd-11. 15. Olson J, Schrager S, Belzer M, Simons L, Clark L. Baseline physiologic and 5. World Health Organization. Moving one step closer to better health and rights psychosocial characteristics of transgender youth seeking care for gender for transgender people. 2020 [Internet]. [cited 2020 January 6]. Available from: dysphoria. J Adolesc Health. 2015;57(4):374-80. http://www.euro.who.int/en/health-topics/health-determinants/gender/news/ 16. Toomey R, Syvertsen A, Shramko M. Transgender adolescent suicide behavior. news/2019/5/moving-one-step-closer-to-better-health-and-rights-for-transgen Pediatrics. 2018;142(4):e20174218. der-people. 17. Health Service Executive Ireland. LGBT health: towards meeting the health care 6. Thomas R, Pega F, Khosla R, Verster A, Hana T, Say L. Ensuring an inclusive needs of lesbian, gay, bisexual and transgender people. 2019. [Internet]. global health agenda for transgender people. Bulletin of the World Health Available from: https://www.hse.ie/eng/services/publications/topics/sexual Organization. 2017;95(2):154-6. /lgbt-health.pdf. 7. Winter S, Diamond M, Green J, Karasic D, Reed T, Whittle S et al. Transgender 18. Casey L, Reisner S, Findling M, Blendon R, Benson J, Sayde J et al. Discrimination people: health at the margins of society. Lancet. 2016;388(10042):390-400. in the United States: experiences of lesbian, gay, bisexual, transgender, and 8. Coleman E, Bockting W, Botzer M, Cohen-Kettenis P, DeCuypere G, Feldman J queer Americans. Health Services Research. 2019;54(S2):1454-66. et al. Standards of care for the health of transsexual, transgender, and 19. James SE, Herman JL, Rankin S, Keisling M, Mottet L, Anafi M. The Report of the gender-nonconforming people. World Professional Association for Transgender 2015 U.S. Transgender Survey. Washington, DC: National Center for Health, Minneapolis, Minn. 2012. [Internet]. Available from: Transgender Equality. 2016. https://www.wpath.org/publications/soc. 20. International Justice Resource Center. Sexual orientation & gender identity. 9. United Nations. Ending violence and discrimination against lesbian, gay, [Internet]. [cited 2020 January 6]. Available from: https://ijrcenter.org bisexual, transgender and intersex people. Geneva, 2015. [Internet]. Available /thematic-research-guides/sexual-orientation-gender-identity/. from: https://www.unicef.org/media/files/Joint_LGBTI_Statement_ENG.pdf. 21. Transgender Equality Network Ireland. Harris S. GIST Training 2019. 2020. 10. Crowley N; HSE. The rainbow report: LGBTI health needs and experiences and [Internet]. [cited 2020 January 6]. Available from: https://www.teni.ie/ health sector responses and practices in the HSE South East Region. 2015. gist-training-2019/. [Internet]. Available from: https://www.lenus.ie/bitstream/handle 22. Pelzer B, Montvidas J, Rensen L. Health-care access of transgender people: a /10147/575304/rainbowreport.pdf?sequence=1&isAllowed=y. medical student approach. Lancet Diabetes Endocrinol. 2016;4(5):388-9. 11. Human Rights Campaign Foundation. Dismantling a culture of violence 2019.

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3D in vitro collagen-based scaffold platform to study neuroblastoma growth and migration

Sanat Rashinkar RCSI medical student

Introduction Results Three-dimensional (3D) collagen-based scaffolds are bridging the gap Both neuroblastoma cell lines – SH-SY5Y and IMR-32 – actively between traditional 2D in vitro cell models and in vivo tumours. 3D infiltrated into the Coll-HyA and Coll-nHA scaffolds, but not the models can be designed to mimic the physiological conditions that Coll-Chon scaffolds, as demonstrated by histological examination partially represent a solid tumour microenvironment.1 and DNA quantification (Figure 3). A major challenge in the drug development pipeline for When quantifying double-stranded DNA (dsDNA) for the IMR 32 neuroblastoma, a paediatric cancer arising from the sympathetic cell line, the amount of dsDNA nearly tripled by day 28 when nervous system, is to accurately represent tumour geometry and compared with day 1 for all three types of scaffolds. A similar trend heterogeneity in in vitro experimental models.1 The aim of this study was observed for the SH-SY5Y cell line. was to characterise neuroblastoma cell growth, migration, and colonisation in 3D in vitro models using collagen-based scaffolds that Discussion model tumour geometry. Collectively, the data demonstrate that collagen-based scaffolds can be successfully used to model neuroblastoma tumour growth, Methods and that there is a direct correlation between total DNA content Neuroblastoma cell line IMR 32 was plated onto three collagen-based and neuroblastoma cell growth and proliferation. scaffolds – hyaluronic acid (Coll-HyA), nanohydroxyapatite The results give important insights into how 3D models can be (Coll-nHA), or chondroitin (Coll-Chon) – each mimicking primary and designed to replicate the physiological conditions that partially bone microenvironments. Cells grown on scaffolds were formalin mimic neuroblastoma tumour microenvironment and determine fixed and paraffin embedded. They were then cut into 10µm sections its growth and migration patterns in different microenvironments. using a microtome, stained with haematoxylin and eosin (H&E), and This suggests that 3D collagen scaffolds can be useful in the study examined using bright-field microscopy (Figure 1). and profiling of neuroblastoma, which may have future Cell proliferation and growth were assessed using the PicoGreen assay implications in clinical settings and drug development. Although for the IMR 32 cell line and compared to the results for neuroblastoma was the focus of this project, this 3D model can be the SH-SY5Y cell line obtained from a previous research project applied to other malignancies. (Figure 2).

FIGURE 1: H&E visualisation of neuroblastoma cell line SH-SY5Y.

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Acknowledgments This project is funded and supported by the Royal College of Children’s Research Centre, Science Foundation Ireland, and Surgeons in Ireland Research Summer School 2019, the National Neuroblastoma UK Fighting Childhood Cancer.

Fig 3A IMR 32 Nano-hydroxyapatite scaffolds

400 350 300 329 250 200 234 150 153 148 100

50 59

dsDNA concentration (ng/ml) 0 Day 1 Day 7 Day 14 Day 21 Day 28 Time in days

Fig 3B IMR 32 GAG chondroitin scaffolds

500 450 400 400 350 300 250 274 200 198 150 174 100 50 83

dsDNA concentration (ng/ml) 0 Day 1 Day 7 Day 14 Day 21 Day 28 Time in days

Fig 3C IMR 32 hyaluronic scaffolds

250

200 194 150 165 147 133 100

50 47

dsDNA concentration (ng/ml) 0 Day 1 Day 7 Day 14 Day 21 Day 28 Time in days

FIGURE 2: H&E visualisation of neuroblastoma cell line IMR-32. FIGURE 3: DNA quantification of IMR 32 cells grown in 3D.

Reference 1. Curtin C, Nolan JC, Conlon R, Deneweth L, Gallagher C, Tan YJ et al. A system exhibits chemosensitivity similar to orthotopic xenograft models.

physiologically relevant 3D collagen-based scaffold – neuroblastoma cell Acta Biomater. 2018;70:84-97.

Volume 13: Number 1. 2020 | Page 113 RCSIsmj book review

It’s all about soul

In The Soul of a Doctor, Harvard medical students write about the lived experience of medical practice says Senior Staff Writer KATIE NOLAN.

The Soul of a Doctor: Harvard Medical Students Face Life and Death Susan Pories, Sachin H. Jain, Gordon Harper (Eds.)

Paperback: 274 pages Publisher: Algonquin Books Published: 2006 ISBN-13: 978-1565125070

One of the great joys of being a medical student is sharing your Medical students may take comfort from experiences with other medical students. Medicine is a rewarding some of the stories as they demonstrate but tough job, and not only because of the hours poring over that the dilemmas facing students are not endless books and learning aids. new or unique, and every encounter is a One day you are learning new techniques, scrubbing in on exciting chance to learn how to be a better doctor. cases, and helping your team to handle their caseload. The next, you can be overwhelmed by the tragedy of a patient’s illness or the All of the themes of the stories are easily identifiable because similar inevitability of death. themes present themselves regularly to students in all fields of The importance of shared experience cannot be overstated for medicine: patients who are convinced they have one diagnosis and medical students trying to navigate all the new experiences that cannot be persuaded otherwise; the first experience of witnessing come when embarking on a career as a doctor. Colleagues become patients receiving a devastating and life-changing diagnosis; tackling your confidantes, counsellors, and supports through tough and difficult feelings and moral questions in the intensive care unit; or, turbulent times. overcoming cultural or social differences to treat a patient. These are The Soul of a Doctor is shared experience put onto the page. It not miraculous stories about curing people, nor are they triumphant. comprises 44 essays recounting the personal experiences and Rather, they touch on the very real feelings, and the anti-climax, that insights gained in the hospital from 44 Harvard medical students. can occur when navigating medicine and treating patients. Medical These experiences will be familiar to the majority of medical students may take comfort from some of the stories as they students who are meeting patients daily and endeavouring to put demonstrate that the dilemmas facing students are not new or their medical knowledge into practice. The stories are grouped unique, and every encounter is a chance to learn how to be a better under four themes: communication; empathy; easing suffering; doctor. It is a highly relatable read for all medical students and indeed and, finding a better way. for all doctors.

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smj Royal College of Surgeons in Ireland RCSI Student Medical Journal [email protected] [email protected]

www.rcsismj.com. Th!nkMedia