Inside: Targeted treatment for Crohn’s disease Volume 11: Number 1. 2018 ISSN 2009-0838 smj

Royal College of Surgeons in Ireland RCSI Student Medical Journal

Big budget brain projects RCSI DEVELOPING HEALTHCARE LEADERS WHO MAKE A DIFFERENCE WORLDWIDE

Acknowledgements

Thank you to RCSI Alumni for their continued support to 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.

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

A 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 club. We would like to thank the following for their support of, and participation in, the journal club, and to express our appreciation of the time, knowledge and expertise they shared with us:

Dr Nurul Aminudin Prof. Fionnuala Breathnach Dr Frank Doyle Dr Joseph Galvin Prof. Arnold Hill Prof. Samuel McConkey Dr Mark Murphy Mr David O'Brien RCSIsmjcontents

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

Executive Committee RCSI Ethics Challenge Director Jenna Geers 5 RCSIsmj Ethics Challenge 2018/2019 Editor-in-Chief Suzanne Murphy Peer Review Director David Maj 6 RCSIsmj Ethics Challenge winner 2017/2018 Senior Editor Rachel Adilman Assistant Peer Review Cameron Chalker Senior Staff Writer Alexandra Mitcham Research spotlight Executive Secretary Oludare Alabi 10 Spotlight on research at RCSI – Prof. Peter Conlon Webmaster Gemma Wright Ballester Interview Peer Reviewers 11 The generalists Andrew Mikhail Matthew McMurray Alison Hunt Case report Jodie Odame Shaghayegh Esfandnia 14 Diagnostic dilemma: a rare cause of lower back pain Elise Halpern Rachel Dharamshi Original articles Tessa Weinberg Monika Cieslak 19 When the brain goes quiet: cortical silence inhibition in schizophrenia Bunmi Adesanya Magar Ghazarian Review articles Moyowa Boyo David Seligman 24 Plastic surgery’s role in aneuploidy Deena Shah 29 The misnomer of the ‘oral contraceptive pill’ Melvin Hoo Chuin Shen Savannah Norman Nadine Copty Staff reviews Sakshi Kirpalaney 35 Doctors and doping in sport Staff Writers 41 Faking it: disease-fighting bacteria and the future of synthetic biology Katie Nolan 46 From womb to withdrawal: born addicted Julia Hunter Jessica Millar 52 Treatment is on target in Crohn’s disease with biologic agents Sumara Jaimungal 59 Out of Africa into a genetic bottleneck: how evolution has shaped modern disease Maria Mikail 67 Are emerging treatments in Parkinson’s disease curative or just buying time? Education Director Claire Gallibois

Education Officers Perspectives Catherine Uhomoibhi 73 HPV vaccination: facts versus fears Farah Adamali 77 Making the match Sannihita Vatturi 82 Is a robot reading my x-rays? Public Relations Director Matthew Patel 86 Big budget brain projects

Public Relations Officer Melissa Mae Gabriel 91 ‘What’s in a name?’

Book review 95 Fitting in JOURNALISM CONTENT DESIGN

The Malthouse, 537 NCR, Dublin 1. Abstracts T: 01-856 1166 F: 01-856 1169 www.thinkmedia.ie 96 Investigating the impact of enhancer methylation on gene expression in metastatic Design: Tony Byrne, Tom Cullen and Niamh Short colorectal cancer Editorial: Ann-Marie Hardiman, Paul O’Grady and Colm Quinn 98 Implications of stroke for informal caregivers: a five-year follow-up

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 follow our blog.

Volume 11: Number 1. 2018 | Page 3 RCSIsmjeditorial and director’s welcome

Rising to the challenges of research

James Bryce once said: “Medicine [is] the only profession that labors campaign can have on a vaccination programme. Senior staff writer incessantly to destroy the reason for its existence”. Alexandra Mitcham examines the role of doctors in doping in sports, and considers our ethical obligations as healthcare professionals. Medicine is a constantly evolving field, striving to move forward even Finally, Carol Rizkalla looks at how we define illness. Through simple when it can seem impossible. As healthcare professionals we attempt to semantics we could be allowing the development of eugenics as halt the disease process and give our patients an acceptable quality of genome editing fails to clarify certain key research terms. In a world that life. In the 11 years since the RCSIsmj was founded, healthcare has seen is constantly moving, we need to stop and consider if we are all on the changes that seemed unimaginable in 2007. In this issue we consider same page when it comes to the everyday terminology we use. how, despite such major advances, a significant number of conditions Despite the problems and challenges, the failures and the still require greater research in terms of both understanding the disappointments, research will always continue to push forward, trying condition, and the development of safe and effective treatments. passionately to eradicate disease from this world. This RCSIsmj is, for Furthermore, we look at how the amazing advances of science have also most students, their first experience of taking their initial tentative steps led to problems and ethical questions. Staff writer Jessica Millar looks at on the road towards life-changing research. the evolving therapies for Parkinson’s disease, and asks if they truly have a role in the treatment process. Maria Mikail considers the impact of cortical inhibition on patients with schizophrenia. Katie Nolan examines the recent increase in synthetic biologic agents and questions their future role in treating conditions from E. coli infection to HIV. Constantly striving for advancement creates a double-edged sword and there is potential for new treatments to be misunderstood, misused, or even exploited. Social media, something that would never have previously impacted on healthcare, now has the power to ‘make or break’ a health campaign. Laura Staunton looks at the impact of the HPV Suzanne Murphy vaccine on the wider public and reflects on the effect a negative media Editor-in-Chief, RCSIsmj 2017-2018

Director’s welcome

I am delighted and honoured to welcome you to this year’s RCSIsmj. interests in a long view of his research career, and invites students to Over the last 11 years it has been the purpose and pleasure of the boldly move forward according to their own curiosity and drive. RCSIsmj to publish students’ research and original academic writing. Each As the time of my involvement with the RCSIsmj comes to a close, I have edition is part of an entirely student-run process and involves an the privilege of handing over the reins to a truly passionate, intelligent, impressive network of collaboration: students submit their own original and creative staff. As always, we are overwhelmingly grateful to the work, and our peer review team scrutinise submissions after Dean’s office and faculty of RCSI, without whose support this publication anonymisation; based on these recommendations, editorial staff select would not be possible and with whose encouragement the RCSIsmj articles for publication, guide alterations and make suggestions, ensuring continues to go from strength to strength. Finally, I hope that you, like that everything that glitters truly is gold. This year we revamped and me, are awed by the success and innovation of those who have fine-tuned our internal processes so as to best showcase the incredible contributed already and find that this edition spurs you on to greater talent and intelligence of our contributors. engagement with medical research in future! Inspiring students to conduct and engage with research is central to our passion and purpose. Our educational staff help provide students with the tools to scrutinise academic publications, continue to run our popular journal clubs, and host passionate faculty to speak about their own publications and work. Our blog, which this year opened to submissions from any RCSIsmj staff member, will open to submissions from all RCSI students next year as a more informal entry to academic writing. As students at the dawn of our careers, we look to those already in the field for wisdom and inspiration; thus, this year we continue the section spotlighting the research of RCSI faculty. Prof. Peter Conlon, Jenna Geers Associate Professor of Medicine at RCSI, speaks about his enthusiasm and Director, RCSIsmj 2017-2018

Page 4 | Volume 11: Number 1. 2018 RCSIsmjprize

Ethics challenge 2018/2019 CONSCIENTIOUS OBJECTION IN MEDICINE

In January 2018 the Conscientious Objection (Medical Activities) Bill place on a doctor’s freedom as it protected vulnerable patients from received a second reading in the United Kingdom’s House of Lords. harm.4 In the United Kingdom2 and Australia5 doctors are permitted This Bill seeks to clarify the extent to which a medical practitioner to refuse women a termination of pregnancy if they object on with a conscientious objection may refrain from participating in religious or moral grounds; however, they are expected to refer the certain medical activities. The focus of these medical practices is woman to a suitable qualified healthcare professional who does not generally related to the withdrawal of life-sustaining treatment and have these objections. activities under the Human Fertilisation and Embryology Act 1990, as well as the Abortion Act 1967.1 At present in the United Kingdom Questions doctors are subject to General Medical Council Guidelines,2 which 1. Should healthcare professionals have an ethical and legal right to allow for doctors to conscientiously object to withdrawal of conscientiously refuse to participate in certain medical practices treatment if their “religious, moral or other personal beliefs” lead that are legal in their jurisdiction? them to do so.3 2. What medical practices should healthcare professionals have a However, a recent case in Canada saw an Ontario court rule that a right to conscientiously object to? group of doctors has a duty to refer a patient for euthanasia. The 3. How should conscientious objection by healthcare professionals court felt that the referral requirement was a reasonable limit to be addressed by the regulatory bodies?

References 1. UK Parliament. Conscientious Objection (Medical Activities) Bill [HL] 4. Symons X. Canadian court tells doctors they must refer 2017-19. [Internet]. Available from: for euthanasia. February 3, 2018. [Internet]. Available from: https://services.parliament.uk/bills/2017-19/conscientiousobjectionmedical https://www.bioedge.org/bioethics/canadian-court-tells-doctors-they- activities.html. must-refer-for-euthanasia/12585. 2. General Medical Council (UK). Good medical practice. Sections 8-16. 5. Australian Medical Council. Good Medical Practice: A Code of 2013. [Internet]. Available from: Conduct for Doctors in Australia. Section 2.4. 2009. [Internet]. https://www.gmc-uk.org/guidance/good_medical_practice.asp. Available from: 3. General Medical Council. Treatment and care towards the end of life: http://www.medicalboard.gov.au/Codes-Guidelines-Policies/Code-of-c good practice in decision making. 2010. [Internet]. Available from: onduct.aspx. https://www.gmc-uk.org/End_of_life.pdf_32486688.pdf.

This is the tenth instalment of the RCSIsmj Ethics Challenge. The Submission guidelines editorial staff would like to congratulate Moyowa Boyo on her Please construct a lucid, structured and well-presented discourse winning essay in the 2017/2018 Ethics Challenge. Please see for the issues raised by this scenario. Please ensure that you have page 6 for her submission. addressed all the questions highlighted and discuss these ethical We invite students to submit an essay discussing the ethical issues academically, making sure to reference when necessary. questions raised in the scenario presented. Medical ethics is an Your paper should not exceed 2,000 words. essential aspect of the medical curriculum and we hope to Your essay will be evaluated on three major criteria: encourage RCSI students to think critically about ethical situations 1. Ability to identify the ethical issues raised. that arise during their education and subsequent careers. All essays 2. Fluency of your arguments. will be reviewed by a faculty panel of experts and the winning essay 3. Academic quality with regard to depth of research, will be published in the 2019 print edition of the RCSIsmj. The appropriateness of references and quality of sources. deadline for submission of entries will be separate from the general submission deadline for the 2019 edition of the RCSIsmj. Please visit Good luck! our website at www.rcsismj.com for specific dates. Please contact us The winning entry will be presented with a prize at the launch at [email protected] with any questions or concerns. of the next issue.

Volume 11: Number 1. 2018 | Page 5 RCSIsmjethics challenge

ETHICS CHALLENGE WINNER 2017/2018 Bariatric surgery for adolescents

Moyowa Boyo RCSI medical student

Introduction Paediatric bariatric surgery presents a unique ethical challenge for for many adolescents. Paediatric bariatric surgery provides an physicians, healthcare institutions, patients, and their families. It is a intervention that may be more effective than a strictly medical or topic that deserves thorough discussion among healthcare providers lifestyle approach, with the aim of intervening early to prevent or due to the ethical implications of performing surgery on a halt the progression of comorbidities associated with obesity. In vulnerable population. Obesity in children and adolescents is the adult population with morbid obesity, bariatric surgery has defined as a body mass index (BMI) at or above the 95th percentile become the only intervention that reliably produces significant and compared to peers of the same age and sex.1 From 2011-2014, the sustained weight loss.11 In recent years, there has been an increase prevalence of obesity in children and adolescents in the US aged in the use of bariatric surgery for treatment of obesity in between two and 19 years was 17%, with 12.7 million children and adolescents.11,12 Despite this, bariatric surgery in this population adolescents affected.2 In Ireland, obesity in children and adolescents remains relatively underutilised, most likely due to multifactorial increased ten-fold among boys and nine-fold among girls from barriers such as concerns regarding safety, ethical implications, and 1975 to 2016.3 Obesity in adolescence is associated with type 2 long-term effects on the growing adolescent.11 In addition, there is diabetes, hypertension, obstructive sleep apnoea (OSA), a general consensus that non-operative treatment remains dyslipidaemia, non-alcoholic steatohepatitis, polycystic ovary superior.13 The ethical debate regarding paediatric bariatric surgery syndrome, and various musculoskeletal diseases.4 In addition, there centres on the principles of beneficence, non-maleficence, are serious psychological consequences of obesity, such as low autonomy, and justice, taking into account the risk and safety self-esteem and social exclusion.4,5 Research shows that obese profile of the procedure and the current lack of knowledge children are at a higher risk of becoming obese adults.6,7 In addition, concerning the long-term implications of bariatric surgery in the these adolescents will incur disproportionately higher medical care paediatric population. costs as adults.8 More harrowing is the knowledge that the risk of dying from obesity increases by 6-7% for Ethical implications every two years lived with obesity.9 Although Beneficence recent trends show that obesity in children and Beneficence requires physicians to act in the best adolescents has plateaued in interests of their patients at all times. high-income countries, there For paediatric patients with obesity, remains a large paediatric beneficence necessitates taking population battling obesity and action to reverse or halt the its associated complications.3 progression of the physical and Currently, the principal psychological comorbidities approach to obesity in associated with obesity. In the adolescence is conservative setting of paediatric bariatric medical management with surgery, where there is lack of behavioural and dietary long-term data about the modifications.10 However, effects and outcomes of the strategies such as family-based operation, the concept of behavioural therapy coupled beneficence takes a central role. with caloric reduction and physical activity have proven Weight loss efficacy effective in only 50% of patients Current research demonstrates with severe obesity.10 This that bariatric intervention suggests a critical need for a more produces a significant reduction effective weight reduction solution in weight and metabolic profile in

Page 6 | Volume 11: Number 1. 2018 RCSIsmjethics challenge

the paediatric adolescent population.14-17 A three-year prospective Non-maleficence study on weight loss and health status after bariatric surgery in The principle of non-maleficence is an ethical duty to do no harm to adolescents revealed a mean percentage weight loss of 27% (95% patients. As it is well known that bariatric intervention has confidence interval [CI], 25-29) in the overall cohort.14 Another considerable risks both during and after the procedure, multicentre cohort study of 41 adolescents receiving the Roux-en-Y non-maleficence stands as perhaps the strongest ethical issue gastric bypass (RYGB) for morbid obesity showed a 37% decrease in surrounding paediatric bariatric surgery.23,24 BMI at one year post surgery, along with substantial improvements in triglycerides, total cholesterol, and fasting blood glucose.13 This Risk and complications was in comparison to non-surgical patients, who achieved a 3% The two most commonly performed operations in the paediatric reduction in BMI with medical management alone after one year.17 population are the RYGB and the laparoscopic adjustable gastric band (LAGB). Potentially lethal early postoperative complications of In light of the risks associated with the RYGB include anastomotic leak, massive bleeding, and pulmonary embolism.14,16 Other complications include wound bariatric surgery, beneficence warrants infection, anastomotic stricture, marginal ulceration, incisional that all potential adolescent bariatric hernias, symptomatic cholelithiasis, and remote weight regain.8,19 surgery patients undergo a trial of Long-term nutritional deficiencies in calcium, vitamin D, iron, folate, and vitamins B1, B6, and B12 exist, requiring patients to comply medical management. with strict micronutrient supplementation.8,14,19 In addition, symptoms of abdominal pain, nausea, vomiting and diarrhoea may For the obese paediatric adolescents who are unsuccessful with become problematic for patients.8 The LAGB carries mechanical and medical therapy, beneficence favours bariatric intervention, as it acts infectious complications, such as malpositioning of the AGB and in the best interest of the patient by improving overall health and gastric obstruction or erosion.8,19 In a systematic review of 950 well-being.8 However, while there is significant weight reduction morbidly obese paediatric patients who underwent bariatric surgery, associated with bariatric surgery, in both aforementioned studies the there were 108 re-admissions (11.4%) and 91 re-operations (9.6%) majority of participants were still obese at one and three years in a three-year period.25 There was one reported death due to a following surgery, respectively.14,17 In addition, a small percentage of hypoglycaemic event after the procedure.25 Bariatric surgery requires patients began regaining weight within one year of the strict compliance in the postoperative phase, as well as life long. procedure.14,17 In light of the risks associated with bariatric surgery, One study found that only 13% of paediatric patients continued beneficence warrants that all potential adolescent bariatric surgery taking nutritional supplements as required at six-year follow-up.26 patients undergo a trial of medical management. This would ensure Given the significant risks and complications associated with the that only those patients who are unsuccessful with medical therapy procedure, the paucity of evidence showing sustained long-term are eligible for the procedure, as beneficence would favour medical weight loss, and the fact that long-term complications remain therapy alone if the patient is indeed able to achieve sustained largely unknown, the principal of non-maleficence becomes difficult weight loss. As there are no reliable long-term data on bariatric to uphold. Coupled with the need for strict life-long compliance to surgery in the paediatric population, beneficence will depend on the diet and nutrient supplementation, there remains a high likelihood risk–benefit profile of each individual patient, taking into account of causing harm through bariatric surgery in the paediatric their initial response to medical therapy alone. population. Therefore, the benefits of the procedure for each individual child must outweigh the potential short- and long-term Relief of comorbidities and psychosocial benefits consequences in order for the ethical principal of non-maleficence Bariatric intervention can provide significant improvement in to be truly upheld. comorbidities associated with obesity, such as hypertension, diabetes, dyslipidaemia, abnormal kidney function, and OSA.14,17,18 In Autonomy and informed consent particular, there is significant resolution of hypertension, type II Autonomy dictates that individual choice and self-governing be diabetes, and OSA with bariatric surgery.19 Resolution of honoured, particularly as it pertains to one’s own body. In paediatrics, comorbidities favours beneficence, as it offers direct benefit to parents are given the decision-making power under the assumption patient health. Research shows that obese paediatric patients that parents are in the ideal position to know what is best for their experience reduced quality of life and social marginalisation.19,20,21 child. An adult is believed to have capacity to weigh the risks and One study found that severely obese children and adolescents had a benefits of an operation before consenting to the procedure; health-related quality of life similar to those who had been diagnosed however, in the paediatric population, it can be difficult for patients with cancer.20 Following bariatric surgery, numerous studies have and their families to fully understand the risks, complications, and shown improvements in depressive symptoms, self-esteem, life-long implications of the procedure.8 It is imperative that both health-related quality of life, and body image.22 The benefits received parents and the patient understand the operative risks and risk of from relief of comorbidities and increased quality of life support the unintended complications, as well as the irreversible nature of the principle of beneficence by enhancing health and well-being. RYGB, before consenting to the procedure.8

Volume 11: Number 1. 2018 | Page 7 RCSIsmjethics challenge

Because the evidence regarding long-term effectiveness and safety of Conclusion bariatric procedures is not clear, it is difficult to inform eligible Ultimately, the decision to perform bariatric surgery on patients in a way that ensures valid informed consent. Prior research adolescents is fraught with ethical challenges. Research has has shown that, postoperatively, patients undergoing bariatric surgery shown that bariatric surgery in adolescents is effective for do not remember information given preoperatively regarding achieving short-term weight loss, improving metabolic profile, potential complications.27 Barriers to providing valid informed consent and achieving resolution of comorbidities. Whether the procedure in paediatric bariatric surgery include the differences in perception of achieves long-term sustainable weight loss in adolescents is obesity, and its impact, between parents and adolescents.10,28,29 largely unknown. The complications and risk profile of the Parents report significantly more impairment in health-related quality procedure in adolescents present an ethical challenge, as the risks of life domains compared with their children.29 This introduces the of a procedure must not outweigh the benefits. It is difficult to risk that a parent’s coercion might underlie an adolescent’s assent, present patients and parents with accurate information regarding rather than a true desire to receive the surgery.28,30 Therefore, in order the long-term implications of the procedure, which produces for autonomy and informed consent to be honoured, a thorough challenges with respect to autonomy and informed consent in an assessment should be performed of an adolescent’s cognitive, social, already vulnerable population. As the incidence of bariatric and emotional development, as well as their decision-making capacity surgery increases in the adolescent population, equal access to and independent role in the decision-making process.30 the procedure will move to the forefront of the discussion, as unfair access can increase prejudice and discrimination towards Justice obese adolescents.28,36 Justice is the ethical principle that states that each person should It is clear that while bariatric surgery is not without risk, it has receive equitable treatment and a fair share of health resources. For strong advantages when compared with medical management of paediatric bariatric surgery, the issue of justice lies in the access to the severe obesity in adolescents. In Ireland, a paediatric bariatric surgery. A study of adult patients who underwent bariatric surgery surgery programme would provide a relevant strategy to address found that 84% of patients were Caucasian women with most having severe obesity in adolescents. high income levels.31,32 Fewer African Americans, Hispanics, However, such a programme would require strict regulations in low-income individuals, and males received the surgery than order to ensure that it provides a service that acts in the best expected, based on morbid obesity statistics.33 It is likely that a similar interests of all patients. These regulations should include strict trend is reflected in paediatric bariatric candidates, as research shows guidelines on age and BMI eligibility for the procedure, a that non-Hispanic black and Hispanic children had higher prevalence mandatory trial of medical management prior to receiving rates of overweight and obesity compared to other demographics.34 surgery, thorough psychological assessment of an adolescent’s This indicates an unjust distribution of resources; paediatric bariatric development and decision-making capacity, a lengthy informed surgery programmes must provide equal access to and participation consent process allowing for understanding of operative risks and in these programmes regardless of socioeconomic class in order to potential complications, and a close, evidence-based follow-up fairly align with the principle of justice. As the incidence of paediatric programme. In addition, paediatric bariatric surgery programmes bariatric surgery increases, the cost of the procedure will play a have a duty to conduct long-term research and provide equal significant role in the principle of justice. A recent study on the access to the procedure, regardless of socioeconomic status. cost-effectiveness of bariatric surgery in adolescents with obesity Despite its risks, paediatric bariatric surgery offers a solution to revealed that bariatric surgery incurs a substantial initial cost and address obesity in adolescents. By carefully balancing the ethical morbidity, but may become cost-effective by five years principles of beneficence, non-maleficence, autonomy, and justice postoperatively.35 However, the present lack of clinical trials with at with the risk and safety profile of the procedure, it is possible to least five years of follow-up makes it difficult to confidently capture establish an adolescent bariatric surgery programme that achieves the financial impact of the operation. Excluding patients from significant weight loss, resolution of comorbidities, and improved consideration for the procedure due to a lack of financial resources quality of life, while honouring and upholding these fundamental would violate the ethical principle of justice. principles.

References

1. Centers for Disease Control and Prevention. Defining Childhood 3. Abarca-Gómez L, Abdeen Z, Hamid Z, Abu-Rmeileh N, Acosta-Cazares Obesity. 2017. [Internet]. [cited 2017 December 27]. Available from: B, Acuin C et al. Worldwide trends in body-mass index, underweight, https://www.cdc.gov/obesity/childhood/defining.html. overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 2. Centers for Disease Control and Prevention. Childhood Obesity Facts. population-based measurement studies in 128.9 million children, 2017. [Internet]. [cited 2017 December 27]. Available from: adolescents, and adults. Lancet. 2017;390(10113):2627-42. https://www.cdc.gov/obesity/data/childhood.html. 4. Dietz WH. Health consequences of obesity in youth: childhood

Page 8 | Volume 11: Number 1. 2018 RCSIsmjethics challenge

predictors of adult disease. Pediatrics. 1998;101(3 Pt 2):518-25. bariatric surgery for pediatric obesity. Ann Surg. 2008;248(5):763-76.

5. Russell-Mayhew S, McVey G, Bardick A, Ireland A. Mental health, 20. Schwimmer J, Burwinkle TM, Varni JW. Health-related quality of life of

wellness, and childhood overweight/obesity. J Obes. 2012;2012:1-9. severely obese children and adolescents. JAMA. 2003;289(14):1813-9.

6. Serdula M, Ivery D, Coates R, Freedman D, Williamson D, Byers T. Do 21. Strauss R, Pollack H. Social marginalization of overweight children. Arch

obese children become obese adults? A review of the literature. Prev Pediatr Adolesc Med. 2003;157(8):746-52.

Med. 1993;22(2):167-77. 22. Kubik J, Gill R, Laffin M, Karmali S. The impact of bariatric surgery on

7. Whitaker R, Wright J, Pepe M, Seidel K, Dietz W. Predicting obesity in psychological health. J Obes. 2013;2013:837989

young adulthood from childhood and parental obesity. N Engl J Med. 23. Pories W. Bariatric surgery: risks and rewards. J Clin Endocrinol Metab.

1997;337(13):869-73. 2008;93(11 Suppl. 1):s89-s96.

8. Caniano D. Ethical issues in pediatric bariatric surgery. Semin Pediatr 24. Longitudinal Assessment of Bariatric Surgery (LABS) Consortium et al.

Surg. 2009;18(3):186-92. Perioperative safety in the longitudinal assessment of bariatric surgery.

9. Abdullah A, Wolfe R, Stoelwinder J, de Courten M, Stevenson C, Walls N Engl J Med. 2009;361(5):445-54.

H et al. The number of years lived with obesity and the risk of all-cause 25. Shoar S, Mahmoudzadeh H, Naderan M, Bagheri-Hariri S, Wong C,

and cause-specific mortality. Int J Epidemiol. 2011;40(4):985-96. Parizi A et al. Long-term outcome of bariatric surgery in morbidly obese

10. Levine M, Ringham R, Kalarchian M, Wisniewski L, Marcus M. Is adolescents: a systematic review and meta-analysis of 950 patients with

family-based behavioral weight control appropriate for severe pediatric a minimum of 3 years follow-up. Obes Surg. 2017;27(12):3110-7.

obesity? Int J Eat Disord. 2001;30(3):318-28. 26. Rand C, Macgregor A. Adolescents having obesity surgery: a 6-year

11. Zwintscher N, Azarow K, Horton J, Newton C, Martin M. The increasing follow-up. South Med J. 1994;87(12):1208-13.

incidence of adolescent bariatric surgery. J Pediatr Surg. 27. Madan AK, Tichansky DS, Taddeucci RJ. Postoperative laparoscopic

2013;48(12):2401-7. bariatric surgery patients do not remember potential complications.

12. Tsai W, Inge T, Burd R. Bariatric surgery in adolescents: recent national Obes Surg. 2007;17(7):885-8.

trends in use and in-hospital outcome. Arch Pediatr Adolesc Med. 28. Hofmann B. Stuck in the middle: the many moral challenges with

2007;161(3):217-21. bariatric surgery. Am J Bioeth. 2010;10(12):3-11.

13. Iqbal C, Kumar S, Iqbal A, Ishitani M. Perspectives on pediatric bariatric 29. Zeller MH, Modi AC. Predictors of health-related quality of life in obese

surgery: identifying barriers to referral. Surg Obes Relat Dis. youth. Obesity (Silver Spring). 2006;14(1):122-30.

2009;5(1):88-93. 30. Wee C, Pratt J, Fanelli R, Samour P, Trainor L, Paasche-Orlow M. Best

14. Inge T, Courcoulas A, Jenkins T, Michalsky M, Helmrath M, Brandt M et practice updates for informed consent and patient education in weight

al. Weight loss and health status 3 years after bariatric surgery in loss surgery. Obesity (Silver Spring). 2009;17(5):885-8.

adolescents. N Engl J Med. 2016;374(2):113-23. 31. Santry HP, Gillen DL, Lauderdale DS. Trends in bariatric surgical

15. Olbers T, Gronowitz E, Werling M, Mårlid S, Flodmark C, Peltonen M et procedures. JAMA. 2005;294(15):1909-17.

al. Two-year outcome of laparoscopic Roux-en-Y gastric bypass in 32. Livingston EH, Ko CY. Socioeconomic characteristics of the population

adolescents with severe obesity: results from a Swedish Nationwide eligible for obesity surgery. Surgery. 2004;135(3):288-96.

Study (AMOS). Int J Obes (Lond). 2012;36(11):1388-95. 33. Flum D, Khan T, Dellinger E. Toward the rational and equitable use of

16. Strauss R, Bradley L, Brolin R. Gastric bypass surgery in adolescents with bariatric surgery. JAMA. 2007;298(12):1442-4.

morbid obesity. J Pediatr. 2001;138(4):499-504. 34. Skinner AC, Skelton JA. Prevalence and trends in obesity and severe

17. Lawson M, Kirk S, Mitchell T, Chen M, Loux T, Daniels S et al. One-year obesity among children in the United States, 1999-2012. JAMA Pediatr.

outcomes of Roux-en-Y gastric bypass for morbidly obese adolescents: 2014;168(6):561-6.

a multicenter study from the Pediatric Bariatric Study Group. J Pediatr. 35. Klebanoff M, Chhatwal J, Nudel J, Corey K, Kaplan L, Hur C.

2006;41(1):137-43. Cost-effectiveness of bariatric surgery in adolescents with obesity. JAMA

18. Inge T, Xanthakos S, Zeller M. Bariatric surgery for pediatric extreme Surg. 2017;152(2):136-41.

obesity: now or later? Int J Obes (Lond). 2007;31(1):1-14. 36. Hofmann B. Bariatric surgery for obese children and adolescents: a

19. Treadwell J, Sun F, Schoelles K. Systematic review and meta-analysis of review of the moral challenges. BMC Med Ethics. 2013;14:18.

Volume 11: Number 1. 2018 | Page 9 RCSIsmjresearch spotlight

SPOTLIGHT ON research at RCSI RCSI’s Prof. PETER CONLON takes us through his research interests, and offers advice to researchers at the beginning of their careers.

Inherited kidney disease I am involved in three major areas of clinical research. The first involves the identification of inherited forms of kidney disease. Twenty years ago I started a project while in Duke University, USA, which I have continued in collaboration with them, but also established here in Dublin. It is apparent that many forms of kidney disease, while initially thought to be ‘sporadic’, are in fact of a hereditary nature. We initially started collecting large families where individuals had kidney disease that ran in the families, and by collecting these families we were able to identify – in collaboration with superb molecular genetics in Duke University and Prof. Gianpiero Cavalleri at the RSCI – specific genes, some of them novel genes never before described, associated with the cause of kidney failure. This has become very important in the era of live donor transplantation, because it is essential that we do not take a kidney from somebody who may have the underlying disease themselves. Understanding the gene that causes kidney failure also allows us to Testing genes have a better understanding of the mechanism of disease and, Thirdly, as a result of this detailed information related to clinical therefore, to develop treatments to try and ameliorate it. In the last outcomes, we have been able to undertake a study involving seven or eight years the sequencing of genes has become much genome-wide association studies (GWAS). In these studies we test simpler utilising next-generation sequencing (NGS) and using this more than 610,000 gene variations in the donor and the recipient, technology we can now undertake a whole exome sequence, to which we can impute 22 million variations, and then associate enabling us to apply a molecular diagnosis to more than half the these variations with the outcome of the transplant recipient. patients that we have studied. Recently, for example, we published a paper looking at 2,000 transplant donors and recipients, and the association of gene Transplantation variation with long-term transplant outcome. We have done this in Secondly, I have had a long interest in renal transplantation. The collaboration with colleagues in Dublin, Ireland and the UK, and National Kidney Transplant Service for the Republic of Ireland is more recently established the i-gene consortium, which is made up co-ordinated through Beaumont Hospital, and at Beaumont we of many centres across Europe and the US. have undertaken a whole series of studies defining the outcome of kidney transplantation. Many years ago we established a national Advice for researchers renal transplant registry, in which we record annually and in detail the clinical outcomes of every patient – more than 5,000 – who has Pick a subject that you are really interested in and, most ever had a kidney transplant in Ireland. We have done this with the importantly, find people to help you do this (i.e., find excellent support of the hospital, and we employ a full-time database collaborators). If you are interested in the disease or condition manager and statistician. We have a particular interest in you will generally be able to find people across the world, or in post-transplantation cancer, and have developed a collaboration your own city, who have a similar interest, and if you bring with the National Cancer Registry Ireland (NCRI), and have analysed enthusiasm to the project they will be more than willing to work the outcomes of more than 3,000 kidney transplants and their with you. association with various forms of cancer.

Page 10 | Volume 11: Number 1. 2018 RCSIsmjinterview

The generalists ALEXANDRA MITCHAM spoke to three GPs about the challenges of general practice, and the reasons why it could be a fulfilling career option for medical graduates.

General practice is a career path that few medical students initially profession, by colleagues, trainees, and general practitioners (GPs) identify as their primary interest, but which many take up post themselves, is commonplace. Here, Dr Mark Murphy, Dr Emma graduation. It is a broad pursuit with the opportunity to see a variety of Wallace, and Dr Ellen Stuart discuss their experiences as GPs, address pathologies and develop strong, continuous interpersonal relationships attitudes towards the profession, and propose ways of encouraging with patients, and it holds a significant degree of autonomy with medical students to pursue what is evidently a fulfilling, challenging, respect to one’s career path. Despite this, stigmatisation towards the and diverse profession.

Volume 11: Number 1. 2018 | Page 11 RCSIsmjinterview

The doctors

Dr Mark Murphy (MM) is a GP in Dr Emma Wallace (EW) is a graduate Dr Ellen Stuart (ES) is a GP and south Dublin and lecturer in the of UCD and a GP in north Dublin. She is lecturer at the RCSI. She is also a Department of General Practice at the a senior lecturer in general practice and qualified physiotherapist and has worked RCSI. He is completing his PhD in Director of the senior cycle general in palliative care. She completed her MSc affiliation with the Health Research practice teaching programme at the in health sciences and clinical education, Board (HRB) Centre for Primary Care, RCSI. She completed her PhD in 2015 and has a special interest in reflection, investigating chronic disease with the HRB Structured Population and palliative care, and musculoskeletal management. He is currently Chair of Health-services and Research Education education. She is currently conducting Communications in the Irish College of (SPHeRE) programme examining research with the HRB Centre for Primary General Practitioners (ICGP). predictors of adverse health outcomes in Care Research involving best evidence for older people attending general practice. medical education.

What initially drew you to general practice? MM: I didn’t have a deadset desire leaving medical school. After three or be very good at one thing. I was keen to learn, and what attracted me four years in hospital, I was frustrated. [The work] consisted of extensive to medicine was the vast knowledge base, and the ability and privilege investigations, and I didn’t get to know patients. When patients came to of putting this knowledge into practice. Another big draw was that the outpatient clinics, I was seeing one specific small disease, but they often training scheme was four years and allowed work–life balance, because had five or six other conditions for which they saw other specialists. I felt you’re in charge of your own working week and how you frame it. In that many other factors determined their health, but could only really be other specialties, you’re training for upwards of six years, doing call in addressed through getting to know [the patient] over time. I saw [in house, and as a mature student this didn’t appeal to me. general practice] the benefits of continuity of care, getting to know patients over time, and co-ordination of care, [and] I really liked the You have each mentioned variety and continuity of care as variety of general practice. strengths of general practice. Are there any other positives that come to mind? And what about challenges? EW: For me it was about variety; I really enjoyed all aspects of MM: Firstly, there is clinical autonomy, [and] general practice allows for medicine and liked the idea of seeing a diverse range of patients. I also innovation. As a GP, you’re able to work in a system in the way you want really liked the idea of building long-term relationships over time with to; you can be a master of your own destiny. And, of course, there are patients and their families. I’ve found it a privilege being able to look lots of exciting academic opportunities. GPs are also the centrepiece of after patients over a long period of time, and seeing people’s highs most healthcare policy systems; the future is leaning towards GP-led and lows. primary care. Like all jobs, there are challenges. When getting involved in general ES: I think it was the variety and the challenge of general practice that practice, there are a lot of hats you have to wear. I spend half the week drew me to it. I was attracted to looking after people ‘from the cradle to in clinical practice, I am four years into a PhD, and I also lecture. On top the grave,’ and from all walks of life. I’m drawn to being able to do lots of that, I am involved in political policy as Chair of Communications for of things reasonably well, versus one thing extremely well. I specialised the Irish College of General Practitioners, so it’s a very busy week, but it’s within physiotherapy before I did medicine, so I knew what it was like to also very rewarding.

Page 12 | Volume 11: Number 1. 2018 RCSIsmjinterview

EW: I’ve enjoyed the flexibility in terms of being able to combine my EW: Well it’s interesting: that hasn’t been my experience. But broadly clinical work with my other interests. I completed a structured PhD speaking, if you look at the literature, general practice is becoming less programme and continued working as a GP throughout, which was attractive as a career option for medical graduates. I think the problem is fantastic because I was able to combine two aspects of my professional multifaceted. I certainly think the perceived status of general practice, life that I really enjoy. In terms of a difficult part, I find it challenging not compared to other hospital specialties, may not be seen as equal. There being able to access services for my patients. Limited access to may have been difficulties in having general practice perceived as a diagnostics and a long waiting list for some outpatient appointments are specialty due to its shorter training time; however, most GPs will have real challenges, and pose much difficulty for patients. As a result, since done some other training in addition to the general practice scheme. I you, the GP, are the person they see most often, you almost end up think that we all have conversations where vague disparaging comments apologising for the system. are made in jest, but for medical students hearing [these comments], it may impact their view of general practice as a career. ES: [In terms of challenges], I think everyone has a different type of brain; some people like to be in control of things all the time, while It’s really interesting to hear the commonalities and others can live with uncertainty, and I think the latter suits general differences you’ve each experienced as you’ve made your practice well. This is one of the core attributes you need to function as a way through your careers. In light of what you’ve described, GP. It’s all well and good to train and learn, but when actually do you think there is anything that could be done to draw performing the job you need to be able to walk away from something more students into the general practice stream? and not be 100% certain of the answer. MM: I think it’s important that [the curriculum] reflects the patient’s I also think career wise it’s a tough specialty to advance in as a newly journey through the different settings that have general practice at the established GP in Ireland. You qualify, do your training in which you are core. I also think the medical curriculum needs to reflect the supported, and then you kind of have to figure it out for yourself. primary–secondary care interface; patients almost always end up back at Becoming an assistant in a practice is attractive, and you get paid a their GP after secondary care interventions. I think we need to recognise wage by the owner of the practice. But to move on from being an that general practice is a specialty in its own right. It’s also important for assistant to becoming a partner is a really big jump for people who don’t GPs working in university departments to get to know medical students, have connections or financial backing. If you do hospital specialist and realise that they are role models for general practice. In terms of the training and apply for a consultant post, it’s straightforward, whereas in ‘hidden curriculum’, the undermining of general practice that has taken general practice you have to be more business minded. It requires place historically is something we need to tackle head on. Through all different strengths and negotiation skills, which many are not trained in. these mechanisms, we can improve the perception of general practice at the undergraduate level, and I also think that medical students have After consideration of these pros and cons, and having been leaders in this regard. Students who have engaged in general chosen general practice as your career path, do you feel that practice research have been champions themselves of the potential of there is a stigma associated with the profession? general practice, and have discovered the variety within it. It needs to be MM: I think there’s been a negativity in medical schools around general acknowledged that such students play an important role. practice that has been propagated by GPs themselves, because there are challenges associated with the career. Negative comments and EW: We’ve had a number of medical students come through doing degradation of the specialty within the undergraduate curriculum can be research electives in our department, and I think that shows a different informally made by staff in healthcare settings, and [this] plays a role in academic side and builds an evidence base for general practice; I think shaping attitudes. As professionals and policymakers, we have to it’s very important to show that side of things. In addition, I think more articulate the difficulties without discouraging future GPs. and more GPs will be supported in developing special interests and further training, such as minor surgery or dermatology. This is a nice way ES: To some people, it’s seen as a soft and easy option because the to experience something else alongside general practice, and makes the training scheme is shorter and there isn’t as much demand placed on week more varied. GPs often have a special interest in a diverse range of the trainees. For example, they don’t have to do as much call or as things, so there is huge opportunity there. much research so, with good reason, it is seen, initially, as an easier ES: I think it’s about us as GPs coming together to improve option. In terms of the hierarchy of medicine, I suppose there is a stigma representation. We have good negotiators trying to carve out new attached to it. Even at Government level, when it recently came to contracts with the Government, and I think that’s one way of addressing discussing a new GP contract, it is difficult to negotiate salaries to the the stigma attached to our profession. Considering medical students’ same level as hospital consultants. It’s not just my own personal sense of views of general practice versus other specialties, I suppose the best way stigma, it is also the public’s view of whether a GP is equivalent to a of addressing [how to draw students to the specialty] is through consultant. I think we have a fight on our hands to represent ourselves example. I think, as educators, we need to try to improve the profile of well. We have an incredibly difficult job; it’s one of the most challenging our profession among students and colleagues, and work towards jobs within healthcare. It can be extremely stressful and burdensome, producing good research and education that shows the complexity and but can be equally rewarding, and people thrive on that. depth of general practice.

Volume 11: Number 1. 2018 | Page 13 RCSIsmjcase report

Diagnostic dilemma: a rare cause of lower back pain

Abstract Low back pain is a common presentation with a wide differential diagnosis. One rare, but

Luis Felipe Colón1 important, differential is malignant metastases to the spine. Primary breast cancers have a

Sebastian Flores2 tendency to spread to bone. Male breast cancer is a rare phenomenon, accounting for less

Dr Jorge Isaza3 than 1% of all breast cancer cases. This report presents the case of a 54-year-old male who

1RCSI medical student presented with signs and symptoms of low back pain that initially appeared to be due to

2Louisiana State University. radiculopathy after a work-related injury. After several interventions, visits and imaging Louisiana, USA studies, it was discovered that many of his symptoms were due to silent dissemination of

3Department of Orthopaedics, male breast cancer. There is a lack of literature and guidelines on the work-up of male breast Tulane University, New Orleans, cancer. This case highlights the importance of keeping a high index of suspicion for all Louisiana, USA patients presenting with lower back pain, and the need for evidence and guidelines on the investigation and management of male breast cancer.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 14-18.

Page 14 | Volume 11: Number 1. 2018 RCSIsmjcase report

Introduction Low back pain (LBP) is one of the most common adult disorders, of the world.1,2 One of the more serious and rare aetiologies of LBP with over 80% of adults experiencing it at some time in their lives.1 is malignancy (1% of cases), including primary bone cancer such as It is the leading cause of disability in young adults and the second multiple myeloma, or metastases to bone from primary breast or most common cause of work absence and activity limitation in most prostate adenocarcinoma.3

Table 1: Orthopaedic and spinal surgical procedures.

Procedure Description Indications

Arthroscopy (ATS) A minimally invasive procedure in which May be used as a diagnostic procedure, small incisions are made to insert or for the surgical repair of damaged endoscopes, containing cameras and structures (e.g., menisci).7 instruments, to visualise and operate inside a joint compartment.7

Discectomy Removal of a herniated nucleus pulposus For a HNP compressing a nerve root (HNP). The surgical approach may be or spinal cord, causing pain or neurologic endoscopic or open.8 deficits (e.g., foot drop).8

Vertebroplasty An 11- to 13-gauge needle is advanced For stabilisation of painful osteoporotic into the vertebral body with fluoroscopic or osteolytic vertebral compression guidance to inject pre-mixed bone cement fractures, or management of painful made of PMMA* with barium.8 vertebral hemangioma.8

*PMMA: polymethyl methacrylate.

Case timeline

Initial presentation 3 months post op Return to office Patient presents with 6/10 Patient returns with 6/10 LBP The patient has been receiving LBP after a work-related and bilateral leg pain. He is oncological care, but now injury. First MRI is obtained, treated with analgesics and complains of 10/10 pain in the showing HNP at L5/S1. He is physical therapy. A six-week thoracic region. The patient treated with a corticosteroid follow-up is arranged. undergoes surgery (vertebroplasty) injection. to alleviate his pain.

2 months 8 months 1.5 years

First visit 6 months 1 year

Return to office 4.5 months post op Present Patient now has 7/10 LBP with Patient returns with worsening LBP, The patient is receiving radiculopathy. Examination now 9/10, which is not relieved by oncological care with reveals foot drop on the left, analgesics. A second MRI is ordered, improvement. He has not and zero degrees of spinal which shows diffuse metastatic had new symptoms extension. The patient is disease of the spine and pelvis. The regarding LBP or treated with surgery patient is referred to oncology and radiculopathy. (extrapedicular discectomy). subsequently diagnosed with metastatic breast cancer.

FIGURE 1: Clinical timeline.

Volume 11: Number 1. 2018 | Page 15 RCSIsmjcase report

FIGURE 4: Sagittal T1-weighted MRI with contrast of the lumbar spine, showing diffuse metastatic disease of the lumbar and thoracic spine. The most marked fractures include: anterior wedge compression fracture at L1 (red arrow) with marrow oedema and visible metastases; compression fracture at L3 with marrow oedema (green arrow); and, acute-appearing compression fracture at L4 (blue arrow). Visible metastases enhancing FIGURE 2: Lateral spinal x-ray taken FIGURE 3: Sagittal T1-weighted MRI with contrast can be seen during the patient’s first visit. Imaging of the lumbar spine, without contrast, at T12 (purple arrow). shows minimal displacement at L4/5 showing a posterolateral disc bulge at (red arrow), but overall looks benign. L5/S1.

Although metastases to the spine are a rare cause of LBP, many denied any known drug allergies. With regard to his social history, malignancies, particularly breast cancer, have a tendency to spread he had a 20 pack year smoking history, drank alcohol occasionally, to bone and create lytic lesions.4 Male breast cancer (MBC) is an and denied using any recreational drugs. The patient was employed even rarer phenomenon, accounting for less than 1% of all breast offshore, in manual labour, but he had not been working since the cancer cases.5 Due to low suspicion and a lack of standardised accident. His family history was non-significant and negative for guidelines for treatment and surveillance, most cases of MBC are cancer. The patient denied weight loss, fever, or any other only diagnosed once the disease has disseminated and the chances associated symptoms. of a cure are diminished.4,6 On examination, the patient was obese (BMI: 34.7), and was This case report presents a 54-year-old male treated with spinal oriented to time, place, and person. On inspection, the patient had surgery for radiculopathy (known colloquially as a ‘pinched nerve’), a small effusion in his left knee. while silently developing primary MBC with metastatic On palpation of the back, there was tenderness to the left of the dissemination into bone and viscera. The case describes a rare and midline in the area of L4 and down into the gluteal area. Lumbar perplexing disease presentation that is largely absent from the spine flexion was 60 degrees, extension was 20 degrees, and left medical literature and merits attention. and right lateral flexion were both 20 degrees; all of these movements produced equal pain. While testing motor function, Case there was weakness in the left leg in all muscle groups. Reflexes in A 54-year-old African American male presented to a spinal surgery the lower extremities were decreased bilaterally. On sensory testing, clinic complaining of lower back and left knee pain that began after there was dysaesthesia in the left leg involving the L4 and L5 a work-related accident two months previously (Figure 1). The dermatomes. Straight leg test of the left lower limb was positive, patient reported constant pain since this work-related injury, when a producing lower back pain. On gait testing, the patient ambulated large pipe hit him in the lower back and left lower extremity. He with a slight limp on the left. described the pain as an aching, shooting sensation with radiation Anteroposterior, lateral (Figure 2) and flexion-extension x-rays from his lower back down to his left leg. The pain was alleviated by showed only minimal displacement at L4/5. An MRI (Figure 3) rest and exacerbated by sitting, standing, and lying down. He rated taken the following week showed herniation of the nucleus pulposus the pain a 6/10. Associated symptoms included numbness and (HNP) at L5/S1. The patient was then treated with a transforaminal tingling in his left lower extremity. Since the injury, the patient had steroid injection at L4/5, which provided only temporary relief. Two undergone an arthroscopy (ATS; see Table 1) as treatment for his months later, the patient returned with worsening back pain, now left knee pain, which provided mild relief. rated 7/10, radiating down his left leg (Figure 1). Physical The patient’s past medical history was negligible, with no other examination revealed that spinal extension was now 0 degrees, and surgical history. The patient was not taking any medications, and on gait testing, the patient ambulated with a limp and left foot

Page 16 | Volume 11: Number 1. 2018 RCSIsmjcase report

FIGURE 5: Transverse section of T1-weighted MRI FIGURE 6: Coronal section of a FIGURE 7: Transverse section of a thorax/abdomen/pelvis (TAP) CT with contrast showing a fractured L1 with multiple thorax/abdomen/pelvis (TAP) CT without without contrast at the level of L1, showing several metastatic metastases. contrast showing diffuse metastases from T12 lesions in the vertebral body. to L5 and in the pelvic bones. drop. To address these worsening symptoms, the patient was FIGURE 8: Full-body PET scan showing malignant scheduled for an extrapedicular discectomy at L4/5 (Table 1). The activity throughout the axial skeleton, pelvic patient tolerated this surgery well, and reported postoperative bones, lungs, and liver. symptomatic relief. At four-and-a-half months postoperatively, the patient again complained of worsening pain (9/10), which was not relieved by analgesia. A second MRI was taken with contrast (Figures 4 and 5), one year after the first MRI, which showed diffuse metastatic disease in the spine and pelvis, with pathologic fractures on several thoracic and lumbar vertebrae. The patient was immediately referred to a haematology-oncology specialist for a malignancy workup and full-body CT (Figures 6 and 7) and PET scan (Figure 8). The patient was formally diagnosed with primary malignancy of the breast, with metastases to the thoracic and lumbar spine, pelvic bones, lungs and liver. He commenced treatment with chemotherapy and adjuvant tamoxifen. At a return visit to the clinic, it was discovered that one year prior to his work accident, the patient had attended an urgent care clinic regarding a painful right breast lump. At the time, he was diagnosed with lymphadenitis and Discussion discharged with a ten-day course of antibiotics. Among the causes of LBP, malignancy is a rare but serious At this return clinic visit, four months after his cancer diagnosis, the aetiology that must be ruled out with a thorough history and patient complained of 10/10 pain around his T12 vertebra, and appropriate investigations.3 The ‘red flags’ for LBP secondary to inquired about undergoing a surgical procedure to alleviate this malignancy include a history of cancer and/or unexplained pain. Following multidisciplinary discussion, it was decided that the weight loss, neither of which were present in this patient’s patient was fit for a T12 vertebroplasty (Table 1). The patient history.1 The first MRI did not show any signs of disseminated tolerated the procedure well, and received significant relief of his j18 disease in the lumbar spine, although the cancer may have been LBP and leg pain. spreading through the lymphatic system and other viscera. The At the time of writing, the patient was continuing chemotherapy history of a work-related accident and the specific findings of a and hormonal therapy, with improvement in his malignant lesions in HNP at L4/5, with no sign of metastatic disease on the first MRI, terms of size and spread, as seen on repeat imaging. provided a straightforward cause for the patient’s presenting

Volume 11: Number 1. 2018 | Page 17 RCSIsmjcase report

symptoms and did not trigger further investigations for MBC, which are currently simply extrapolated from information malignancy. The team at the spinal surgery clinic was on female breast cancer.10 This case might have been approached confounded at the difference between the two MRI studies taken differently if the patient had been a postmenopausal (similar to one year apart (Figure 3 vs Figure 4). Although breast cancer is our patient’s age) female presenting with bony or back pain. In commonly associated with skeletal dissemination, the speed or this scenario, metastatic breast cancer would have been an degree of dissemination is individualised for each patient.4 In just important, and statistically more likely, differential diagnosis to one year, this patient went from having a lack of visible consider. Such a woman’s case could have been further secondary malignancies in the lumbar spine to having fully investigated clinically with a breast examination, which is not disseminated disease. No similar cases were found in the routinely performed on male patients presenting with back pain. literature at the time of publication. Furthermore, neither the past It is important to note that such cases may present to a variety of medical history nor the systems review at his initial visit revealed medical and surgical specialties, such as a spinal surgeon for the urgent care clinic visit where he had presented with a painful painful metastases to the axial skeleton, or a gastroenterologist breast lump. for symptomatic metastases to the liver.5 When the patient returned to the spinal surgeon’s office following This case may serve to alert physicians in any specialty to keep an his cancer diagnosis, the focus of treatment became pain open mind and broad differential diagnosis when evaluating each management rather than cure, and hence a vertebroplasty was patient, and as a reminder of the importance of ruling out sinister performed. This procedure has been shown to provide rapid conditions. A higher index of suspicion and a short panel of stabilisation and analgesia in metastatic cases of vertebral blood tests might have increased the chances of discovering compression fracture, with significant improvements in quality this patient’s malignant condition earlier, before its widespread of life.4 dissemination. This patient’s case is unique, as he presented with two uncommon problems: LBP secondary to malignancy (<1% of Conclusion causes of LBP); and, MBC (<1% of breast cancers).1,3 Although This case highlights the importance of keeping a heightened the incidence of MBC has been increasing in the last 25 years, it vigilance for uncommon, serious conditions in patients presenting is still a rare condition with few examples found in the literature.9 to any medical specialty. Future research in this area should focus This case highlights the importance of keeping a high level of on large-scale trials evaluating novel methods for early detection suspicion for malignancy in any patient (male or female) of MBC in the community. Such medical evidence will hopefully presenting with a breast lump, and points to the need for specific lead to the development of established guidelines for the guidelines on the diagnosis, clinicopathology and treatment of diagnosis and management of MBC.

References 1. Patrick N, Emanski E, Knaub MA. Acute and chronic low back pain. Med 6. Herkowitz HN. Rothman-Simeone: The Spine (6th ed.). Philadelphia;

Clin North Am. 2016;100(1):169-81. Saunders/Elsevier, 2011:1041-1050, 1596-1609, 1704-1719. (E-book.)

2. Shaikh M, Ostor AJ. Evaluating the patient with low back pain. Practitioner. 7. Sedighi A, Hamed EA, Mohammadian K, Behnood S, Kalaghchi B. Clinicopathologic

2015;259(1788):21-4, 2-3. characteristics of male breast cancer: a report of 21 cases in radiotherapy center of

3. Deyo RA, Rainville J, Kent DL. What can the history and physical Hamedan, Iran. Asian Pac J Cancer Prev. 2013;14(12):7381-3.

examination tell us about low back pain? JAMA. 1992;268(6):760-5. 8. Kiluk JV, Lee MC, Park CK, Meade T, Minton S, Harris E et al. Male breast

4. Lopez-O’Rourke VJ, Orient-Lopez F, Fontg-Manzano F, Fernandez-Mariscal cancer: management and follow-up recommendations. Breast J.

E, Combalia A, Vilarrasa-Sauquet R et al. Pathological vertebral 2011;17(5):503-9.

compression fracture of C3 due to a breast cancer metastasis in a male 9. Azar, FM. Campbell’s operative orthopaedics. (13th ed.). Philadelphia;

patient. Spine (Phila Pa 1976). 2009;34(16):E586-90. Elsevier, 2017:2486-2566. (E-book.).

5. Zurrida S, Nole F, Bonanni B, Mastropasqua MG, Arnone P, Gentilini O et 10. Reis LO, Dias FG, Castro MA, Ferreira U. Male breast cancer. Aging Male.

al. Male breast cancer. Future Oncol. 2010;6(6):985-91. 2011;14(2):99-109.

Page 18 | Volume 11: Number 1. 2018 RCSIsmjoriginal article

When the brain goes quiet: cortical silence inhibition in schizophrenia

Abstract The use of non-invasive brain stimulation techniques, such as transcranial magnetic stimulation (TMS), has demonstrated that patients with schizophrenia are deficient in cortical inhibition. These

deficits can be due to impaired gamma-aminobutyric acid B (GABAB) activity, which may be involved in the underlying pathophysiology. Previous studies demonstrate altered cortical inhibition

in relation to various GABA properties; however, the level of impairment involving GABAB receptors in patients with schizophrenia remains unclear. The purpose of this study was to examine the cortical silent period (CSP) by TMS measures in patients with schizophrenia and healthy controls. CSP duration was measured by electromyography (EMG) analysis and was the main TMS paradigm studied in 10 patients with schizophrenia and 10 healthy controls. There was no statistical significance between increased CSP duration in patients with schizophrenia and healthy controls; additionally, there were no significant findings when observing CSP duration and positive and negative symptom scale (PANSS) in patients with schizophrenia. However, the increased duration of disease was positively correlated to CSP duration in patients with schizophrenia compared to healthy controls. Our findings suggest that impaired cortical inhibition is seen as disease duration is lengthened.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 19-23.

Introduction Schizophrenia, a psychiatric disorder affecting 1% activity in cortical inhibition may be due to a of the population internationally, affects social and combination of factors that cumulatively leads to occupational function in patients due to chronic cognitive function deficits.9 For example, and recurrent psychosis.1 The exact neuro-anatomical studies suggest that decreased pathophysiology underlying schizophrenia is still GABA interneuron populations in the prefrontal poorly understood.2 However, the supporting cortex result in reduced grey matter volume.9 combination of neuropathology, pharmacology, Furthermore, decreased levels of gene expression in Maria Mikail1 and neurophysiology research suggests that glutamic acid decarboxylase, a functional enzyme Reza Zomorrodi2 patients with schizophrenia have deficits in crucial for GABA synthesis, can contribute to altered Yoshihiro Noda2 underlying cortical inhibition.3-4 General cortical connectivity in patients with Jeff Daskalakis2 psychopathology can be assessed clinically by using schizophrenia.4,8,10 Two subtypes of GABA receptors

1 RCSI medical student the standardised positive and negative syndrome mainly contribute to cortical inhibition: GABAA and 2 5 University of Toronto, CAMH, scale (PANSS). Cortical inhibition in the central GABAB, with fast-acting and slow-acting inhibitory Temerty Centre for Therapeutic nervous system is mainly modulated by action properties, respectively.3,11 The inhibitory Brain Intervention gamma-aminobutyric acid (GABA), which is properties of each GABA receptor subtype can be essential in neuroplasticity and in regulating cortical explored by the use of transcranial magnetic glutamatergic excitability.6-8 Dysfunctional GABA stimulation (TMS), a non-invasive neurological

Volume 11: Number 1. 2018 | Page 19 RCSIsmjoriginal article

20 subjects

Control Patients with schizophrenia n=10 n=10 p=0.61

Inclusion criteria Exclusion criteria Inclusion criteria Able to give consent Positive urine drug screen Age 18-59 Age 18-59 History of seizures MINI and SCID criteria of schizophrenia or MMSE score >27 Alcohol or drug abuse schizoaffective disorder Non-smoker and negative urine drug ECT within six months of experiment Clinically stable screen or prescribed medications Unable to provide consent Able to give consent

FIGURE 1: Inclusion and exclusion criteria of participants in the study. technique, to modulate or trigger cortical inhibitory and excitatory GABAB function. It is hypothesised that patients with schizophrenia 7,9,12 activity. Inhibitory GABAA activity can be indexed by using would demonstrate deficiencies in cortical inhibition, resulting in a short-interval cortical inhibition (SICI).13 The SICI protocol involves the shorter duration of CSP compared with healthy subjects. As genetic administration of a suprathreshold of conditioning TMS pulse, which is postmortem studies show decreased structural protein levels of GABAB followed by a second subthreshold TMS pulse.11 The administration of receptors in patients with schizophrenia, this study provides further the conditioning pulse produces a decrease in the amplitude of response understanding of GABA-ergic physiological dysfunction to further

17 to the test pulse, which is reflective of GABAA receptor-mediated advance future potential therapeutic interventions. 11,14 neurotransmission. However, in this situation, GABAB observation is of importance when determining cortical inhibition in patients with Methods

15 schizophrenia. GABAB can be indexed using cortical silent period Subjects (CSP).9 During the CSP protocol, the target muscle is activated tonically The Ethical Review Board approved the study protocol at the Centre for while a TMS pulse is administered to the corresponding motor region.9 Addiction and Mental Health in accordance with the Declaration of This can be achieved by placing the TMS coil over a certain region of the Helsinki; additionally, all participants provided written informed motor cortex and stimulating muscles in the periphery, which is referred consent.9 The study included a total of 20 subjects (10 cases and 10 to as a motor-evoked potential (MEP).12,16 As a result, the MEP response age- and sex-matched controls). Ten of the subjects had a DSM-IV is inhibited by 50-90% of the GABAB interneuron population, thereby diagnosis of schizophrenia from the Centre for Addiction and Mental eliciting a period of silence recorded by cessation of peripheral muscle Health.3 Inclusion criteria for patients with schizophrenia included: 1. movement, referred to as the cortical silent period (CSP).3,9,12 The age between 18 and 59 years; 2. fulfilled Mini-International duration of the CSP can be measured by electromyography (EMG) by Neuropsychiatric Interview (MINI) and Structured Interview for DSM-IV placing electrodes over the first dorsal interossei (FDI) and observing the (SCID) criteria of schizophrenia or schizoaffective disorder; 3. clinically silent period, which reflects cortical inhibition.3,9,12 Previous studies stable disease course; and, 4. ability to give consent according to the related to cortical inhibition have observed different parameters in MacArthur Competence Assessment Tool (MacCAT). Exclusion criteria patients with schizophrenia when compared to healthy controls with the for the schizophrenia group included: 1. positive urine drug screen; 2. use of TMS, such as resting motor threshold, SICI, intracortical history of seizures; 3. alcohol or drug abuse; 4. electroconvulsive facilitation, and motor-evoked potential amplitudes.7 However, the therapy within six months of this experiment; and, 5. inability to objective of this study is to compare the duration of CSP in patients with provide consent. The 10 healthy control participants were matched for schizophrenia compared to healthy subjects, as it reflects underlying age (p=0.61) and sex. Additionally, inclusion criteria for healthy

Page 20 | Volume 11: Number 1. 2018 RCSIsmjoriginal article

Table 1: Patient demographics and clinical characteristics. The positive and negative syndrome scale5 was used to assess disease severity in patients with schizophrenia.

Patients with schizophrenia Healthy subjects (n=10) (n=10)

Age 42.7±9 40.7±13.5

Sex (M:F) 6:4 5:5

PANSS score5 50.3 N/A

Total N/A FIGURE 2: Cortical silent period. A-C represent CSP following muscle Positive 10.78 N/A action potentials after multiple muscle stimuli in a healthy participant. Negative 12.56 N/A D represents the overall average CSP duration in a healthy individual. CSP was measured from the beginning of MEP to return of background General 23.56 N/A muscle activity. controls included: 1. ability to give consent; 2. age 18-59; 3. of the central sulcus, about 45° in the direction of the midsagittal Mini-Mental State Examination (MMSE) score >27; and, 4. line.9,16,19 non-smokers and negative for recreational substances or prescribed medications (Figure 1). The demographics and data from the Resting motor threshold participants are summarised in Table 1. Before measuring participants’ At the beginning of each session the rMT was determined by applying CSP, patients with schizophrenia were assessed for their positive and a single pulse of TMS over the motor cortex to elicit MEPs from the negative syndrome scale (PANSS).5 After assessment, participants were right FDI.18,20 rMT was defined as the minimal intensity used to brought to the lab to measure CSP duration. stimulate a resting muscle to evoke MEPs with a peak-to-peak amplitude >50V consecutively when five out of ten pulses are Measure of cortical inhibition by electromyography administered.9,16,20 The EMG electrodes were placed over the right FDI, the bulk of the thenar eminence, and over the first metacarpophalangeal joint. In Cortical silent period addition, a ground electrode was placed over the supinated right CSP was observed when subjects voluntarily contracted the right FDI forearm. Patients were seated in a comfortable armchair and were in a muscle when the left motor threshold was stimulated at 140% of the relaxed position while awake and with eyes open.9,16 The EMG rMT.9,16 Fifty stimuli were administered to the participants every five motor-evoked potential readings were amplified and filtered seconds, when the FDI muscle was contracted at 20% of maximal (band-pass 2Hz to 5kHz), digitalised at 5kHz (Micro 1401; Cambridge contraction, which was measured by a strain gauge meter.9,16,21 The Electronics Design), and monitored on a computer screen.9,16 duration of CSP was measured from the onset of MEP to the return of background muscle activity as observed from EMG. Multiple CSP Transcranial magnetic stimulation durations were then indexed using multiple stimuli. The average TMS pulses were applied in a monophasic fashion and were duration of CSP for patients with and without schizophrenia was then administrated using a 7cm figure-of-eight coil and the use of determined, as shown in Figure 2. Magstim 200 stimulators (The Magstim Company; Whitland, UK) that were connected by a Bistim module (The Magstim Company; Results Whitland, UK). Administration of the TMS was concentrated over the Brain-evoked potentials were stimulated by the use of TMS and left motor cortex to elicit MEPs from the right FDI.18,19 recorded using a 64-channel EEG on 20 study subjects (10 cases; 10 Coil administration was placed perpendicular to the accepted direction age- and sex-matched controls). In this sample, the mean duration of

Volume 11: Number 1. 2018 | Page 21 RCSIsmjoriginal article

60

0.2 * 55 * ** * R=0.68, P=0.029 R=0.41, P=0.23 50 * 0.18 * * * * * * * 45 * ** 0.16 * * <> * 40 * * * *

* Age 0.14 * * <> * 35

CSP CSP (second) * * 0.12 * * 30 * * * * 25 * * 0.1 * 20 0.08 0.1 0.12 0.14 0.16* 0.18* 0.2 0.22 * SCZ HC CSP

FIGURE 3: CSP duration in patients with schizophrenia (SCZ) and FIGURE 5: CSP duration and patient’s age. CSP duration in seconds healthy subjects (HS). Data was collected from 10 healthy controls and (x-axis) and age (y-axis) correlation were observed between healthy 10 patients with schizophrenia. The x-axis represents the two different controls (blue) and patients with schizophrenia (red). Healthy controls groups and the y-axis represents the CSP duration in seconds. Silent showed no significance in data (r=-0.41, p=0.23). Patients with periods were calculated from the beginning of MEP to the return of schizophrenia showed statistically significant findings between age and background muscle activity. The mean CSP in healthy controls was 0.14 CSP duration (r=0-.68, p=0.029). sec ± 0.03, while in patients with schizophrenia CSP was 0.16 ± 0.03, and did not statistically differ (t(9)=1.23, p=0.23). The median value CSP between healthy subjects (0.14 sec ± 0.03) and subjects with between the two groups is represented by the red line, while the mean schizophrenia (0.16 sec ± 0.03) did not differ significantly (t(9)=1.23, value is represented by a green dot. p=0.23). Figure 3 shows the CSP duration between healthy and control subjects. There was no significant correlation between CSP duration and

65 schizophrenia symptom severity (r=-0.22, p=0.54), as shown in Figure 4. Total mean PANSS score in the patients with schizophrenia was 50.3. * R=0.22, P=0.54 Our results showed a statistically significant correlation between CSP 60 duration and age in patients with schizophrenia (r=-0.68, p=0.029). However, there were no statistically significant findings in healthy 55 * * * controls (r=-0.41, p=0.23). * * 50 Discussion PANSS * Our results showed that patients with schizophrenia did not have an 45 increased CSP duration when compared to healthy controls (Figure 3). * Additionally, there was no association between CSP duration and PANSS

40 value in patients with schizophrenia (Figure 4). However, when examining the correlation between age and CSP duration, there was a * statistically significant finding in patients with schizophrenia that was not 35 * 0.12 0.13 0.14 0.15 0.16 0.17 0.18 0.19 0.2 0.21 observed in healthy controls (Figure 5). This prolonged CSP duration CSP was seen in older subjects with schizophrenia and may represent FIGURE 4: CSP duration and PANSS scale. The x-axis represents the CSP impaired cortical inhibition as the duration of disease increases, thus duration (seconds) in patients with schizophrenia. The y-axis represents reflecting impaired ability of neurons to hyperpolarise.9 the PANSS scale (symptom severity) exhibited in 10 patients with While other groups found a relationship between a prolonged duration schizophrenia. There was no statistically significant finding between the of CSP in patients with schizophrenia treated with clozapine when two variables (r=-0.22, p=0.54). compared to controls, our group was not able to replicate this finding.9

Page 22 | Volume 11: Number 1. 2018 RCSIsmjoriginal article

This prolonged CSP duration may be explained by clozapine having treatment.4 There are several limitations to consider in our study,

3,9 GABAB receptor antagonistic affects. This suggests that there is which may have affected the results. Primarily, the small sample size some relationship between cortical inhibition and schizophrenia, as is not adequate to definitively draw conclusions when comparing medication can increase CSP duration or normalise it.3,9 In addition, the two different populations. Secondly, patients were questioned our results did not show a relation between CSP duration and on medications prior to participating in the study; however, the increased PANSS. However, two previously conducted studies showed study did not exclude medicated patients. Therefore, medication different results, indicating that if a correlation between CSP duration effects may have acted as a confounding variable on CSP duration. and PANSS exists, it remains very small.3 The use of neurophysiological Future studies should account for these limitations to verify the technology represents a novel form of non-invasive brain stimulation current findings. This work demonstrates that no statistical therapy (NIBS) examining aberrancies in cortical inhibition and significance between CSP duration and PANSS score is observed in neuroplasticity in patients with schizophrenia.4 Findings from the patients with schizophrenia. However, a correlation between CSP current evidence suggesting that there are impairments in cortical duration and disease duration in patients with schizophrenia was inhibition may contribute to the pathophysiology underlying observed. This study demonstrates a platform that can be used for schizophrenia. Future pharmacological and non-pharmacological future studies to observe cortical inhibition in patients with clinical approaches can enhance inhibition as a form of targeted schizophrenia.

References 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental transcranial magnetic stimulation combined with electroencephalography.

Disorders (5th ed.) (DSM-5). London: American Psychiatric Publishing, 2013. Front Neural Circuits. 2016;10:73.

2. Patel KR, Cherian J, Gohil K, Atkinson D. Schizophrenia: overview and 13. Wagle-Shukla A et al. Effects of short interval intracortical inhibition and

treatment options. P T. 2014; 39(9):638-45. intracortical facilitation on short internal intracortical facilitation in human

3. Kaster TS et al. Clozapine potentiation of GABA mediated cortical inhibition in primary motor cortex. J Physiol. 2009;587(Pt 23):5665-78.

treatment resistant schizophrenia. Schizophr Res. 2015;165(2-3):157-62. 14. Michel FJ, Trudeau LE. Clozapine inhibits synaptic transmission at GABAergic

4. Bhandari A et al. A review of impaired neuroplasticity in schizophrenia synapses established by ventral tegmental area neurons in culture.

investigated with non-invasive brain stimulation. Front Psychiatry. 2016;7:45. Neuropharmacology. 2000;39(9):1536-43.

5. Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale 15. Rogasch NC, Daskalakis ZJ, Fitzgerald PB. Cortical inhibition, excitation, and

(PANSS) for schizophrenia. Schizophr Bull. 1987;13(2):261-76. connectivity in schizophrenia: a review of insights from transcranial magnetic

6. Kelsom C, Lu W. Development and specification of GABAergic cortical stimulation. Schizophr Bull. 2014;40(3):685-96.

interneurons. Cell Biosci. 2013;3(1):19. 16. TMS User Manual Version 1.0. Centre for Addiction and Mental Health.

7. Radhu N et al. A meta-analysis of cortical inhibition and excitation using 17. Fatemi SH, Folsom T, Thuras PD. Deficits in GABAB receptor system in transcranial magnetic stimulation in psychiatric disorders. Clin Neurophysiol. schizophrenia and mood disorders: a postmortem study. Schizophr Res.

2013;124:1309-20. 2011;128(1-3):37-43.

8. Fischer B, Marder S, Hermann R. Schizophrenia: Epidemiology and pathogenesis. 18. Frantseva M, Cui J, Farzan F, Chinta LV, Velazquez J, Daskalakis Z. Disrupted

UpToDate, 2017. [Internet]. [cited 2017 Mar 31]. Available from: cortical conductivity in schizophrenia: TMS-EEG study. Cereb Cortex.

https://www-uptodate-com.proxy.library.rcsi.ie/contents/schizophrenia-epid 2014;24(1):211-21.

emiology-and-pathogenesis?source=see_link#H31673341. 19. Ilmoniemi R, Kicic D. Methodology for combined TMS and EEG. Brain

9. Daskalakis Z et al. Increased cortical inhibition in persons with schizophrenia Topogr. 2010;22(4):233-48.

treated with clozapine. J Psychopharmacol. 2008;22(2):203-9. 20. Temesi J, Gruet M, Rupp T, Verges S, Millet GY. Resting and active motor

10. Benes FM. Regulation of cell cycle and DNA repair in post-mitotic GABA thresholds versus stimulus-response curves to determine transcranial magnetic

neurons in psychotic disorders. Neuropharmacology. 2011;60(7-8):1232-42. stimulation intensity in quadriceps femoris. J Neuroeng Rehabil. 2014;11:40.

11. Mann EO et al. Distinct roles of GABA(A) and GABA(B) receptors in balancing 21. Poston B, Kukke SN, Paine RQ, Francis S, Hallett M. Cortical silent period

and terminating persistent cortical activity. J Neurosci. 2009; 29(23):7513-8. duration and its implications for surround inhibition of a hand muscle. Eur J

12. Farzan F et al. Characterizing and modulating brain circuitry through Neurosci. 2012;36(7):2964-71.

Volume 11: Number 1. 2018 | Page 23 RCSIsmjreview

Plastic surgery’s role in aneuploidy

Abstract In this article, the three most common aneuploidies and the role of plastic surgery for treating the symptomology of each are examined. For many years, plastic surgery for these conditions was considered only for its functional purposes – a means to correct structural abnormalities that impaired normal daily activities. However, with the emergence of research around the psychosocial effects of dysmorphias on the lives of patients with aneuploidies, the role of plastics may broaden to include strictly cosmetic corrections in the treatment regimen. Inga Muser This is not without its ethical considerations, and these arguments are discussed alongside RCSI medical student relevant anecdotes and research.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 24-28.

Page 24 | Volume 11: Number 1. 2018 RCSIsmjreview

Introduction in order to improve only the cosmetic appearance of their Aneuploidies present a broad range of medical challenges. While dysmorphic features. Currently, it is not unlawful in the United plastic surgery is well established as a means of correcting States for parents to request and obtain plastic surgery in these congenital defects that confer functional difficulties – many of cases, although the majority of surgeries performed on children which are discussed here – the use of plastics to correct cosmetic with Down syndrome are for functional reasons.5 dysmorphias is less accepted as standard. Here, the three most common aneuploidies are characterised and As medicine moves towards a more holistic approach to health the role of plastic surgery for each is examined. Success rates are and seeks to improve quality of life for patients in as many ways explored, as are ethical challenges and current views in practice. as possible, the cosmetic dysmorphias associated with aneuploidies are beginning to gain attention. Surgical correction Trisomy 21 of these deformities may be considered trivial to outsiders, but Trisomy 21 (Down syndrome) is the most common of all research presents a different view. Studies have suggested that aneuploidies, with a prevalence of 1 in 700 live births.6 It comes improving the cosmetic appearance of certain dysmorphic with a host of abnormalities including mental retardation, facial features in trisomies can lead to improved social interactions and abnormalities, webbing of the skin of the neck, and broad hands. interpersonal relationships, especially in children – a benefit that A multidisciplinary approach is generally considered the best is undeniably positive when considered from a quality of life treatment for Down syndrome, and in the last decade the debate point of view. over the role of plastic surgery in treatment has become more prevalent in medical literature. Functional plastic surgeries (such Plastic surgery in patients with genetic as those to correct a cleft palate for improved feeding and conditions to improve functional speech) are the most popular; however, cosmetic approaches outcomes such as speech, breathing, and have also gained traction.2 nutrition are widely accepted and utilised Macroglossia as part of the medical treatment of these Reduction of the tongue is one of the most popular plastic conditions. Surgery to improve cosmetic surgeries performed in patients with trisomy 21, as the outcomes outcomes, however, is undoubtedly are often positive both functionally and cosmetically. plagued with ethical questions. Macroglossia corrections may facilitate phonation, better eating and drinking, reduce sleep apnoea (which affects approximately A study in Israel (n=277) found that cosmetic plastic surgery to 50-75% of all patients),3,6 and improve facial appearance. alter some of the more characteristic facial features of Down syndrome in school-age children led to increased social Cleft palate/lip acceptance by their peers. Postoperatively, patients were viewed Down syndrome (along with many other syndromes like as being significantly more “good-hearted”, “socially acceptable”, Waardenburg and Pierre Robin) is associated with a higher risk for “intelligent”, and “attractive” than preoperatively.1 Other studies a cleft lip or palate. Surgical intervention improves feeding, have mirrored these findings,2,3 with one even suggesting that speech, and phonation. Patients and their families often opt for teachers display better attitudes towards postoperative patients in these treatments to maximise language ability and clarity of the classroom.4 speech, as well as to decrease aspiration risk. While parents of post-op patients rated their child’s appearance Other surgical interventions can be taken when dealing with as being “noticeably more attractive” and also reported “happier Down syndrome. Augmentation of the bridge of the nose can personal, family, and social lives”,4 adult strangers rated efface the epicanthus, and a hypotonic lower lip and microgenia postoperative patients as no more attractive than preoperatively,5 can also be improved. perhaps explaining some of the public pushback against subjecting these patients to surgery. Indeed, there has been Cosmetic approaches pushback, and there are those who argue that it is unethical to As mentioned above, patients with trisomy 21 may opt to expose children with impaired mental capacities to major surgery undergo corrective surgery for cosmetic purposes. In a case from

Volume 11: Number 1. 2018 | Page 25 RCSIsmjreview

New York, a 15-year-old boy with Down syndrome had his ears struggle with extreme shyness and social anxiety. Breast pinned by the Little Baby Face Foundation, a charity that reduction surgery has met with considerable success.10 The provides free plastic surgeries to bullied children with deformities. gynaecomastia seen in Klinefelter’s is more severe than that seen Despite having trouble vocalising, upon seeing his new ears for in obese male teenagers without the genetic condition, and is the first time he exclaimed “amazing, just like Dad’s”.7 much harder to treat with diet and exercise.10 Boys going through puberty find these abnormal fat deposits to be especially While medical treatment of trisomies concerning, and it can affect their confidence and willingness to must focus on dangerous or life-limiting participate in sport and other activities. conditions, part of the goal of treatment The feminine fat distribution associated with the condition has also involves maximising quality of life. been corrected with some considerable success using specialised liposuction,11 similar to liposuction done in children and adolescents to correct abnormal fat deposits due to other genetic XXY: Klinefelter syndrome conditions.11 Klinefelter syndrome affects approximately one in 500 live male Interestingly, a rare variant of Klinefelter’s (XXXXY) presents with births.8 Hypotonicity and learning disabilities may be present in incomplete cleft palates, while typical XXY Klinefelter’s does not, infancy and childhood, but symptoms begin to manifest themselves and some studies suggest using this feature as a method to more aggressively during and after puberty. Teenagers and men distinguish typical from atypical Klinefelter’s (which helps to tend towards longer legs, a shorter torso, and broader hips guide treatment options).12 compared to peers. They also exhibit less muscular frames, weak As discussed above, surgical correction of a cleft palate improves bones, social problems, and gynaecomastia. Facial features include language and speech skills, which in turn can improve social sparse or absent facial hair, prognathism, and a short philtrum. interactions with peers and classmates. Some patients find more confidence in their appearance by undergoing surgery to correct the prognathism,9 axillary hair, short (45,X): Turner syndrome philtrum, and abnormal fat distribution. Turner syndrome affects approximately one in every 2,000 live female births13 and has some similarities to Klinefelter’s, but with Liposuction and gynaecomastia important distinguishing characteristics. Turner syndrome affects Gynaecomastia can become a point of concern for men and only females, and in infants manifests as swollen hands and feet, teenagers with Klinefelter syndrome, many of whom already a webbed neck, low hairline, and very small nails.14,15 During

Page 26 | Volume 11: Number 1. 2018 RCSIsmjreview

adolescence, patients with this condition do not go through a dysmorphic features, these surgeries should be considered, but normal growth spurt, leaving them shorter than their peers. not mandatory.5 Despite some strong backlash that labels Furthermore, breast buds do not develop properly, and affected cosmetic surgery in these cases as a rejection of the child and individuals have amenorrhoea and increased webbing of the neck. their condition,22 there remains a growing interest in these procedures. Indeed, the National Down Syndrome Society in The National Down Syndrome Society New York reports that they are sometimes inundated with calls in New York reports that they requesting information on cosmetic surgery.23 Klinefelter and are sometimes inundated with Turner syndromes are characterised far less by intellectual calls requesting information disability, and therefore many of these patients are deemed competent to make healthcare and surgical decisions on their on cosmetic surgery. own. Many of these patients do, in fact, opt to undergo procedures for their cosmetic concerns such as gynaecomastia, Webbed skin of the neck with undeniably positive self-reported outcomes of self-esteem Plastic surgery can help to correct the wide, webbed neck that is and even significant decreases in bullying and depression.10,24 often the most obvious physical abnormality in Turner Herein, however, there arises an issue of resource allocation. For syndrome.16 Correction surgeries for these abnormalities are example, the NHS in the UK (a public healthcare system), like usually twofold. The first procedure uses a butterfly correction many other such systems, imposes essentially a blanket ban on technique; the second uses a posterior Z-plasty. This type of funding for cosmetic surgeries.25,26,27 two-stage surgery has been met with success in many cases,17 While special cases can be brought to the IFR (International and reported patient satisfaction is considerably high. Since this Funding Request) committee for consideration, these requests are abnormality of Turner syndrome can be quite obvious, it can often turned down.28 affect the way a patient dresses, and many patients consider this anomaly cosmetically distressing.17 Indeed, there has been pushback, Turner syndrome is also associated with multiple pilomatricomas and there are those who argue (prevalence rate of 2.6%),18,19 which must be carefully monitored that it is unethical to expose children as they can continuously grow. Pilomatricomas are benign skin with impaired mental capacities to tumours of the hair matrix. While they are not malignant, many major surgery in order to improve patients with multiple pilomatricomas find these distressing only the cosmetic appearance of cosmetically as they often present on the face, and can be large enough to show through clothing. These are easily removed their dysmorphic features. surgically, often under local anaesthetic, and with proper technique leave a minimal scar. Conclusion While medical treatment of aneuploidies must prioritise Ethics dangerous or life-limiting conditions, part of the goal of Plastic surgery in patients with genetic conditions to improve treatment also involves maximising quality of life. As the life functional outcomes such as speech, breathing, and nutrition are expectancy for many people with genetic conditions continues to widely accepted and utilised as part of the medical treatment of rise, this will become increasingly important. Plastic surgery these conditions. Surgery to improve cosmetic outcomes, already plays a role in providing correction of physical however, is undoubtedly plagued with ethical questions. Namely, abnormalities from a functional point of view, but it is also concern arises in patients with severe intellectual disability, as becoming increasingly popular – and perhaps beneficial from a some research considers subjecting these individuals to major patient satisfaction point of view – to involve plastics for cosmetic surgery simply for cosmetic reasons to be cruel and reasons. Plastic surgery may have a larger, previously overlooked unjustified.20,21 Another school of thought argues that because role to play in improving the quality of life for patients with there is some evidence of greater social acceptance and even chromosomal abnormalities, both from a functional and cosmetic personal satisfaction after cosmetic correction of characteristic point of view.

Volume 11: Number 1. 2018 | Page 27 RCSIsmjreview

References 1. Strauss RP, Mintzker Y, Feuerstein R, Wexler MR, Rand Y. Social perceptions 15. National Human Genome Research Institute. (2016). Nail, Small. 2016.

of the effects of Down syndrome facial surgery: a school-based study of [Internet]. [Accessed 2016]. Available from:

ratings by normal adolescents. Plast Reconstr Surg. 1988;81(6):841-51. https://elementsofmorphology.nih.gov/index.cgi?tid=164fef3895cda7aa.

2. May DC, Turnbull N. Plastic surgeons’ opinions of facial surgery for 16. Eppley B. Plastic surgery case study – webbed neck correction with otoplasties. 2015.

individuals with Down syndrome. Ment Retard. 1992;30(1):29-33. [Internet]. [Accessed 2016]. Available from:

3. Lewandowicz E, Kruk-Jeromin J. The indications and the plan of plastic http://exploreplasticsurgery.com/tag/webbed-neck-correction/#sthash.dVlPUq6k.dpuf.

operations in children with Down’s syndrome. Acta Chir Plast. 17. Hikade KR, Bitar GJ, Edgerton MT, Morgan RF. Modified Z-plasty repair of

1995;37(2):40-4. webbed neck deformity seen in Turner and Klippel-Feil syndrome. Cleft Palate

4. Arndt EM, Lefebvre A, Travis F, Munro IR. Fact and fantasy: psychosocial Craniofac J. 2002;39(3):261-6.

consequences of facial surgery in 24 Down syndrome children. Br J Plastic 18. Handler MZ, Derrick KM, Lutz RE, Morrell DS, Davenport ML, Armstrong AW.

Surg. 1986;39(4):498-504. Prevalence of pilomatricoma in Turner syndrome: findings from a multicenter

5. Kravetz S, Weller A, Tennenbaum R, Tzuriel D, Mintzker Y. Plastic surgery study. JAMA Dermatol. 2013;149(5):559-64.

on children with Down syndrome: parents’ perceptions of physical, 19. Maeda D, Kubo T et al. Multiple pilomatricomas in a patient with Turner

personal, and social functioning. Res Dev Disabil. 1992;13(2):145-56. syndrome. J Dermatol. 2014;41(6):1346-8138.

6. Centers for Disease Control and Prevention. Data and Statistics. 20. Aylott J. Should children with Down’s syndrome have cosmetic surgery? Br J

Occurrence of Down syndrome in the United States. 2014. [Internet]. Nurs. 1999;8(1):33-8.

[Accessed 2016]. Available from: 21. Jones RB. Parental consent to cosmetic facial surgery in Down’s syndrome. J

www.cdc.gov/ncbddd/birthdefects/downsyndrome/data.html. Med Ethics. 2000;26(2):101-2.

7. Roberts, H. ‘Now they’re just like Dad’s’: Family delighted as Downs 22. Katz S, Kravetz S. Facial plastic surgery for persons with Down syndrome:

syndrome boy, 15, who endured lifetime of bullying gets ‘new ears’. Daily research findings and their professional and social implications. Am J Ment

Mail, 2012. [Internet]. [Accessed 2016]. Available from: Retard. 1989;94(2):101-10.

http://www.dailymail.co.uk/news/article-2085501/Down-Syndrome-boy-C 23. Springer I. Plastic surgery for Down syndrome. Washington Post. 1988. [Internet]. Available from:

harlie-Cardillo-15-endured-lifetime-bullying-gets-new-ears.html. https://www.washingtonpost.com/archive/lifestyle/wellness/1988/06/07/plastic-surgery-for-dow

8. University of Texas Medical Branch. Medical Genetics and Dysmorphology. n-syndrome/0d477b9e-3665-49a7-81b4-06f2f32ae8a2/?utm_term=.06ac58841201.

Abnormalities of Chromosomes Number (Aneuploidy). 2008. [Internet]. 24. Paduch DA, Schlegel PN, Bergadá I, Rey RA. Male hypogonadism. In:

[Accessed 2016]. Available from: Sarafoglou K, Hoffmann GF, Roth KS (eds.). Pediatric Endocrinology and

http://www.utmb.edu/pedi_ed/CORE/MedicalGenetics/page_11.htm. Inborn Errors of Metabolism. New York: McGraw-Hill, 2009:575-600.

9. Purnak S, Ada S et al. Diagnosis of variant Klinefelter syndrome in a 25. Adams S. “Third of health authorities ‘still imposing blanket treatment bans’”.

21-year-old male who presented with sparse facial hair. Ann Dermatol. The Telegraph, 2012. [Internet]. Available from:

2012;24(3):368-9. https://www.telegraph.co.uk/news/health/news/9539341/Third-of-health-aut

10. Singer-Granick CJ, Reisler T, Granick M. Gynecomastia and Klinefelter horities-still-imposing-blanket-treatment-bans.html.

syndrome. Eplasty. 2015;15:ic61. 26. Department of Health, UK. The Operating Framework for the NHS in England

11. Berenguer B, de la Cruz L et al. Liposuction in children: clinical utility. Cir 2012-13. 2012. [Internet]. Available from:

Pediatr. 2005;18(4):188-91. https://www.gov.uk/government/publications/the-operating-framework-for-th

12. Velidedeo lu HV et al. Uncommon Klinefelter’s variant (49,XXXXY) with e-nhs-in-england-2012-13.

cleft palate. Ann Plast Surg. 1997;39(2):213-5. 27. National Audit Office of the NHS. Progress in Making NHS Efficiency Savings.

13. Daniel MS et al. (2016). Turner syndrome. MedScape, 2016. [Internet]. 2012. [Internet]. Available from:

[Accessed 2016]. Available from: https://www.nao.org.uk/report/progress-in-making-nhs-efficiency-savings/.

http://emedicine.medscape.com/article/949681-overview. 28. Russell J, Swinglehurst D, Greenhalgh T. ‘Cosmetic boob jobs’ or

14. Mayo Clinic. Turner syndrome. 2016. [Internet]. [Accessed 2016]. Available from: evidence-based breast surgery: an interpretive policy analysis of the rationing

http://www.mayoclinic.org/diseases-conditions/turner-syndrome/basics/sy of ‘low value’ treatments in the English National Health Service. BMC Health

mptoms/con-20032572. Serv Res. 2014;14:413.

Page 28 | Volume 11: Number 1. 2018 RCSIsmjreview

The misnomer of the ‘oral contraceptive pill’

Abstract Oral contraception is one of the most commonly prescribed medications globally. Despite the vast body of literature describing the non-contraceptive health benefits of the combined oral contraceptive pill, widespread knowledge of these benefits in both medical education and the community is still lacking. Some of the most problematic gynaecological health issues may be treated with the combined oral contraceptive pill, including: endometrial and ovarian cancers; endometriosis; ovarian cyst accidents; and, menstrual cycle abnormalities. Thus, the incorporation of evidence-based information in standard medical education, and in turn in patient communication, could significantly impact gynaecological health. The goal of this review is to increase awareness of the non-contraceptive benefits of the combined oral contraceptive pill by providing a summary of current clinical observations.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 29-34.

Introduction Since its development in the 1960s, the oral and progestogen, is one of the more common contraceptive pill (OCP) has been one of the forms of oral contraception. The COCP effectively most widely used prescriptions globally. stops ovulation by suppressing gonadotropin Approximately 15% of females in developed release, thereby reversibly inhibiting fertility.4 In Kelly Gutpell countries are currently using it,1 and 50-80% of the early 1980s it became evident that the OCP, RCSI medical student females admit to using an OCP at some point in in addition to its contraceptive efficacy, also had their lives.2,3 In particular, the combined oral non-contraceptive health benefits. Some of the contraceptive pill (COCP), consisting of oestradiol earliest reports were of its effects on

Volume 11: Number 1. 2018 | Page 29 RCSIsmjreview

endometriosis, pelvic inflammatory disease (PID) and the literature regarding the COCP for these non-contraception dysmenorrhoea.5 Over the past three decades, a number of studies gynaecological issues. have contributed to this growing body of literature and it is now well accepted that contraception is only one of many potential uses of the COCP.6 Increased knowledge regarding Females seeking contraception are typically prescribed a COCP by non-contraceptive COCP uses, however, their general practitioner.7 As such, most general practitioners have may enable clinicians to more effectively a thorough understanding of the advantages and disadvantages of care for their patients by broadening prescribing the COCP for this scenario. Increased knowledge the range of gynaecological issues regarding non-contraceptive COCP uses, however, may enable potentially treatable at the level clinicians to more effectively care for their patients by broadening of general practice. the range of gynaecological issues potentially treatable at the level of general practice. This is an especially important point given that persistent Effects of the COCP on ovarian tissue gynaecological complaints are often untreated at the general Ovarian cancer is the fourth most common cause of invasive cancer practice level and are instead referred on to gynaecological death in Ireland.9 It is insidious, often presenting late and carrying a specialists. In Ireland, 18.7% of patients on the gynaecology poor prognosis. One of the most well-documented and significant outpatient waiting list have been waiting for over one year for an benefits of the COCP is the reduced risk of ovarian cancer. Even initial appointment.8 short-term COCP use is protective, as it has been shown to reduce Thus, given the growing body of literature supporting the use of the the risk of ovarian neoplasms in females who use it for less than one COCP for managing a variety of gynaecological conditions, it is year.10 Risk reduction increases with length of use, with one imperative that general practitioners are equipped with the proper prospective study reporting up to an 80% decrease in risk of ovarian knowledge surrounding these non-contraceptive benefits. The aim cancer if the COCP is taken for more than 10 years.11 Importantly, of this review is to provide future clinicians with the current state of the effect of the COCP in preventing ovarian cancer is long lasting,

Page 30 | Volume 11: Number 1. 2018 RCSIsmjreview

Table 1: Indications and contraindications of the combined oral contraceptive pill.

Labelled indications Off-label indications Relative contraindications1 Absolute contraindications2

• Contraception • PCOS • Age >35 and smokes 0-14 cigarettes/day • Age >35 and smokes >15 cigarettes/day

• Acne3 • Endometriosis • Breastfeeding >6 weeks post partum • Pregnancy

• Amenorrhoea • Controlled hypertension (<140/90mmHg) • Breastfeeding

• Menorrhagia • Gallbladder disease • Hypertension (>160/100mmHg)

• Fibroid-related anaemia • Known hyperlipidaemia • History of DVT or PE

• Dysmenorrhoea • Diabetes for >20 years or with known complications • Known genetic thrombophilia

• Use of anticonvulsants • History of CAD or stroke

• Rifampicin therapy • Migraines with aura

• Migraines without aura and age >35 • Current breast cancer

• Previous breast cancer • Liver disease (viral hepatitis, cirrhosis,

benign or malignant hepatic tumour)

• Major surgery with prolonged immobility

PCOS = polycystic ovary syndrome DVT = deep vein thrombosis PE = pulmonary embolism CAD = coronary artery disease

1. Relative contraindications refer to category 3 conditions. These conditions carry risks that are considered to outweigh the advantages of the COCP.42 2. Absolute contraindications refer to WHO category 4 conditions. These conditions carry unacceptable risks and therefore should never be combined with the COCP.42 3. In the US and the UK, only a limited number of COCPs have been approved to treat acne.43,44 even after cessation. The Royal College of General Practitioners’ Oral beyond 5cm, or are associated with pain, will likely require surgical Contraception Study, which followed over 44,000 ever and never intervention as treatment. As such, proper use of the COCP in females users of the COCP for 44 years, demonstrated that this protective with previous cyst formation may prevent progression to surgery. effect may last for over three decades.12 In this study, the average In patients with PCOS, which is the most common endocrine disorder decrease in risk of ovarian cancer was determined to be 33%, which among females of reproductive age, the androgen-lowering effect of is close to figures previously reported in smaller, shorter studies. This the COCP renders it an effective treatment option.19 The health benefit is especially important in high-risk groups, including androgen-lowering activity is accomplished via decreased androgen females with endometriosis or those with BRCA 1 or BRCA 2 secretion from the ovaries and increased secretion of sex mutations, both of which are associated with an increased risk of hormone-binding protein from the liver. In addition to irregularities developing ovarian cancer.13,14 The beneficial effect of the COCP on with menstruation, one of the most common symptoms related to ovarian cancer is mainly attributed to its suppression of ovulation, hyperandrogenism in PCOS patients is hirsutism, which is excess protecting the surface epithelium from recurring injury. This overall male-pattern hair growth. COCP formulations with a higher oestradiol effect is shown to have other ovary-related benefits as well, including component effectively prevent this troubling symptom associated prevention of ovarian cyst formation,15 polycystic ovary syndrome with PCOS.20 This effect is especially pronounced when combined (PCOS),16 and ovulation pain, known as mittelschmerz.4 Ovarian cysts with an anti-androgen such as cyproterone acetate.21 Another are a common gynaecological issue, with a vast majority of common problem attributed to PCOS is infertility, and indeed many transvaginal ultrasounds showing ovarian cysts in premenopausal females diagnosed with PCOS end up seeking fertility treatment.22 A females at any time.16 Although the majority of ovarian cysts are 2015 study examining the effects of pretreatment with the COCP benign and resolve on their own, problems may arise clinically if prior to in vitro fertilisation reported that it improved the result of the torsion occurs, or if the cyst ruptures or haemorrhages. The COCP procedure, leading to more pregnancy outcomes.23 effectively prevents recurrence of ovarian cyst formation and therefore prevents these complications from arising.17,18 It is important to note, Effects on endometrial tissue however, that the COCP is not an effective treatment for pre-existing One of the more widely used non-contraceptive benefits of the ovarian cysts. Cysts that persist for multiple menstrual cycles, grow COCP is for symptomatic pain relief associated with endometriosis.24

Volume 11: Number 1. 2018 | Page 31 RCSIsmjreview

Endometriosis is the abnormal growth of the innermost layer of the prevention of PID is imperative, especially in sexually active females. uterus in an extra-uterine location including, for example, growth of The COCP thickens cervical mucus, which makes it difficult for the endometrial tissue in the fallopian tubes, ovaries, or the pouch of bacteria to ascend the reproductive tract.4 Although barrier methods Douglas. A COCP with a high component of progestin has been are ultimately key for prevention, the Women’s Health Study in the shown to not only alleviate the pain associated with the condition, 1980s reported a 50% reduction in the risk of PID owing to use of but also to reduce regrowth and prevent the need for surgery. The the OCP.35 While other studies have failed to reach such a high risk effect of the COCP on endometriosis is so significant that the Royal reduction, subsequent findings have since supported the effect of College of Obstetricians and Gynaecologists recommends it as the COCP on reduced infection rates compared to non-users.38,39 first-line treatment for the condition.25,26 Since endometriosis is a chronic disorder, the COCP can be beneficial due to patients being The beneficial effect of the COCP able to remain on the drug for an extended length of time.24 on ovarian cancer is mainly attributed Endometrial hyperplasia, which is observed in PCOS, obesity, and to its suppression of ovulation, oestrogen-secreting tumours, is also suppressed with a protecting the surface epithelium progestin-containing COCP.27 The COCP can play a significant from recurring injury. protective role in these females as endometrial hyperplasia is a known risk factor for endometrial cancer.28 In fact, for every five years a Non-gynaecological benefits of the COCP female is on a COCP containing a high dose of progestin, there is an A number of non-gynaecological health benefits of the COCP also associated 24% decrease in the risk of developing endometrial exist. Along with endometrial and ovarian cancers, the COCP has cancer.29 Similar to the protective effect of the COCP in reducing also been shown to reduce the risk of colorectal cancer. A 2009 ovarian cancer risk, this risk reduction of endometrial cancer is also meta-analysis of 23 studies concluded that ever users had a 19% durable, lasting more than 30 years after use has ceased. lower risk of colorectal cancer compared to never users, with an even lower relative risk if use was within the previous ten years.40 One of the most well-documented Acne control is an important off-label use of the COCP. A 2007 and significant benefits of the Cochrane meta-analysis reviewed 23 randomised controlled trials COCP is the reduced risk that assessed the effect of the COCP on acne. The review concluded of ovarian cancer. that the COCP reduces total number of facial lesions, severity of lesions, and improves self-assessed acne compared to placebo.41 The Other gynaecological benefits of the COCP COCP thus contributes an added quality of life benefit for females In addition to the effects of the COCP on maintaining quiescence of seeking both contraception and improved skin complexion. endometrial and ovarian tissue, a number of other gynaecological benefits have been reported. Dysmenorrhoea, or painful Conclusion menstruation, is a common disorder that is a major cause of missed There is an abundance of literature describing ‘off-label’ uses of the school in adolescents and missed work in premenopausal females. COCP. This review summarises some of the most common and The COCP is first-line treatment in females experiencing significant labelled and off-label uses of the COCP (Table 1) and dysmenorrhoea.30 A specific formulation, dienogest-estradiol provides information on other benefits, such as reducing the risk of valerate, was also approved by the FDA in 2012 as a treatment for endometrial and ovarian cancers. Despite these benefits, COCP menorrhagia, abnormal uterine bleeding during menstruation, treatment must involve careful consideration of the various which is associated with anaemia and social distress.31-33 A 2012 conditions where contraindications may preclude its use (Table 1). study examining the effects of this formulation found up to a 60% While this review provides students and clinicians with the current reduction in menorrhagia after only six months of treatment.34 One state of the literature regarding the benefits of the COCP, limitations of the earliest reported non-contraceptive benefits of the COCP is its do exist. Importantly, this review does not provide information protective effect against PID.35,36 PID is an infection, usually of regarding how differences in age and fertility status may impact the bacterial origin, of the upper female reproductive tract. Fibrotic beneficial effects of the COCP. Furthermore, the benefits described tissue laid down in the repair process following an infection can lead herein are dose specific, so awareness of the different formulations to infertility, ectopic pregnancy, and chronic pelvic pain.37 Thus, that exist is important to consider when making treatment

Page 32 | Volume 11: Number 1. 2018 RCSIsmjreview

decisions. Given the vast number of health benefits conferred by the The non-contraceptive benefits of the COCP are an important topic COCP, increasing patient and clinician knowledge of these effects is in medical education as they have a number of implications for vital. Although the benefits are now quite well known, and further future clinical practice. First, clinicians with evidence-based benefits may be emerging, barriers to its widespread use do exist. knowledge of these benefits can more efficiently and effectively Some of the most common barriers may include religious and treat patients. This point is especially important in a general practice personal beliefs towards contraception, monthly costs to the setting whereby proper management of gynaecological disorders at uninsured, inadequate awareness of the off-label uses, and presence this level may alleviate the long waiting times currently in place for of patient risk factors. In addition to health conditions that preclude consultation with gynaecologists. Although general practitioners are use of the COCP in some females (Table 1), physicians should also the main prescribers of these medications, it is also important for a be aware of the other disadvantages of the COCP. Some females wide range of clinicians to be aware of these effects. When taking a report minor side effects including nausea, headache, breast patient history, it is imperative to not assume a contraceptive tenderness, and breakthrough bleeding.45 Additionally, it does not purpose for use of the COCP, as this prescription alone may actually confer protection against sexually transmitted diseases and the indicate an underlying health issue not offered in the past medical barrier method is therefore still essential for safe sexual practice. The history. Taken together, the health benefits of the COCP should not onus is therefore on the clinician to effectively provide unbiased, be overlooked. Instead, increased awareness of the evidence-based information regarding these health benefits to non-contraceptive benefits should be introduced in medical patients of all backgrounds to help them navigate the best course of education as it may have a significant impact on future patient care treatment that aligns with both their personal and health needs. in both a general practice and specialist setting.

References 1. Christin-Maitre S. History of oral contraceptive drugs and their use 9. National Cancer Registry Ireland. Cancer Factsheet: Ovary. 2017.

worldwide. Best Pract Res Clin Endocrinol Metab. 2013;27(1):3-12. [Internet]. [updated May 2017, cited 2018 January 18]. Available from:

2. Skouby SO. Contraceptive use and behavior in the 21st century: a https://www.ncri.ie/sites/ncri/files/factsheets/ovary.pdf.

comprehensive study across five European countries. Eur J Contracept 10. Lurie G, Wilkens LR, Thompson PJ et al. Combined oral contraceptive use

Reprod Health Care. 2004;9(2):57-68. and epithelial ovarian cancer risk: time-related effects. Epidemiology.

3. Mosher WD, Jones J. Use of contraception in the United States: 2008;19(2):237-43.

1982-2008. Vital Health Stat 23. 2010;(29):1-44. 11. Kumle M, Weiderpass E, Braaten T et al. Risk for invasive and borderline

4. Rivera R, Yacobson I, Grimes D. The mechanism of action of hormonal epithelial ovarian neoplasias following use of hormonal contraceptives: the

contraceptives and intrauterine contraceptive devices. Am J Obstet Norwegian-Swedish Women’s Lifestyle and Health Cohort Study. Br J

Gynecol. 1999;181(5 Pt 1):1263-9. Cancer. 2004;90:1386-91.

5. Starks GC. Therapeutic uses of contraceptive steroids. J Fam Pract. 12. Iversen L, Sivasubramaniam S, Lee AJ et al. Lifetime cancer risk and

1984;19(3):315-21. combined oral contraceptives: the Royal College of General Practitioners’

6. Nappi RE, Serrani M, Jensen JT. Noncontraceptive benefits of the estradiol Oral Contraception Study. Am J Obstet Gynecol.

valerate/dienogest combined oral contraceptive: a review of the literature. 2017;216(6):580.e1-580.e9.

Int J Womens Health. 2014;6:711-8. 13. Brinton LA, Sakoda LC, Sherman ME et al. Relationship of benign

7. Sweeney L-A, Molloy GJ, Byrne M et al. A qualitative study of prescription gynecologic diseases to subsequent risk of ovarian and uterine tumors.

contraception use: the perspectives of users, general practitioners and Cancer Epidemiol Biomarkers Prev. 2005;14:2929-35.

pharmacists. PLoS ONE. 2015;10(12):e0144074. 14. Antoniou A, Pharoah PD, Narod S et al. Average risks of breast and ovarian

8. The National Treatment Purchase Fund. Outpatient by specialty as of cancer associated with BRCA1 or BRCA2 mutations detected in case series

29/12/17. [Internet]. [cited 2018 January 18]. Available from: unselected for family history: a combined analysis of 22 studies. Am J Hum

http://www.ntpf.ie/home/pdf//2017/12/nationalnumbers/out-patient/Nati Genet. 2003;72(5):1117-30.

onal02.pdf. 15. Bottomley C, Bourne T. Diagnosis and management of ovarian cyst

Volume 11: Number 1. 2018 | Page 33 RCSIsmjreview

accidents. Best Pract Res Clin Obstet Gynaecol. 2009;23(5):711-24. 30. Schindler AE. Non-contraceptive use of hormonal contraceptives for

16. Al Khalifah RA, Florez ID, Dennis B et al. Metformin or oral contraceptives women with various medical problems. J Pediat Obstet Gynecol.

for adolescents with polycystic ovarian syndrome: a meta-analysis. 2008;34:183-200.

Pediatrics. 2016;137(5):pii:e20154089. 31. Jensen JT, Parke S, Mellinger U et al. Effective treatment of heavy menstrual

17. Payne JH, Maclean RM, Hampton KK et al. Haemoperitoneum associated bleeding with estradiol valerate and dienogest: a randomized controlled

with ovulation in women with bleeding disorders: the case for trial. Obstet Gynecol. 2011;117(4):777-87.

conservative management and the role of the contraceptive pill. 32. Rafie S, Borgelt L, Koepf ER et al. Novel oral contraceptive for heavy

Haemophilia. 2007;13(1):93-7. menstrual bleeding: estradiol valerate and dienogest. Int J Wom Health.

18. Grimes DA, Jones LB, Lopez LM et al. Oral contraceptives for functional 2013;5:313-21.

ovarian cysts. Cochrane Database Syst Rev. 2009;(4):CD006134. 33. Heikinheimo O, Fraser I. The current status of hormonal therapies for heavy

19. Badawy A, Elnashar A. Treatment options for polycystic ovary syndrome. menstrual bleeding. Best Pract Res Clin Obstet Gynaecol. 2017;40:111-20.

Int J Wom Health. 2011;3:25-35. 34. Fraser IS, Jensen J, Schaefers M et al. Normalization of blood loss in

20. Batukan C, Muderris II. Efficacy of a new oral contraceptive containing women with heavy menstrual bleeding treated with an oral contraceptive

drospirenone and ethinyl estradiol in the long-term treatment of hirsutism. containing estradiol valerate/dienogest. Contraception.

Fertil Steril. 2006;85(2):436-40. 2012;86(2):96-101.

21. van Zuuren EJ, Fedorowicz Z, Carter B, Pandis N. Interventions for 35. Rubin GL, Ory HW, Layde PM. Oral contraceptives and pelvic

hirsutism (excluding laser and photoepilation therapy alone). Cochrane inflammatory disease. Am J Obstet Gynecol. 1982;15;144(6):630-5.

Database Syst Rev. 2015;(4):CD010334. 36. Burkman RT. Oral contraceptives: current status. Clin Obstet Gynecol.

22. Trent ME, Rich M, Austin SB et al. Fertility concerns and sexual behavior in 2001;44(1):62-72.

adolescent girls with polycystic ovary syndrome: implications for quality of 37. Soper DE. Pelvic inflammatory disease. Obstet Gynecol. 2010;116(2 Pt

life. J Pediatr Adolesc Gynecol. 2003;16(1):33-7. 1):419-28.

23. Pan JX, Liu Y, Ke ZH et al. Successive and cyclic oral contraceptive pill 38. Wolner-Hanssen P, Eschenbach DA, Paavonen J et al. Decreased risk of

pretreatment improves IVF/ICSI outcomes of PCOS patients and symptomatic chlamydial pelvic inflammatory disease associated with oral

ameliorates hyperandrogenism and antral follicle excess. Gynecol contraceptive use. JAMA. 1990;263:54-9.

Endocrinol. 2015;31(4):332-6. 39. Jatlaoui TC, Riley HE, Curtis KM. The safety of intrauterine devices among

24. Harada T, Momoeda M, Taketani Y, Hoshiai H, Terakawa N. Low-dose oral young women: a systematic review. Contraception. 2017;95(1):17-39.

contraceptive pill for dysmenorrhea associated with endometriosis: a 40. Bosetti C, Bravi F, Negri E, La Vecchia C. Oral contraceptives and colorectal

placebo-controlled, double-blind, randomized trial. Fertil Steril. cancer risk: a systematic review and meta-analysis. Hum Reprod Update.

2008;90(5):1583-8. 2009;15(5):489-98.

25. Haider Z, D’Souza R. Non-contraceptive benefits and risks of 41. Arowojolu AO, Gallo MF, Lopez LM, Grimes DA, Garner SE. Combined oral

contraception. Best Pract Res Clin Obstet Gynaecol. 2009;23(2):249-62. contraceptive pills for treatment of acne. Cochrane Database Syst Rev.

26. Derouich S, Attia L, Slimani O et al. Medical treatment of endometriosis. 2007;(1):CD004425.

Tunis Med. 2015;93(7):407-12. 42. World Health Organization. Medical Eligibility Criteria for Contraceptive

27. Onstad MA, Schmandt RE, Lu KH. Addressing the role of obesity in Use. (4th ed.) Geneva: WHO, 2009.

endometrial cancer risk, prevention, and treatment. J Clinical Oncol. 43. O’Connell K, Westhoff C. Pharmacology of hormonal contraceptives and

2016;34:35:4225-30. acne. Cutis. 2008;81(1 Suppl.):8-12.

28. Weiderpass E, Adami HO, Baron JA et al. Use of oral contraceptives and 44. Seaman HE, Vries CS, Farmer RD. Differences in the use of combined

endometrial cancer risk (Sweden). Cancer Causes Control. contraceptives amongst women with and without acne. Hum Reprod.

1999;10(4):277-84. 2003;18:515-21.

29. Collaborative Group on Epidemiological Studies on Endometrial Cancer. 45. Lawrie TA, Helmerhorst FM, Maitra NK, Kulier R, Bloemenkamp K,

Endometrial cancer and oral contraceptives: an individual participant Gülmezoglu AM. Types of progestogens in combined oral contraception:

meta-analysis of 27,276 women with endometrial cancer from 36 effectiveness and side-effects. Cochrane Database Syst Rev.

epidemiological studies. Lancet Oncol. 2015;16(9):1061-70. 2011;(5):CD004861.

Page 34 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Doctors and doping in sport

Abstract The World Anti-Doping Agency (WADA) has a zero-tolerance policy against athlete use of performance-enhancing substances (PES). Despite enforcement of doping legislation by sporting bodies and strict penalties if caught, PES use remains rampant among athletes striving to gain an edge on the competition. Physicians are inherently tied to doping as many PES are only available if prescribed and require professional supervision to ensure safety and effectiveness; however, a misalignment exists between what is mandated by the WADA and the ethical obligation physicians have to patient care. Under WADA codes, physicians are barred from abetting athlete use of PES, but doctors are duty bound to oversee patient care regardless of the behaviour in which patients may engage (including substance use) by their respective medical professional codes. Consequently, the boundaries of physician involvement Alexandra Mitcham in patient-athlete care are blurred when PES use is involved and warrant discussion in order RCSI medical student to maintain the integrity of both the sporting and medical professions.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 35-40.

Volume 11: Number 1. 2018 | Page 35 RCSIsmjstaff review

Introduction participant – the desire of the athlete, the team, or its fans should As competition in professional sport pushes athletes to new not be contributing factors.6 The IMC guidelines do not physical extremes, and financial payouts to the winning circle comment on sport directly; however, they express the need for increase, many athletes have turned to performance-enhancing confidentiality to enable patients to speak honestly, and for substances (PES) as a way to set themselves apart from the pack. respect of patient autonomy.5 Physicians must also adhere to The process of doping is not an independent undertaking; federal laws and regulations surrounding patient privacy. Irish because many PES may only be legally accessed through physicians are not required by law to report illegal drug use physicians, and because of the wealth of knowledge doctors can unless there is a medical emergency, qualified scientific provide regarding the effects of drugs and removal of drugs from research/audit, court-ordered criminal investigation, or suspected the system, the relationship between doping in sport and child abuse.6 It is legal for Irish physicians to prescribe medication physicians can be considered intrinsic.1 The World Anti-Doping for off-label use as deemed fit, but there must be a medical need Agency (WADA), funded by both sporting bodies and identified by a clinical examination.5 Under these laws, physicians government, created the World Anti-Doping Code (WADC) in are not permitted to prescribe pharmaceuticals for the purpose of 1999, which consists of codes of practice that athletes and performance enhancement, but are not legally bound from a support staff must abide by to compete, including a list of medical perspective to report PES use. prohibited substances.2,3 The most recent edition of the WADC (2015) is consulted by over 600 signatories globally including the The AMA Code of Ethics explicitly states Irish Sports Council.2 The WADC (2015) has defined PES as that a physician’s only consideration substances that meet at least two of the following criteria: should be the medical care of the participant – the desire of the athlete, I has the potential to enhance performance; the team, or its fans should not be I represents an actual or potential health risk; and, contributing factors. I violates the spirit of sport.2

Although much current literature discourages physicians from Physician support of anti-doping practices prescribing PES on the grounds that they are pharmaceuticals The WADA asserts that physicians should support anti-doping used for non-therapeutic purposes and are prohibited by elite legislation.2,8 Kayser and colleagues highlight four arguments for sporting bodies, the issue is not black and white.4 Codes of ethics physician support of anti-doping policy.8 The first argument is and laws put forward by sporting and medical governing bodies that anti-doping policy must be enforced to maintain an equal blur the role of the physician in the care of PES-using playing field among competitors. Physicians are ethically bound patient-athletes and warrants further discussion. to discourage PES use, as PES are only available to a confined population and grant unfair advantage to the athlete versus their Physicians’ duty to the athlete, ethics, and the law non PES-using peers, in turn compromising the integrity of Physicians have a legal and ethical duty to each patient they see, athletic competition.3,9-10 which is dictated by multiple bodies. They are each held to the A second reason for physicians to support anti-doping is to professional codes of conduct of their respective country – for protect athletes’ health due to side effects associated with PES example, the Irish Medical Council (IMC) Guide to Professional (Table 1). Physicians have an obligation to proactively advocate Conduct and Ethics for Registered Medical Practitioners (2009)5 for the cessation of activities that have known preventable or the American Medical Association (AMA) Code of Ethics adverse health effects in the interest of practising (2016)6 – as well as the Hippocratic Oath and tort law. In non-maleficence.6 addition, practitioners involved in athlete care are responsible for There is considerable uncertainty surrounding the longitudinal adhering to the rules set by the governing body of the sport they effects of steroid use as many PES have not been investigated in are involved with.7 The AMA Code of Ethics explicitly states that a healthy patients who do not require the drug in a therapeutic physician’s only consideration should be the medical care of the context.8,17 The long-term effects of PES use may become more

Page 36 | Volume 11: Number 1. 2018 RCSIsmjstaff review

apparent in the future given that steroid use is beginning in intervention for a therapeutic purpose.5,6 Finally, Kayser et al. athletes younger than ever before;18 a study by Irving (2002) argue that participation in doping can be considered an conducted in the United States found that steroid use in study unnecessary risk. There is an inherent risk assumed through participants began as early as 11 years of age.19 Until longitudinal participation in sport despite measures taken to prevent injury. effects are better ascertained, there is further reason for However, PES use is not a necessary part of competition, and as physicians to be anti-doping advocates. such can be considered undue risk to the athlete, which should Thirdly, by advocating against athlete PES use, physicians uphold not be supported by the medical profession.8 professional probity mandated by their respective governing bodies, as PES use is not classified by the AMA or IMC as medical Physicians are ethically bound to discourage PES use, as PES are Table 1: Side effects of commonly used PES. only available to a confined population Drug type Chronic effects and grant unfair advantage to the athlete versus their non 11-13 Anabolic steroids Reduced fertility PES-using peers, in turn Gynaecomastia/masculinisation compromising the integrity Hypertension of athletic competition. Arrhythmias

Muscle injury Complications of physician involvement in anti-doping Atherosclerosis Despite legislation in place, PES use remains prevalent and Clotting problems athletes are turning to physicians for consultation. A scoping

Hepatic cellular damage review estimated the global prevalence of doping in elite sports as between 14 and 39%,20 and a recent study indicated that 25% Neoplasm/carcinoma formation of Irish GPs have been consulted for advice on PES use in sport.21 Psychiatric and behavioural disorders It is the responsibility of a physician to serve patients’ best interests while respecting their autonomy, and to maintain 13,14 Amphetamines Anxiety confidentiality, unless: Arrhythmias

Hypertension I it would put others at risk to withhold the information; I those being informed are also bound by confidentiality; or, Hallucinations I a medical emergency necessitates disclosure.

Erythropoietin13,15 Pulmonary embolism PES use is ultimately the choice of the athlete and does not fit Stroke cleanly under any of these exceptional circumstances surrounding Myocardial infarction confidentiality. While PES use is not in the realm of behaviour that a physician should encourage because it is not a

5,6 Growth hormone13,16 Acromegaly pharmaceutical prescribed for therapeutic benefit, a doctor does have the duty of care for the patient irrespective of the Hypertension patient’s choices, in turn falling into violation of the WADC’s Cardiomyopathy definition of aiding and abetting doping behaviour.1,2 The WADC Diabetes mellitus (2015) states that: “Support staff may be charged with a doping Osteoporosis offence if they are deemed to administer or attempt to administer Vision loss any prohibited substance or method to any athlete in competition or out-of-competition or assist, encourage, aid, abet,

Volume 11: Number 1. 2018 | Page 37 RCSIsmjstaff review

cover up or engage in any other type of complicity involving scholarly, speculative types. They are interested in immediate antidoping”.2 As a result, physicians are at a fork in the road, problems: making somebody strong, relaxed, mean or quick and neither leading to a correct outcome: if they comply with the in getting a player back in the game as soon as possible. They are codes of just medical practice, they are in violation of the WADC, not likely to wait around for a double-blind control study to find but if they adhere to the WADC, they potentially jeopardise out if the drug is effective or what it will do to the liver three patient well-being and ethically fall short if they fail to provide years later. They are interested in today”.27 appropriate care to a PES-using patient-athlete. The role of the physician is complicated further when a sport The ‘lesser harm’ approach organisation employs a physician to oversee athlete health. A different stance to a physician’s role in athlete doping is the Sporting bodies typically deem it the responsibility of the team ‘lesser harm’ approach, which applies when an athlete disregards physician to determine whether injured athletes return to play.4,22 physician discouragement of PES use.25 It holds that it is in the Conflict can occur when the preferred course of action differs best interest of athletes, as patients, to be supervised by a depending on whether the primary concern is the athlete’s physician while taking medication as an alternative to immediate return to competition or their long-term health.4,23,24 unsupervised, off-label self-medication. Under this view, Physicians can be held liable if they prescribe medication to allow practitioners do not support the use of PES but because early re-entry to competition while the athlete is still in recovery, physicians are bound to confidentiality by medical codes of if the medication is designated as a prohibited PES.7,25 practice, athletes may seek to consult doctors to monitor their health without fear of being reported to their respective sport’s “Support staff may be charged with governing institution if they continue PES use. This perspective a doping offence if they are deemed simultaneously allows physicians to uphold codes of patient care to administer or attempt to administer and patient autonomy. Some suggest that the physician is any prohibited substance or method responsible for overseeing the athlete on the basis of existing scientific evidence, with the underlying message that PES use to any athlete in competition undermines the integrity of sport, and conversely, that the or out-of-competition or physician should not exaggerate the detrimental effects of PES assist, encourage, aid, abet, use to dissuade use in the interest of maintaining cover up or engage in any patient-physician trust.28 other type of complicity involving antidoping.” Current state of affairs and proposed code changes In a recently publicised doping controversy involving the Practitioners are often put under pressure by team management International Association of Athletics Federations (IAAF), an and players to comply if they wish to keep their job and avoid anonymous whistleblower leaked confidential IAAF blood test being undersold by another physician willing to meet team records from 2001 to 2012 indicating that 146 Olympic medals demands.26 However, this may conflict with the practitioner’s were won by athletes who had “suspicious” test results, and over ethical views given the known sanctions against doping and 800 athletes recorded blood tests described by experts as “highly knowledge of potential acute and chronic health consequences to suggestive of doping, or at the very least abnormal”.29,30 Irish the athlete.4,24 boxer Michael O’Reilly, tipped for the podium in the Rio Furthermore, the physician risks being disbarred by the relevant Olympics, tested positive on a sample just prior to the games and sporting body, in turn ruining their reputation and decimating was barred from competition.31 their client base.25 In contrast, some physicians can become As a result, WADA appears to be enforcing stricter sanctions to enveloped in the team’s success to the detriment of the athlete, deter athlete use of PES and physician abetting of such practices. embodied by a historical quote from an anonymous sports A recent example is the case of Kenyan marathon runner Rita medicine practitioner published in Sports Illustrated: “…as a Jeptoo, who tested positive for EPOr, a recombinant form of generality, team physicians tend to be men of action, not erythropoietin, two weeks before her first place finish at the 2014

Page 38 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Chicago Marathon.32 The initial penalty issued to Jeptoo was two Some suggest that the physician years; however, the IAAF appealed the case (successfully) for a is responsible for overseeing the longer sentence stating that it fell under the WADA’s definition of athlete on the basis of existing scientific aggravating circumstances (Table 2). evidence, with the underlying message The investigation unveiled a longstanding arrangement between that PES use undermines the Jeptoo and her doctor, which went unreported by either party integrity of sport, and conversely, and was concealed from her manager and coach. The appeal was upheld and Jeptoo’s ban has been extended to 2018.32 that the physician should not exaggerate the detrimental effects Table 2: WADA definition of aggravating of PES use to dissuade use in circumstances. the interest of maintaining patient-physician trust. I Using PES in addition to being part of a large doping scheme; I the athlete having used multiple prohibited substances or The anti-doping dispute is riddled with conflicts between what a prohibited substance on multiple occasions; and, is best for the athlete, the club, the sport, and the physician. I the athlete engaging in deceptive or obstructing conduct While physicians taking a strong anti-doping stance in line with to avoid the detection or adjudication of an anti-doping the WADC benefits the integrity of sport and athlete health rule violation. from the perspective that no PES use is best practice, it deters athletes from consulting physicians to monitor their health out Conclusion of fear of being banned from participation. These controversies suggest that the WADA and medical codes of If an athlete feels unable to consult physicians, the end result practice should work towards developing guidelines for may be continuation of risk-taking behaviour until an acute physicians working closely with athletes to provide an improved health concern arises. specialised standard of care. For example, protocol expansion and While this issue remains a grey area for all parties involved, it is clarification would be helpful in circumstances where the athlete evident that there is a need for the medical community to began using illicit substances prior to consulting a particular define the practice of sports medicine, and duties and physician, began using substances without their doctor’s prior obligations of team physicians,7 so that athlete health can be knowledge, or used PES in spite of advice against use by their optimised and the rectitude of both the medical and athletic physician.33 professions remains intact.

References 1. McNamee M, Phillips N. Confidentiality, disclosure and 5. Irish Medical Council. Guide to Professional Conduct and doping in sports medicine. Br J Sports Med. Ethics for Registered Medical Practitioners. Dublin: Medical 2011;45(3):174-7. Council. 2009. [Internet]. Available from: 2. World Anti-Doping Agency. World Anti-Doping Code. https://www.medicalcouncil.ie/News-and-Publications/Publ 2015. [Internet]. Available from: ications/Professional-Conduct-Ethics/Guide-to-Professional- https://www.wada-ama.org/en/resources/the-code/world-a Conduct-and-Behaviour-for-Registered-Medical-Practitioner nti-doping-code. s-pdf.pdf. 3. Vernec AR. Doping, ethics, and the sport physician. Curr 6. American Medical Association. Code of Medical Ethics. Sports Med Rep. 2013;12(5):283-4. American Medical Association. 2016. [Internet]. Available from: 4. Testoni D, Hornik CP, Smith PB, Benjamin Jr DK, McKinney https://www.ama-assn.org/about-us/code-medical-ethics. Jr RE. Sports medicine and ethics. Am J Bioeth. 7. Koller DL. Team physicians, sports medicine, and the law: 2013;13(10):4-12. an update. Clin Sports Med. 2016;35(2):245-55.

Volume 11: Number 1. 2018 | Page 39 RCSIsmjstaff review

8. Kayser B, Mauron A, Miah A. Current anti-doping policy: a 2009. [Internet]. Available from: critical appraisal. BMC Med Ethics. 2007;8:2. http://www.fims.org/about/code-ethics/. 9. Bernstein J, Perlis C, Bartolozzi AR. Ethics in sports 23. Polsky S. Winning medicine: professional sports team medicine. Clinical Orthop Rel Res. 2000;(378):50-60. doctors’ conflicts of interest. J Contemp Health Law and 10. Loland S, McNamee M. Fair play and the ethos of sports: Policy. 1997;14(2):503. an eclectic philosophical framework. J Phil Sport. 24. Mitten MJ. Team physicians and competitive athletes: 2000;27(1):63-80. allocating legal responsibility for athletic injuries. 11. Maravelias C, Dona A, Stefanidou M, Spiliopoulou C. University of Pittsburgh Law Review. 1993;55:129. Adverse effects of anabolic steroids in athletes: a constant 25. Hoberman J. Sports physicians and the doping crisis in threat. Toxicol Lett. 2005;158(3):167-75. elite sport. Clin J Sport Med. 2002;12(4):203-8. 12. Landry GL, Primos Jr WA. Anabolic steroid abuse. Adv 26. DiCello N. No pain, no gain, no compensation: exploiting Pediatr. 1990;37:185-205. professional athletes through substandard medical care 13. Tokish JM, Kocher MS, Hawkins RJ. Ergogenic aids: a administered by team physicians. Clevel State Law Rev. review of basic science, performance, side effects, and 2001;49(3):507-38. status in sports. Am J Sports Med. 2004;32(6):1543-53. 27. Gilbert B. Drugs in sport, Part 1: problems in a turned-on 14. Westfall DP, Westfall TC. Miscellaneous sympathomimetic agonists. In: Brunton LL, Chabner BA, Knollmann BC. world. Sports Illustrated. 1969;23:64-72. Goodman & Gilman’s Pharmacological Basis of 28. Dunn WR, George MS, Churchill L, Spindler KP. Ethics in Therapeutics. McGraw-Hill Education/Medical, 2010. sports medicine. Am J Sports Med. 2007;35(5):840-4. 15. Rasmussen P, Kim YS, Krogh-Madsen R, Lundby C, Olsen 29. Roan D. Leaked IAAF doping files: Wada ‘very alarmed’ by NV, Secher NH et al. Both acute and prolonged allegations. BBC Sport: Athletics. August 2, 2015. administration of EPO reduce cerebral and systemic [Internet]. [cited 2016 October 30]. Available from: vascular conductance in humans. FASEB J. http://www.bbc.com/sport/athletics/33749208. 2012;26(3):1343-8. 30. Daly M, Roan D. Adidas to end IAAF sponsorship deal early 16. Saugy M, Robinson N, Saudan C, Baume N, Avois L, in wake of doping crisis. BBC Sport: Athletics. January 24, Mangin P. Human growth hormone doping in sport. Br J 2016. [Internet]. [cited 2016 October 30]. Available from: Sports Med. 2006;40(Suppl. 1):i35-9. http://www.bbc.com/sport/athletics/35385415. 17. Fost N. Ethical dilemmas in medical innovation and 31. Grant M. Shamed boxer Michael O’Reilly arrives home research: distinguishing experimentation from practice. after doping scandal. Independent Sport. August 13, Semin Perinatol. 1998;22(3):223-232. 2016. [Internet]. [cited 2016 October 30]. Available from: 18. Dawson RT. Drugs in sport – the role of the physician. J http://www.independent.ie/sport/rio-2016-olympics/sham Endocrinol. 2001;170(1):55-61. ed-boxer-michael-oreilly-arrives-home-after-doping-scanda 19. Irving LM, Wall M, Neumark-Sztainer D, Story M. Steroid l-34961973.html. use among adolescents: findings from Project EAT. J 32. Press Association. Boston Marathon winner Rita Jeptoo has Adolesc Health. 2002;30(4):243-52. drugs ban extended to 2018. The Guardian: Athletics, 20. de Hon O, Kuipers H, van Bottenburg M. Prevalence of October 26, 2016. [Internet]. [cited 2016 October 30]. doping use in elite sports: a review of numbers and methods. Sports Med. 2015;45(1):57-69. Available from: 21. Woods CB, Moynihan A. General practitioners knowledge, https://www.theguardian.com/sport/2016/oct/26/rita-jept practice and training requirements in relation to doping in oo-boston-marathon-winner-drugs-ban-extended. sport. Ir Med J. 2009;102(1):8-10. 33. Calandrillo SP. Sports medicine conflicts: team physicians 22. Federation International de Medecine Sportive. Principles vs. athlete-patients. St. Louis University Law Journal. and ethical guidelines for health care for sports medicine. 2005;50:185.

Page 40 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Faking it: disease-fighting bacteria and the future of synthetic biology

Abstract Synthetic biology is a growing field incorporating genetic engineering, cell and molecular biology, and systems biology. This expanding research domain aims to engineer new biological pathways, organisms, and devices, as well as redesign existing systems to augment and treat a range of pathologies. The introduction of rational design and specified engineering to existing biological paradigms holds much promise for the treatment of genetic and metabolic disorders, and will help scientists to identify new research models and systems. Of particular interest to industry and medicine are engineered bacterial organisms. Research with these ‘cyborg’ bacteria is being explored for use in altering the gut microbiome to treat metabolic disorders such as phenylketonuria. These altered bacteria are also being used as novel antibacterials that can defend the host against colonisation with pathological bacterial strains such as Pseudomonas aeruginosa. As with all novel therapies, further research is required to determine the side effects and drawbacks of these novel systems. Biological containment is also of paramount importance, as altered microbes could introduce unwanted ecological diversity. While further strides in research are required, synthetic biology is proving to be an exciting and growing field of research that could yield multiple medical therapies and therapeutic devices in the future.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 41-45.

Introduction Synthetic biology is an emerging field that aims biotechnology, and holds the potential to tackle to inform and forward-engineer cell behaviour multiple problems within diagnostic and Katie Nolan using molecular biology techniques and therapeutic medicine. Genetic engineering and RCSI medical student protocols.1 It combines multiple disciplines in the roots of synthetic biology began with science, from molecular biology, genetic regulation of the lac operon in 1961, followed by engineering and systems biology to the discovery of restriction enzymes and

Volume 11: Number 1. 2018 | Page 41 RCSIsmjstaff review

molecular editing tools and, in subsequent years, the advancement hydroxylase, phenylalanine levels in the blood become raised and can of polymerase chain reaction and DNA sequencing.2-4 Building on lead to irreversible neurological deficits. The HSE estimates that one in the genome-editing prowess of the CRISPR/Cas gene editing system, 4,500 babies born in Ireland has PKU and yet, currently, strict dietary synthetic biology uses modified genomes in cells to create control is the only available treatment.16 phenotypic and functional changes.5 Synthetic biology aims to augment biological processes in a controlled One promising area of research in synthetic manner by rewiring existing cellular genomics to form new circuits or biology is focused on the body’s own novel artificial biological pathways. This could give scientists the ability to commensal flora and the homeostatic design a biological system in a systematic manner, through rational benefits they confer on the human system. design, for a specified functional purpose.6 These novel gene circuits, or Disruption of this bacterial balance synthetic cells, consist of an inducer, a ligand, and an output signal, and has been shown to play a role in can be constructed using many different biological systems including RNA, viruses, and bacteria.7 Genetically modified microbes can be used decreased host immunity and therapeutically as an efficient mode of drug delivery, and have been metabolic disorders. referred to as “live microbial vectors”.8 This new technology means that rather than growing recombinant bacteria and extracting the The gut microbiota profile of patients with PKU on a therapeutic material, these microbes can be delivered directly to the phenylalanine-controlled diet demonstrates enrichment of different patient and act directly at their target site.9 microbes compared to healthy controls.17 Differences in glucose and amino acid metabolism are also attributed to these differing gut Metabolic disorders and a role in the gut microbiota profiles.17 Synthetic microbes engineered to remove excess One promising area of research in synthetic biology is focused on the phenylalanine could provide a treatment alternative to dietary restriction. body’s own commensal flora and the homeostatic benefits they confer Synlogic has engineered a synthetic microbe (SYNB1618) for safe on the human system. Disruption of this bacterial balance has been removal of phenylalanine in PKU rodent models, which could prevent shown to play a role in decreased host immunity and metabolic the need for patients to remain on life-long restrictive diets to control disorders.10,11 Loss of host bacteria in the intestinal lumen can lead to phenylalanine levels.15 Phenylalanine lyase genes inserted into increased pathogen invasion and inflammation, due to weakened Lactobacillus reuteri demonstrated a probiotic that significantly decreased immune responses, loss of antimicrobial factors, and loss of metabolites blood phenylalanine levels within days of host inoculation, and remained that normally confer a survival advantage on host bacteria.12 However, in the PKU mouse model system for up to four months.18 Researchers protection of commensal bacteria is not only important in the gut. could not detect any immune response to the phenylalanine-targeting Disruption of Staphylococcus epidermidis, the dominant commensal probiotic.18 Administration in Lactobacilli overcame the challenges posed bacteria of the skin, can lead to colonisation and biofilm formation by by stomach acid and digestive enzymes, which make direct the pathogenic strain Staphylococcus aureus.13 Changes in the human administration of phenylalanine ammonia lyase impossible.18 lung microbiome have also been implicated in the development of Glucagon-like peptide 1 (GLP-1) is a peptide hormone secreted by asthma and allergy.14 Replacing such lost or damaged commensal intestinal L-cells during digestion that acts on the pancreas to increase bacteria with engineered non-pathogenic bacterial strains that carry insulin production. GLP-1 has been limited in its therapeutic potential by targeted therapies for metabolic or immune disorders could drastically its short half-life. Wei et al. describe an engineered strain of reduce daily pharmaceutical use and improve patient outcomes. Bifidobacterium longum that can secrete a biologically active form of Synlogic, a Massachusetts Institute of Technology (MIT) spinoff GLP-1.19 Commensal bacteria secreting GLP-1 pose a novel treatment company, is using engineered microbes to treat metabolic diseases such option for type 2 diabetes mellitus (T2DM). Alternatively, Lactobacillus as urea cycle disorder and phenylketonuria (PKU). In the case of urea gasseri engineered to secrete an inactive full-length form of GLP-1 was cycle disorder, engineered E. coli Nissle degrade and remove excess shown to convert intestinal epithelial cells into insulin-producing cells in ammonia from the body in the form of excretable amino acids. This a diabetic rat model.20 The newly converted cells were capable of therapeutic ‘biotic’ prevents hyperammonaemia and ammonia toxicity.15 maintaining 25-33% insulin-producing capacity, and could provide an PKU is an inborn error of metabolism characterised by reduced levels of oral drug alternative for diabetes treatment in the future.20 the enzyme phenylalanine hydroxylase. Without phenylalanine GLP-1-mediated therapy is not limited to T2DM; introduction of

Page 42 | Volume 11: Number 1. 2018 RCSIsmjstaff review

GLP-1-secreting commensal bacteria has also been shown to induce construct for up to 40 weeks, and prevented HIV infection in the intestinal endocrine cells to produce insulin and lower blood glucose in monkeys following multiple HIV inoculation attempts.26 While only an insulin-dependent diabetic rat model.20 currently examined in rhesus models, this synthetic construct has been The use of engineered microbes in the treatment of metabolic disorders shown to be more potent than treatment with bNAb, and was also is promising. Augmenting gut microbes overcomes many of the shown to be less immunogenic.26 complex drug delivery challenges of traditional pharmaceutical therapies; Research is also focused on the control of novel HIV vaccines. To date, with encouraging evidence of the longevity of these microbes within the HIV live attenuated vaccines have shown the most promise in host system, synthetic microbes could provide a relatively simple and non-human primate models, but pose too many risks for use in clinically useful alternative. humans.27 Deletion of nef genes from the viral genome generated a live attenuated SIV vaccine with an average protection rate of 95% against Synthetic biology for HIV prevention SIV infections, compared to 7% for other SIV vaccine types.28 Synthetic By the end of 2015, approximately 36.7 million people worldwide were biology is now being explored further in the realm of HIV vaccines. It has living with HIV/AIDs, with an estimated 2.1 million newly infected been used to design unnatural amino acids that can suppress specific individuals in 2015 alone.21 While antiretroviral therapy can control the nonsense codons on the HIV virus, and to create a functional on/off virus, current research is focused on alternative therapies aimed at switch for the HIV live attenuated vaccine to offer more tightly controlled prevention and cure. treatment in the future.29 Research has shown that loss of Lactobacillus species in the vagina, such as that which occurs in bacterial vaginosis, can raise the risk of HIV Replacing such lost or damaged commensal contraction in women, in part due to an altered immune response.22 bacteria with engineered non-pathogenic One research group modified Lactobacillus jensenii to secrete the antiviral bacterial strains that carry targeted therapies protein cyanovirin; in studies using monkeys, researchers demonstrated for metabolic or immune disorders could that an intravaginal dose of the engineered bacteria protected 63% of drastically reduce daily pharmaceutical use monkeys exposed to simian immunodeficiency virus (SIV), compared to and improve patient outcomes. 35% in the control group.23 Recombinant Lactococcus lactis has been investigated for use as a HIV vaccine. Chamcha et al. expressed the HIV Gag protein on the pili of L. Bacteria fighting bacteria lactis to allow the recombinant protein be presented to the host immune These engineered microbes are not only of benefit to individual patients; system.24 Mice were inoculated orally and intragastrically for four in fact, they have a wider therapeutic benefit for the healthcare system months, and B and T cell responses were monitored. Researchers noted and population as a whole. Engineered E. coli have been generated that strong Gag-specific immunoglobulin A (IgA) and immunoglobulin G can target Pseudomonas aeruginosa cells through direct sensing of (IgG) immune responses in blood and faecal samples, as well as CD8+ T molecules excreted by the bacteria. These E. coli have been engineered cell responses in mucosal sites and mesenteric lymph nodes.24 Induction to excrete microsin S and DNase I, which degrade P. aeruginosa biofilms of humoral and cellular immune responses to HIV through an oral and kill the bacterium directly.30,31 probiotic vaccine such as this presents a novel approach to HIV Similarly engineered Lactococcus lactis strains have been designed to prevention, and demonstrates the potential role for synthetic biology in combat multidrug-resistant Enterococci. The L. lactis is designed to vaccine design.24 identify cCF10, a pheromone released from E. faecalis, and to release At present, natural antibodies known as broadly neutralising antibodies bacteriocins, toxins that can kill drug-resistant E. faecalis and E. faecium (bNAb) are a main focus in the field of HIV therapeutics.25 A research strains.32 Toxin A (TcdA) and toxin B (TcdB) are cytotoxic virulence group at the Scripps Institute in Florida has designed a synthetic factors expressed by Clostridium difficile. L. lactis engineered to express construct composed of parts of the CD4 and CCR5 receptors that bind non-toxic fragments of these virulence factors, administered in vivo, the HIV virus’s envelope glycoprotein. This construct, named eCD4-Ig, significantly reduces weight loss and mortality following C. difficile acts like a neutralising antibody and prevents the virus from binding to challenge.26 This novel oral L. lactis vaccine could present an alternative the surface of white blood cells.26 The research team inoculated rhesus treatment for nosocomial antibiotic-induced diarrhoea.33 monkeys with an adeno-associated virus (AAV) stably expressing the Targeted systems such as these represent a new era of medicine; with eCD4-Ig construct. This delivery system led to stable expression of the the ominous rise in antibiotic resistance and reduced efficacy of

Volume 11: Number 1. 2018 | Page 43 RCSIsmjstaff review

antibiotic therapies, synthetic biological approaches may prove to be the used in the production of dairy products and requires thymidine to future of antimicrobial therapies. survive. Thymidine is found in the human body, but is not naturally occurring in the environment, meaning microbes that colonise the host Biocontainment and control systems would be unable to survive if excreted into the environment.37 Careful The field of synthetic biology is expanding rapidly and with a seemingly engineering and selection of these microbes may thus offer successful endless number of possibilities. It is therefore imperative that the containment and provide control when treating patients. To further scientific community devotes time and focus to systems control and address environmental safety, Rovner et al. described genetically regulation. When it comes to utilising these systems in humans, clinicians engineered E. coli that require exogenously supplied synthetic amino must be able to regulate or halt the artificial system rapidly and acids for survival.38 Similarly, Collins et al. have created microbial efficiently in the event of side effects or unforeseen events. Ye et al. ‘kill-switches’ in genetically engineered E. coli. The ‘deadman’ kill-switch designed a synthetic signalling cascade that can augment metabolic requires microbes to be fed a compound called anhydrotetracycline, activity in cell and mouse models through light-induced transgene which prevents expression of a toxin (TetR) within the cells and thus expression.34 The researchers designed a system in which illumination of prevents cell death.39 In the absence of anhydrotetracycline, the melanopsin-expressing cells triggers a cascade leading to activation of microbial cells die due to TetR toxicity.39 the transcription factor (TF) nuclear factor of activated T cells (NFAT). NFAT signalling was shown to promote expression of GLP-1, a hormone Conclusion that controls blood glucose levels.34 Implantation of these cells into a While synthetic biology is an emerging field, it holds much promise for a T2DM mouse model led to optogenetic control of blood glucose levels wide range of medical disorders. As the field expands and moves in vivo.34 Spatiotemporal control of gene expression using optogenetics is increasingly into the public domain, additional research will be needed a key example of synthetic biology control systems. One research group to assess the risk–benefit ratio and long-term effects of genetically described their LightOn system, which uses a TF activated by LED blue engineered organisms. While the prospect of using non-pathogenic light to bind downstream promoters and promote expression of target bacteria to replace or enhance a dysfunctional system or pathway in genes.35 Additionally, consumption of genetically engineered microbes disease is an enticing alternative to drug regimens, the lack of evidence for therapeutic purposes begs the question of containment. With so little regarding long-term effects on animals, humans and the environment certainty about the future of these systems, it is imperative that scientists must be a cautionary reminder. Knowingly inoculating a host with a implement ‘control theory’ and negative feedback systems.36 One group, bacterium can only be acceptable under stringent, tested conditions and examining recombinant commensal Lactobacillus lactis to treat gut with a safe, proven mechanism to halt the organism’s growth and inflammation, utilised the strain’s requirement for thymidine to prevent spread, if needed. But perhaps a future in which we can design our own spread of the microbes from the host into the environment.37 L. lactis is biology and remake ourselves is, really, not too distant.

References 1. Cameron DE, Bashor CJ, Collins JJ. A brief history of synthetic biology. Nat 7. Guzman-Trampe S, Ceapa CD, Manzo-Ruiz M, Sanchez S. Synthetic

Rev Microbiol. 2014;12(5):381-90. biology era: improving antibiotic’s world. Biochem Pharmacol.

2. Jacob F, Monod J. Genetic regulatory mechanisms in the synthesis of 2017;134:99-113.

proteins. J Mol Biol. 1961;3:318-56. 8. Magliani W, Conti S, Frazzi R, Pozzi G, Oggioni M, Polonelli L. Engineered

3. Arber W, Linn S. DNA modification and restriction. Annu Rev Biochem. commensal bacteria as delivery systems of anti-infective mucosal

1969;38:467-500. protectants. Biotechnol Genet Eng Rev. 2002;19:139-56.

4. Smith LM, Sanders JZ, Kaiser RJ, Hughes P, Dodd C, Connell CR et al. 9. Maxmen A. Living therapeutics: scientists genetically modify bacteria to

Fluorescence detection in automated DNA sequence analysis. Nature. deliver drugs. Nat Med. 2017;23(1):5-7.

1986;321(6071):674-9. 10. Brestoff JR, Artis D. Commensal bacteria at the interface of host

5. Ho P, Chen YY. Mammalian synthetic biology in the age of genome metabolism and the immune system. Nat Immunol. 2013;14(7):676-84.

editing and personalized medicine. Curr Opin Chem Biol. 2017;40:57-64. 11. Hur KY, Lee MS. Gut microbiota and metabolic disorders. Diabetes Metab

6. Serrano L. Synthetic biology: promises and challenges. Mol Syst Biol. 2007;3:158. J. 2015;39(3):198-203.

Page 44 | Volume 11: Number 1. 2018 RCSIsmjstaff review

12. Abt MC, Pamer EG. Commensal bacteria mediated defenses against 26. Gardner MR, Kattenhorn LM, Kondur HR, von Schaewen M, Dorfman T,

pathogens. Curr Opin Immunol. 2014;29:16-22. Chiang JJ et al. AAV-expressed eCD4-Ig provides durable protection from

13. Iwase T, Uehara Y, Shinji H, Tajima A, Seo H, Takada K et al. Staphylococcus multiple SHIV challenges. Nature. 2015;519(7541):87-91.

epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal 27. Koff WC, Johnson PR, Watkins DI, Burton DR, Lifson JD, Hasenkrug KJ et al.

colonization. Nature. 2010;465(7296):346-9. HIV vaccine design: insights from live attenuated SIV vaccines. Nat

14. Riiser A. The human microbiome, asthma, and allergy. Allergy Asthma Immunol. 2006;7(1):19-23.

Clin Immunol. 2015;11:35. 28. Li Q, Zeng M, Duan L, Voss JE, Smith AJ, Pambuccian S et al. Live simian

15. Matheson R. Reprogramming gut bacteria as “living therapeutics”. MIT immunodeficiency virus vaccine correlate of protection: local antibody

News. 2016. [Internet]. Available from: production and concentration on the path of virus entry. J Immunol.

http://news.mit.edu/2016/startup-synlogic-reprogramming-gut-bacteria-liv 2014;193(6):3113-25.

ing-therapeutics-0405. 29. Wang N, Yuan, Z, Niu W, Li Q, Guo J. Synthetic biology approach for the

16. Health Service Executive. Phenylketonuria. 2017. [Internet]. Available from: development of conditionally replicating HIV-1 vaccine. J Chem Technol

http://www.hse.ie/eng/health/child/newbornscreening/newbornbloodspot Biotechnol. 2017;92(3):455-62.

screening/Information_for_Professionals/Conditions/PKU/. 30. Hwang IY, Koh E, Wong A, March JC, Bentley WE, Lee YS et al. Engineered

17. Pinheiro de Oliveira F, Mendes RH, Dobbler PT, Mai V, Pylro VS, Waugh SG probiotic Escherichia coli can eliminate and prevent Pseudomonas

et al. Phenylketonuria and gut microbiota: a controlled study based on aeruginosa gut infection in animal models. Nat Commun. 2017;8:15028.

next-generation sequencing. PLoS One. 2016;11(6):e0157513. 31. Hwang IY, Tan MH, Koh E, Ho CL, Poh CL, Chang MW. Reprogramming

18. Durrer KE, Allen MS, Hunt von Herbing I. Genetically engineered probiotic microbes to be pathogen-seeking killers. ACS Synth Biol.

for the treatment of phenylketonuria (PKU); assessment of a novel 2014;3(4):228-37.

treatment in vitro and in the PAHenu2 mouse model of PKU. PLoS One. 32. Borrero J, Chen Y, Dunny GM, Kaznessis YN. Modified lactic acid bacteria

2017;12(5):e0176286. detect and inhibit multiresistant enterococci. ACS Synth Biol.

19. Wei P, Yang Y, Li T, Ding Q, Sun H. A engineered Bifidobacterium longum 2015;4(3):299-306.

secreting a bioative penetratin-Glucagon-like peptide 1 fusion protein 33. Guo S, Yan W, McDonough SP, Lin N, Wu KJ, He H et al. The recombinant

enhances Glucagon-like peptide 1 absorption in the intestine. J Microbiol Lactococcus lactis oral vaccine induces protection against C. difficile spore

Biotechnol. 2015. [epub ahead of print]. challenge in a mouse model. Vaccine. 2015;33(13):1586-95.

20. Duan FF, Liu JH, March JC. Engineered commensal bacteria reprogram 34. Ye H, Daoud-El Baba M, Peng RW, Fussenegger M. A synthetic

intestinal cells into glucose-responsive insulin-secreting cells for the optogenetic transcription device enhances blood-glucose homeostasis in

treatment of diabetes. Diabetes. 2015;64(5):1794-803. mice. Science. 2011;332(6037):1565-8.

21. US Department of Health and Human Services. The Global HIV/AIDS 35. Ma Z, Du Z, Chen X, Wang X, Yang Y. Fine tuning the LightOn

Epidemic. 2017. [Internet]. Available from: light-switchable transgene expression system. Biochem Biophys Res

https://www.hiv.gov/hiv-basics/overview/data-and-trends/global-statistics. Commun. 2013;440(3):419-23.

22. Mirmonsef P, Krass L, Landay A, Spear GT. The role of bacterial vaginosis 36. Del Vecchio D, Dy AJ, Qian Y. Control theory meets synthetic biology. J R

and trichomonas in HIV transmission across the female genital tract. Curr Soc Interface. 2016;13(120).

HIV Res. 2012;10(3):202-10. 37. Steidler L, Neirynck S, Huyghebaert N, Snoeck V, Vermeire A, Goddeeris B

23. Lagenaur LA, Sanders-Beer BE, Brichacek B, Pal R, Liu X, Liu Y et al. et al. Biological containment of genetically modified Lactococcus lactis for

Prevention of vaginal SHIV transmission in macaques by a live recombinant intestinal delivery of human interleukin 10. Nat Biotechnol.

Lactobacillus. Mucosal Immunol. 2011;4(6):648-57. 2003;21(7):785-9.

24. Chamcha V, Jones A, Quigley BR, Scott JR, Amara RR. Oral immunization 38. Rovner AJ, Haimovich AD, Katz SR, Li Z, Grome MW, Gassaway BM et al.

with a recombinant Lactococcus lactis-expressing HIV-1 antigen on group Recoded organisms engineered to depend on synthetic amino acids.

A Streptococcus pilus induces strong mucosal immunity in the gut. J Nature. 2015;518(7537):89-93.

Immunol. 2015;195(10):5025-34. 39. Chan CT, Lee JW, Cameron DE, Bashor CJ, Collins JJ. ‘Deadman’ and

25. Burton DR, Hangartner L. Broadly neutralizing antibodies to HIV and their ‘Passcode’ microbial kill switches for bacterial containment. Nat Chem

role in vaccine design. Annu Rev Immunol. 2016;34:635-59. Biol. 2016;12(2):82-6.

Volume 11: Number 1. 2018 | Page 45 RCSIsmjstaff review

From womb to withdrawal: born addicted

Abstract The current opioid epidemic has not come without an associated impact on neonates and their mothers. Exposure to opiates in utero puts neonates at risk of having neonatal abstinence syndrome (NAS) and premature birth. This review discusses the increasing relevance of NAS in the world today, as well as its identification, treatment, and potential future consequences for those exposed to opioids in utero. At present, there is insufficient evidence to clearly determine Julia Hunter superior neonatal evaluation tools, first-line and adjunctive treatment methods, or long-term RCSI medical student outcomes, and thus further research into these areas is necessary.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 46-51.

Page 46 | Volume 11: Number 1. 2018 RCSIsmjstaff review

What is NAS and why is it so pertinent today? Since the early 2000s, the incidence of NAS and the rate of Neonatal abstinence syndrome (NAS) is a postnatal withdrawal antenatal opiate use have been on the rise.4,5 This change has been syndrome occurring following the abrupt cessation of in utero best documented in the United States where one 2000-2009 study exposure to opioids. As opioids are small, lipophilic compounds saw a nearly three-fold increase in the number of cases of NAS, and capable of crossing both placental and blood-brain barriers, maternal another study of American neonatal ICU admissions due to NAS use places neonates at risk of suffering from NAS. With the majority of recorded an increase of more than 300% between 2004 and opioid receptors located in the gastrointestinal tract (GIT) and central 2013.4,5 NAS may occur as a result of prescriptions for opioids in nervous system (CNS), NAS often manifests as GIT dysfunction, CNS pregnant women, non-prescription opioid use, or the use of opioids irritability, and autonomic overactivity.1 The manifestations of NAS are for addiction treatment. While the incidence of NAS has been less thought to be multifactorial and vary widely depending on the timing frequently documented outside of the US, a 2010 report by the and type of opioid use throughout pregnancy, and have also been International Narcotics Control Board reported a significant rise in shown to vary between preterm and full-term infants (Table 1).2 This the use of opioid analgesics in Europe, Australia, and New Zealand is of particular importance as preterm infants are born to in the 2000s, compared to the level of use seen in the 1980s and approximately 30% of women on methadone maintenance therapy, 90s, indicating that NAS is a problem of increasing global compared to 11% of mothers in the general population.3 relevance.6 Despite the rising rate of use reported in these areas, from 2007-2009 the average consumption of opioid analgesics per Table 1: NAS symptoms and their relative frequency in person in North America was five times greater than that seen in preterm vs full-term infants.2 Europe and Oceania, and in 2009 the US was responsible for 56% of global morphine consumption.6 In addition to the individual More frequently scored in preterm infants (P<0.05) health outcomes associated with NAS, it also places an enormous Hyperactive Moro reflex and increasing burden on national health services. In 2012, NAS Tachypnoea cost almost $316 million in the US alone.7 Poor feeding

Identification of NAS More frequently scored in term infants (P<0.05) One of the great challenges that exists in the current epidemic of Sleep disturbance NAS is the appropriate identification of at-risk neonates. On the Tremors surface, identification of mothers who use opioids seems like an Restlessness achievable goal; however, it is fraught with complications owing to Increased muscle tone the numerous and significant potential legal and social ramifications Excoriations for the mother. In the US, 24 states consider substance abuse during Sweating pregnancy to be child abuse, and the Child Abuse Prevention and Fever Treatment Act mandates that child protective services are notified of Nasal stuffiness newborns who are substance exposed.8,9 Sneezing It has been argued that a uniform and universally administered Excessive sucking questionnaire would be the best approach to identify drug-using Loose stools mothers, so that physicians are able to make necessary treatments available to the mother and neonate.10 An approach such as this avoids the bias of selective testing, and has been shown to improve Occurred in less than 5% of both term and preterm infants the identification rate, as one study reports positive opioid tests in Yawning 20% of mothers without any risk factors.11 Nasal flaring An alternative to using questionnaires is biological drug testing of Regurgitation/vomiting the mother, which has been shown to yield higher rates than Seizures self-reported opioid use; however, this approach may have reduced Data shown has not been adjusted for the effects of preterm birth or psychiatric medication exposure. efficacy owing to the fact that maternal consent for testing is required.12

Volume 11: Number 1. 2018 | Page 47 RCSIsmjstaff review

Assessment using the Finnegan scoring system is typically performed every three to four hours, and includes all observations made within the inter-observation period. It evaluates 31 items, and scores them from 1-5 depending on symptom severity. An algorithmic approach to management states that pharmacologic treatment should be employed when three scores ≥8, or two scores ≥12, are recorded.20 At present, there are also a number of more simplistic tools used in clinical practice that provide subjective evaluation of neurologic, respiratory, autonomic and gastrointestinal dysfunction.21-24 Research to date has not clearly or consistently identified which of the many approaches is superior, and thus further assessment and comparison of existing tools is recommended.25,26 A US survey found that only 55% of American neonatology fellowship programmes had a written protocol for the treatment of NAS, and 69% utilised a published NAS assessment tool.19 With the growing prevalence of NAS in the US and around the world, the 2014 World Health Organisation guidelines for the identification and management of substance use and substance use disorders in Hair, blood and meconium can serve as biologic specimens for pregnancy have recommended that hospitals have protocols in testing the neonate. While useful in reaching a diagnosis, results place for the assessment and management of neonates with NAS, obtained via these specimens may be imperfect as they vary based and that staff should be appropriately trained to be competent in on the time of sampling post partum, and on the timing of utilising the assessment tools.27 maternal drug use during pregnancy.13 However, these specimens are not generally constrained by the same policies and thus often do Treatment of NAS not require maternal consent.12,14 In order to ensure that diagnoses The initial stabilisation of infants by the provision and monitoring of are not missed due to the timing of sample collection or variability fluids and electrolytes is crucial, and may avoid the need for in the detection period, approaches that combine both clinical pharmacotherapy in some cases.28 Following stabilisation and evaluation and biological testing are recommended.1 Even with the accurate diagnosis, early treatment of NAS focuses on the combination of these tools, a diagnosis of NAS is often hard to minimisation of environmental stimulation.28 This may be achieved reach due to the challenges associated with obtaining accurate by ensuring that the surrounding environment is dark, as well as information on maternal substance use during pregnancy, postnatal ensuring that neonates are comforted and provided sufficient caloric detection of opioids, and the need to accurately exclude other intake to supplement losses via vomiting, loose stools, or increased pathological disorders.15 Thus, all neonates at risk for NAS should be energy expenditure. Breastfeeding is recommended in mothers who carefully monitored in hospital for the emergence of signs and are receiving opioid substitute therapy and who do not have other symptoms of withdrawal, to ensure that cases do not go contraindications to breastfeeding.29 Breastfeeding of those with undiagnosed (Table 1).16 The appropriate duration of in-hospital NAS has been associated with a shorter hospital stay, and reductions observation varies on a case-by-case basis, and should vary with in both symptom severity and need for pharmacotherapy.30-32 opioid exposure risk. Recent evidence also supports rooming-in of mothers with neonates In order to objectively identify NAS and guide appropriate with NAS, which has also been shown to reduce the length of treatment, a number of assessment tools have been utilised in hospital stay and the need for pharmacological therapy, and to clinical practice. Since its creation in 1975, the Finnegan Neonatal enhance maternal satisfaction and involvement in care.33,34 In the Abstinence Scoring Tool has been widely used in both its original 30-91% of cases where non-pharmacologic care is inadequate to and modified forms.17,18 In the US a 2006 study found that the treat the signs and symptoms of NAS due to in utero opioid Finnegan scale was used in 65% of neonatology divisions who exposure, pharmacologic treatment is indicated.35,36 The significant responded.18,19 variability in the percentage of neonates requiring pharmacologic

Page 48 | Volume 11: Number 1. 2018 RCSIsmjstaff review

intervention has been attributed to the varying degree of opiate Maternal considerations addiction seen in different study populations.36 At present, there is While a thorough discussion of the maternal issues related to in utero no uniformly accepted standard of care for pharmacological opioid use is beyond the scope of this article, it is important to briefly intervention.1 Recent studies have shown that pharmacological consider the concurrent factors that may complicate pregnancy, such treatment that follows a protocol results in a shorter duration of as maternal substance abuse, psychiatric disorders, cigarette use, treatment and hospital stay, suggesting that protocol-based infection, and psychosocial issues.48 Often, multidisciplinary care is interventions are a means to contribute to outcome vital in order to properly address complex patient needs.48 A 2010 improvement.37,38 Morphine is often the treatment of choice due to evaluation revealed that more than 60% of opioid-dependent women its well-established efficacy in treating NAS and its short half-life, reported psychiatric symptoms, with 12% revealing they had suicidal which allows for appropriate dose adjustment.39-41 Morphine has, ideation.49 Consequently, mental health screening should be however, been shown to increase the length of hospital stay.42 A performed in opioid-dependent women so that concurrent frequently used alternative to morphine is methadone.19 With a psychiatric disorders can be assessed, and case-specific risk–benefit longer half-life, methadone requires less frequent administration, but evaluation of pharmacologic intervention can be conducted.50 poses more difficulty with respect to dose adjustment. Additionally, studies have shown that most opioid-dependent pregnant Recent research has indicated that buprenorphine is a promising women smoke cigarettes.51,52 In isolation, cigarette smoking in treatment alternative to morphine and methadone; it offers a pregnancy is associated with increased risks to the foetus, such as reduced length of pharmacological treatment and hospital stay intrauterine growth restriction; in combination with opioids, it has also when compared to both morphine and methadone.43,44 Despite been significantly associated with maternal mood and anxiety showing promising improvements in NAS outcomes, disorders, irrespective of the number of cigarettes smoked.51 Smoking buprenorphine contains a significant amount of ethanol. To date, cessation counselling has been significantly associated with successful however, the risks associated with neonatal ethanol intake have cessation, and is thus of particular importance in this high-risk patient not been thoroughly defined.45 population.53 While the incidence of NAS has been less Long-term effects frequently documented outside of the US, While it has been documented that neonates suffering from NAS are a 2010 report by the International more likely to encounter problems throughout infancy and Narcotics Control Board reported a childhood, the precise effects of both prenatal opioid exposure and significant rise in the use of opioid postnatal treatment (opioid pharmacotherapy) are largely analgesics in Europe, Australia, and New unknown.54-56 Few studies exist evaluating the long-term outcomes Zealand in the 2000s, compared to the of the present opioid epidemic. One 2014 meta-analysis found no level of use seen in the 1980s and 90s, significant psychomotor, cognitive, or neurobehavioural outcomes indicating that NAS is a problem of for opioid-exposed neonates, but was limited by the evaluation of only five studies with small study samples.57 increasing global relevance.

When neonates do not respond to first-line agents, adjunctive Conclusion non-opiate second-line agents may be added to the treatment The recent increase in opioid use has highlighted a number of regimen.46 At present, there is a need for further investigation into knowledge gaps that will require longitudinal investigation, with the second-line agents and their safety profiles. Recently, phenobarbital, aim of improving neonatal outcomes and maternal care, and a GABAA receptor agonist, has emerged as a useful long-acting providing a better understanding of the impact of in utero opioid adjunctive therapeutic agent when there is an insufficient response exposure on childhood outcomes. While research into the

47 to the maximum dose of opiates. Clonidine, a centrally acting a2 appropriate management of NAS has the potential to improve adrenergic receptor agonist, has also been used successfully as an neonatal outcomes, national strategies targeting the opioid adjunctive agent, and has been shown to require a shorter epidemic in the US are urgently required in order to prevent therapeutic duration compared to phenobarbital, enabling more contributory prescribing practices, reduce addiction rates, and treat rapid treatment weaning.47 those presently addicted to opiates.

Volume 11: Number 1. 2018 | Page 49 RCSIsmjstaff review

References 1. Hudak ML, Tan RC. Neonatal Drug Withdrawal. Pediatrics. 14. Wong S, Ordean A, Kahan M. Substance use in pregnancy. J Obstet Gynaecol

2012;129(2):e540-e60. Can. 2011;33(4):367-84.

2. Allocco E, Melker M, Rojas-Miguez F, Bradley C, Hahn KA, Wachman EM. 15. Lazic Mitrovic T, Mikovic Z, Mandic V, Avramovic LH, Cecez D, Stanimirovic A

Comparison of neonatal abstinence syndrome manifestations in preterm et al. Neonatal abstinence syndrome – diagnostic dilemmas in the maternity

versus term opioid-exposed infants. Adv Neonatal Care. ward. Srp Arh Celok Lek. 2015;143(9-10):573-7.

2016;16(5):329-36. 16. Murphy-Oikonen J, Montelpare WJ, Southon S, Bertoldo L, Persichino N.

3. Almario CV, Seligman NS, Dysart KC, Berghella V, Baxter JK. Risk factors for Identifying infants at risk for neonatal abstinence syndrome: a retrospective

preterm birth among opiate-addicted gravid women in a methadone cohort comparison study of 3 screening approaches. J Perinat Neonatal Nurs.

treatment program. Am J Obstet Gynecol. 2009;201(3):326.e1-6. 2010;24(4):366-72.

4. Patrick SW, Schumacher RE, Benneyworth BD, Krans EE, McAllister JM, 17. Zimmermann-Baer U, Notzli U, Rentsch K, Bucher HU. Finnegan neonatal

Davis MM. Neonatal abstinence syndrome and associated health care abstinence scoring system: normal values for first 3 days and weeks 5-6 in

expenditures: United States, 2000-2009. JAMA. 2012;307(18):1934-40. non-addicted infants. Addiction. 2010;105(3):524-8.

5. Tolia VN, Patrick SW, Bennett MM, Murthy K, Sousa J, Smith PB et al. 18. Finnegan LP, Connaughton JF Jr, Kron RE, Emich JP. Neonatal abstinence

Increasing incidence of the neonatal abstinence syndrome in US neonatal syndrome: assessment and management. Addict Dis. 1975;2(1-2):141-58.

ICUs. N Engl J Med. 2015;372(22):2118-26. 19. Sarkar S, Donn SM. Management of neonatal abstinence syndrome in

6. International Narcotics Control Board. Availability of Internationally neonatal intensive care units: a national survey. J Perinatol. 2006;26(1):15-7.

Controlled Drugs: Ensuring Adequate Access for Medical and Scientific 20. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics.

Purposes. New York: 2011. [Internet]. Available from: 2014;134(2):e547-61.

http://www.incb.org/documents/Publications/AnnualReports/AR2015/Engli 21. Lipsitz PJ. A proposed narcotic withdrawal score for use with newborn infants.

sh/Supplement-AR15_availability_English.pdf. A pragmatic evaluation of its efficacy. Clin Pediatr (Phila). 1975;14(6):592-4.

7. Corr TE, Hollenbeak CS. The economic burden of neonatal abstinence 22. Zahorodny W, Rom C, Whitney W, Giddens S, Samuel M, Maichuk G et al.

syndrome in the United States. Addiction. 2017;112(9):1590-9. The neonatal withdrawal inventory: a simplified score of newborn withdrawal.

8. The Guttmacher Institute. Substance use during pregnancy. [Internet]. J Dev Behav Pediatr. 1998;19(2):89-93.

[updated 2017 June 1]. Available from: 23. Green M, Suffet F. The Neonatal Narcotic Withdrawal Index: a device for the

https://www.guttmacher.org/state-policy/explore/substance-use-during-pr improvement of care in the abstinence syndrome. American J Drug Alcohol

egnancy. Abuse. 1981;8(2):203-13.

9. U.S. Department of Health and Human Services Administration for 24. Franck LS, Harris SK, Soetenga DJ, Amling JK, Curley MAQ. The Withdrawal

Children and Families, Administration on Children, Youth and Families, Assessment Tool – Version 1 (WAT-1): an assessment instrument for

Children’s Bureau. The Child Abuse Prevention and Treatment Act. 2010. monitoring opioid and benzodiazepine withdrawal symptoms in pediatric

[Internet]. Available from: patients. Pediatr Crit Care Medicine. 2008;9(6):573-80.

https://www.acf.hhs.gov/sites/default/files/cb/capta2010.pdf. 25. Newnam KM. The right tool at the right time: examining the evidence

10. Terplan M, Minkoff H. Neonatal abstinence syndrome and ethical surrounding measurement of neonatal abstinence syndrome. Adv Neonatal

approaches to the identification of pregnant women who use drugs. Care. 2014;14(3):181-6.

Obstet Gynecol. 2017;129(1):164-7. 26. Orlando S. An overview of clinical tools used to assess neonatal abstinence

11. Wexelblatt SL, Ward LP, Torok K, Tisdale E, Meinzen-Derr JK, Greenberg syndrome. J Perinat Neonatal Nurs. 2014;28(3):212-9.

JM. Universal maternal drug testing in a high-prevalence region of 27. World Health Organization. Guidelines for the identification and management

prescription opiate abuse. Journal Pediatr. 2015;166(3):582-6. of substance use and substance use disorders in pregnancy. 2014. [Internet].

12. Cotten SW. Drug testing in the neonate. Clin Lab Med. Available from:

2012;32(3):449-66. http://apps.who.int/iris/bitstream/10665/107130/1/9789241548731_eng.pdf

13. Ostrea EM Jr. Testing for exposure to illicit drugs and other agents in the 28. Stover MW, Davis JM. Opioids in pregnancy and neonatal abstinence

neonate: a review of laboratory methods and the role of meconium syndrome. Semin Perinatol. 2015;39(7):561-5.

analysis. Curr Probl Pediatr. 1999;29(2):37-56. 29. Reece-Stremtan S, Marinelli KA. ABM clinical protocol #21: guidelines for

Page 50 | Volume 11: Number 1. 2018 RCSIsmjstaff review

breastfeeding and substance use or substance use disorder, revised 2015. 44. Hall ES, Isemann BT, Wexelblatt SL, Meinzen-Derr J, Wiles JR, Harvey S et al. A

Breastfeed Med. 2015;10(3):135-41. cohort comparison of buprenorphine versus methadone treatment for

30. McQueen KA, Murphy-Oikonen J, Gerlach K, Montelpare W. The impact of neonatal abstinence syndrome. J Pediatr. 2016;170:39-44.e1.

infant feeding method on neonatal abstinence scores of methadone-exposed 45. Marek E, Kraft WK. Ethanol pharmacokinetics in neonates and infants. Curr

infants. Adv Neonat Care. 2011;11(4):282-90. Ther Res Clin Exp. 2014;76:90-7.

31. Welle-Strand GK, Skurtveit S, Jansson LM, Bakstad B, Bjarko L, Ravndal E. 46. Wiles JR, Isemann B, Ward LP, Vinks AA, Akinbi H. Current management of

Breastfeeding reduces the need for withdrawal treatment in opioid-exposed neonatal abstinence syndrome secondary to intrauterine opioid exposure. J

infants. Acta Paediatr. 2013;102(11):1060-6. Pediatr. 2014;165(3):440-6.

32. Pritham UA, Paul JA, Hayes MJ. Opioid dependency in pregnancy and length 47. Surran B, Visintainer P, Chamberlain S, Kopcza K, Shah B, Singh R. Efficacy of

of stay for neonatal abstinence syndrome. J Obstet Gynecol Neonatal Nurs. clonidine versus phenobarbital in reducing neonatal morphine sulfate therapy

2012;41(2):180-90. days for neonatal abstinence syndrome. A prospective randomized clinical

33. Holmes AV, Atwood EC, Whalen B, Beliveau J, Jarvis JD, Matulis JC et al. trial. J Perinatol. 2013;33(12):954-9.

Rooming-in to treat neonatal abstinence syndrome: improved family-centered 48. Krans EE, Cochran G, Bogen DL. Caring for opioid dependent pregnant

care at lower cost. Pediatrics. 2016;137(6): pii: e20152929. women: prenatal and postpartum care considerations. Clin Obstet Gynecol.

34. McKnight S, Coo H, Davies G, Holmes B, Newman A, Newton L et al. 2015;58(2):370-9.

Rooming-in for infants at risk of neonatal abstinence syndrome. Am J 49. Benningfield MM, Arria AM, Kaltenbach K, Heil SH, Stine SM, Coyle MG et al.

Perinatol. 2016;33(5):495-501. Co-occurring psychiatric symptoms are associated with increased

35. Strauss ME, Andresko M, Stryker JC, Wardell JN, Dunkel LD. Methadone psychological, social and medical impairment in opioid dependent pregnant

maintenance during pregnancy: pregnancy, birth, and neonate women. A J Addict. 2010;19(5):416-21.

characteristics. Am J Obstet Gynecol. 1974;120(7):895-900. 50. Young JL, Martin PR. Treatment of opioid dependence in the setting of

36. Coyle MG, Ferguson A, Lagasse L, Oh W, Lester B. Diluted tincture of opium pregnancy. Psychiatr Clin North Am. 2012;35(2):441-60.

(DTO) and phenobarbital versus DTO alone for neonatal opiate withdrawal in 51. Chisolm MS, Tuten M, Brigham EC, Strain EC, Jones HE. Relationship between

term infants. J Pediatr. 2002;140(5):561-4. cigarette use and mood/anxiety disorders among pregnant

37. Hall ES, Wexelblatt SL, Crowley M, Grow JL, Jasin LR, Klebanoff MA et al. A methadone-maintained patients. Am J Addict. 2009;18(5):422-9.

multicenter cohort study of treatments and hospital outcomes in neonatal 52. Jones HE, Heil SH, O’Grady KE, Martin PR, Kaltenbach K, Coyle MG et al.

abstinence syndrome. Pediatrics. 2014;134(2):e527-e34. Smoking in pregnant women screened for an opioid agonist medication

38. Hall ES, Meinzen-Derr J, Wexelblatt SL. Cohort analysis of a study compared to related pregnant and non-pregnant patient samples.

pharmacokinetic-modeled methadone weaning optimization for neonatal American J Drug Alcohol Abuse. 2009;35(5):375-80.

abstinence syndrome. J Pediatr. 2015;167(6):1221-5.e1. 53. Chang JC, Alexander SC, Holland CL, Arnold RM, Landsittel D, Tulsky JA et al.

39. Jansson LM, Velez M, Harrow C. The opioid exposed newborn: assessment Smoking is bad for babies: obstetric care providers’ use of best practice smoking

and pharmacologic management. J Opioid Manag. 2009;5(1):47-55. cessation counseling techniques. Am J Health Promot. 2013;27(3):170-6.

40. Mehta A, Forbes KD, Kuppala VS. Neonatal abstinence syndrome 54. Conradt E, Sheinkopf SJ, Lester BM, Tronick E, Lagasse LL, Shankaran S et al.

management from prenatal counseling to postdischarge follow-up care: Prenatal substance exposure: neurobiological organization at one month. J

results of a national survey. Hosp Pediatr. 2013;3(4):317-23. Pediatr. 2013;163(4):989-94.e1.

41. O’Grady MJ, Hopewell J, White MJ. Management of neonatal abstinence 55. Hunt RW, Tzioumi D, Collins E, Jeffery HE. Adverse neurodevelopmental outcome

syndrome: a national survey and review of practice. Arch Dis Child Fetal of infants exposed to opiate in-utero. Early Hum Dev. 2008;84(1):29-35.

Neonatal Ed. 2009;94(4):F249-52. 56. Uebel H, Wright IM, Burns L, Hilder L, Bajuk B, Breen C et al. Reasons for

42. Backes CH, Backes CR, Gardner D, Nankervis CA, Giannone PJ, Cordero L. rehospitalization in children who had neonatal abstinence syndrome.

Neonatal abstinence syndrome: transitioning methadone-treated infants from Pediatrics. 2015;136(4):e811-e20.

an inpatient to an outpatient setting. J Perinatol. 2012;32(6):425-30. 57. Baldacchino A, Arbuckle K, Petrie DJ, McCowan C. Neurobehavioral

43. Kraft WK, Dysart K, Greenspan JS, Gibson E, Kaltenbach K, Ehrlich ME. consequences of chronic intrauterine opioid exposure in infants and preschool

Revised dose schema of sublingual buprenorphine in the treatment of the children: a systematic review and meta-analysis. BMC Psychiatry.

neonatal opioid abstinence syndrome. Addiction. 2011;106(3):574-80. 2014;14(1):104.

Volume 11: Number 1. 2018 | Page 51 RCSIsmjstaff review

Treatment is on target in Crohn’s disease with biologic agents

Abstract Crohn’s disease is a disorder of unknown aetiology, which classically presents with transmural inflammation throughout the gastrointestinal tract, from the mouth to the perianal area. Patients with Crohn’s disease suffer from various non-specific symptoms such as prolonged diarrhoea, abdominal pain, fever and weight loss. To date, treatment has largely involved immunosuppression, but the recent development of a novel class of drugs, the biologics, may revolutionise the treatment of Crohn’s disease. Biologic treatments used in Crohn’s disease include tumour necrosis factor alpha inhibitors (anti-TNF ), adhesion molecule inhibitors, and interleukin-12 (IL-12) and interleukin-23 (IL-23) inhibitors.α These biologics target the underlying immunopathogenesis seen in Crohn’s disease, primarily by decreasing pro-inflammatory cytokines. This article reviews the literature to date on infliximab, an anti-TNF used in Maria Mikail moderate to severe Crohn’s disease, and ustekinumab, an IL-12 and IL-23 inhibitor,α with a RCSI medical student specific focus on mechanisms of action, adverse events, and guidelines for these treatments.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 52-58.

Page 52 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Background Stepwise induction therapy for Crohn’s disease Crohn’s disease is a chronic inflammatory bowel disease (IBD) of unknown aetiology, involving inappropriate transmural granulomatous inflammation of any portion of the gastrointestinal Multidisciplinary team discussion, education, tract (GIT) from the mouth to the perianal region.1-3 The disease is lifestyle modifications, smoking cessation, often characterised by ‘skip lesions’ of inflammation, as continuous adequate nutrition, analgesia, and bowel involvement along the GIT is not seen; this differentiates anti-diarrhoeal medications10 Crohn’s disease from its main differential diagnosis, ulcerative colitis.4 Small intestinal involvement is observed in 80% of patients, with the distal portion of the small bowel, the terminal ileum, being most commonly affected.5,6 The majority of patients with Crohn’s disease experience vague symptoms, such as fatigue, prolonged diarrhoea, abdominal pain, Monotherapy: weight loss, anorexia, and fever, for months to years prior to oral glucocorticoids (prednisolone, diagnosis.6-8 Furthermore, extra-intestinal manifestations can occur, methylprednisolone, IV hydrocortisone) OR such as inflammatory arthropathies, scleritis, nephrolithiasis, and 5-aminosalicylic acid (5-ASA)20 dermatological manifestations.9 The disease course is highly variable between patients, and consists of alternating phases of recurrent acute exacerbations and periods of remission with decreased disease activity.8 As Crohn’s disease progresses, various gastrointestinal complications may arise, including strictures, fistulas, abscesses and, in severe cases, perforation of the GIT, necessitating surgical intervention.10 Improvements in patient quality of life can be Additional pharmacologic treatment: achieved by adequately recognising the variable presentations of azathioprine or mercaptopurine20 Crohn’s disease, thereby leading to timely, accurate diagnosis and management.

Epidemiology The prevalence of Crohn’s disease varies worldwide, with the highest annual prevalence in Europe (322 per 100,000) and North America (319 per 100,000).11 While the geographical distribution Biologic therapy: shows large variability, greater prevalence is seen in the infliximab and adalimumab20 industrialising world and in regions further from the equator, specifically in North America (Manitoba and Northern Alberta), Northern Europe (the United Kingdom), and Australia.2,12 Crohn’s disease exhibits a bimodal age distribution, with a peak in age-specific incidence between ages 10 and 20 years, and a second lesser but notable peak in incidence between ages 50 and 60 years.4 Experimental therapy or surgery10 Pathogenesis of Crohn’s disease While the exact cause of Crohn’s disease is unknown, a complex interplay involving an individual’s genetics, intestinal microbiota, 10 dysfunctional intestinal epithelium, and abnormal immune responses FIGURE 1: Stepwise induction therapy for Crohn’s disease. Education and symptom management are the basis of induction treatment, followed by the use of are thought to play a role in the disease’s underlying active agents such as 5-aminosalicylic acid, corticosteroids, immunosuppressives and immunomodulators and, in severe cases, surgery. Patients usually begin with 2,13 pathogenesis. It is currently understood that Crohn’s disease monotherapy, with additional agents added if symptoms persist.

Volume 11: Number 1. 2018 | Page 53 RCSIsmjstaff review

Current management regimen for Crohn’s disease As the disease course of Crohn’s is highly unpredictable and varies between individuals, the main goals of treatment are to control active disease, reduce recurrence and flares, maintain remission with therapeutic agents, and improve quality of life.17-19 According to National Institute for Health and Care Excellence (NICE) guidelines, once a patient has presented with active disease and has been formally diagnosed with Crohn’s disease, the case should be discussed by a multidisciplinary team. Induction therapy is thereafter begun with glucocorticoids to control the active disease flare.20 Once the active disease has been resolved, patients may commence remission therapy, which is prescribed depending upon disease severity and the extent of GIT involvement.10 The recommended approach is to begin with the least potent therapeutic agent, and supplement additional agents as needed as illness severity increases (Figure 1).10,16,19 Initial disease management should include patient education, analgesia, anti-diarrhoeal medications, and basic lifestyle adjustments such as smoking cessation and adequate nutrition.10,21 Although glucocorticoids have a rapid onset of action and are useful results from chronic inflammation due to abnormal concentrations in the acute setting, long-term steroid use should be avoided due to of pro- and anti-inflammatory mediators in both the innate and the risk of significant side effects, including adrenal insufficiency, adaptive immune systems, resulting in weakened host defences.4,14 diabetes, hypertension and infection, among others.12 Genome-wide association studies of patients with Crohn’s disease Immunomodulators such as 6-mercaptopurine (6-MP), azathioprine show genetic mutations in the NOD2/CARD15 gene, and the (AZA) and methotrexate (MTX) can be used to maintain remission autophagy gene ATG16L1, which play roles in bacterial in a subset of patients.10,22,23 While these medications play a pivotal peptidoglycan recognition and exocytosis of defence granules, role in the transition to and maintenance of remission, they typically respectively.4 Weakened defences lead to the proliferation of altered take three to six months to show therapeutic effects; as such, they GIT microbiota, thereby upregulating the immune system and are typically commenced during active disease flares, to allow NF-KB genes. This promotes an increase in pro-inflammatory sufficient time for their pharmacologic effects to manifest.22 cytokines, such as: interleukins 1, 6, 12 and 18; tumour necrosis In addition, some non-pharmacological management strategies factor alpha (TNFa); and, interferon alpha (IFN-a) and beta include dietary modification and smoking cessation, as smoking (IFN-β).15,16 Upregulation of cytokines and chemokines leads to T cell doubles the risk of developing Crohn’s disease. Although the role of infiltration, predominantly Th1, thereby amplifying the immune diet in Crohn’s disease development is unclear, several studies have response within the intestinal epithelium.4,16 suggested that overall fat intake, meat, and diets high in sugar and As the pathogenesis of Crohn’s disease is not completely omega-6 fatty acids are associated with increased risk of Crohn’s understood, effective treatment strategies are lacking.11 disease. On the other hand, diets consisting of high fruit and fibre Consequently, the majority of current medical therapies used to intake reduce the risk of developing Crohn’s disease.12 However, manage Crohn’s disease (e.g., corticosteroids and further research is needed to establish the precise relationship immunosuppressants) suppress the whole immune system, leading between diet and Crohn’s disease risk. to unwanted effects and an increased risk of infection.11 However, a Although the main goal of treatment is to control inflammation with novel class of drugs, the biologics, has been developed to pharmacological therapy, 80% of patients will require surgery within specifically target the underlying immunopathogenesis of Crohn’s 20 years following diagnosis.12 Unfortunately, surgery is not curative, disease. This article will review the current therapies for Crohn’s but may be indicated when the following complications arise: disease, highlighting recent advances with a specific focus on these obstructive symptoms; fistulas; perianal disease; dependence on novel biologics. steroids; medication failure; dysplasia; or, cancer.1,12 The exact

Page 54 | Volume 11: Number 1. 2018 RCSIsmjstaff review

surgical approach required depends on the underlying various anti-TNFa agents, including infliximab, adalimumab and complication.3 For example, after longstanding Crohn’s disease, certolizumab.31,32 According to NICE guidelines, the addition of stricture development and mechanical obstruction are common.1 In infliximab is only recommended for patients with active Crohn’s this subset of patients, a small segment of bowel is resected and a disease who have failed to respond to, or have specific primary anastomosis is performed.1,12 However, nearly 50% of these contraindications to, first-line treatments.31 patients will require repeat surgery after five years.3 Infliximab is a chimeric immunoglobulin G (IgG) monoclonal antibody, composed of 75% human components and 25% murine Biologic agents components.33 Although the exact mechanism of action of Use of biologics in Crohn’s disease infliximab is still unknown, it is suggested that it binds TNFa with Recently, the introduction of targeted treatments and biologics for high specificity and neutralises it, thereby preventing the cytokine various inflammatory disorders has provided an additional option for from binding to its receptors.33-35 Infliximab is given intravenously patients who fail to respond to first-line agents.23,24 Biologics are over two- to four-hour intervals.36 The first three doses are given laboratory-grown antibodies that specifically target the underlying close together at zero, two, and six weeks, with the remaining doses pro-inflammatory cytokines contributing to Crohn’s disease, rather given at regular six- to eight-week intervals.36 A recent study with than causing widespread dampening of the immune system as is 19-month follow-up assessed various anti-TNFa agents, including seen with glucocorticoids.24 The three main classes of biologic infliximab, adalimumab and certolizumab pegol, and showed that agents used in Crohn’s disease are anti-TNFa, adhesion molecule infliximab had the lowest rates of Crohn’s disease-related inhibitors, and IL-12/IL-23 inhibitors.12 Biologics are used as hospitalisations.28 Additionally, as infliximab enhances mucosal second-line agents in patients with severe Crohn’s disease who have healing, patients receiving infliximab had a reduced need for failed to respond to conventional treatments such as abdominal surgeries and glucocorticoid treatment.33 glucocorticoids, azathioprine, 6-MP and MTX.25 Slowing disease progression leads to an overall increase in quality of life (QoL), and prevents disease-related mortality.28 One major History of biological agents complication of Crohn’s disease, leading to decreased QoL and In 1985, it was hypothesised that TNF, a pro-inflammatory cytokine, eventual need for surgical resection, is the development of perianal played an important role in mediating shock in mice.23 Mice were disease and fistulas.28 A double-blind, placebo-controlled trial of shown to be able to withstand lethal doses of lipopolysaccharide, a patients with draining abdominal or perianal fistulas receiving potent inducer of inflammation and often septic shock, when given a infliximab showed a 50% reduction in the need for abdominal specific polyclonal antiserum against TNF.23 Further studies later surgeries (bowel resection, ostomy placement, and fistula-related identified elevated TNF in various tissues during inflammatory surgeries) compared to patients receiving placebo.28 disorders, such as in the GIT mucosa and lamina propria in patients Although anti-TNFa agents have shown promising results, 23-46% with Crohn’s disease.23 Soon after, a study demonstrated that a single of patients gradually become unresponsive to these agents, dose of chimeric mouse/human anti-TNFa monoclonal antibody eventually requiring increasing drug doses, or drug discontinuation promoted colonic ulceration healing within just four weeks of within one year.37 Over time, antibodies to infliximab are generated treatment.26 A large number of studies have since been conducted, by the body’s immune system.37 Immune complex formation results and concluded that biologics are more efficacious for Crohn’s disease in increased drug clearance by the reticuloendothelial system, management compared to other modalities, with reduced side resulting in decreased therapeutic concentrations.37 As such, despite effects, improved compliance, and superior clinical outcomes.26-28 many trials showing promising outcomes with infliximab monotherapy, current guidelines state that the highest remission Infliximab rates for moderate to severe Crohn’s disease are achieved with TNFa, produced by leukocytes in Crohn’s disease, leads to effects infliximab in combination with azathioprine or methotrexate.10,12,27,31 such as increased gastrointestinal inflammation, elevated cytokines, The synergistic effects seen with such combination therapy result in enhanced expression of adhesion molecules required for leukocyte decreased production of antibodies against anti-TNFa, and thus recruitment, and inhibition of apoptosis in pro-inflammatory higher levels of infliximab.12,37 cells.29,30 Targeting this specific cytokine for induction and As Crohn’s disease is a heterogeneous disease, all patients should maintenance therapy in Crohn’s disease can be achieved with not necessarily be started on the most intensive therapy

Volume 11: Number 1. 2018 | Page 55 RCSIsmjstaff review

immediately.37,38 Initiating combination therapy very early following includes an intravenous infusion, with doses determined by patient diagnosis should be reserved for patients who have extensive disease, body weight (6mg/kg).46 The maintenance regimen is then delivered classified by: involvement of both the small and large intestine, or subcutaneously at eight weeks following the initial delivery, followed upper GIT; presence of perianal fistulas; presence of severe intestinal by maintenance doses every 12 weeks.12,43,44,46 Following a 44-week lesions as seen on endoscopy; or, patients presenting with follow-up trial, clinical remission was significantly higher in patients extraintestinal tract involvement early on.37,39 However, although receiving ustekinumab at eight-week intervals (53.1%), compared to combination therapy with infliximab plus azathioprine has shown 12-week intervals (48.8%) and placebo (35.9%).47 Adverse drug favourable outcomes, patients have reported an increased incidence reactions included arthralgia, pyrexia, upper respiratory tract of opportunistic infections.12 infections, erythema at the site of injection, itching, and abdominal Infliximab and other anti-TNFa biologics share similar adverse drug discomfort.46,48,49 While research has shown promising outcomes with reactions.12 Immediate adverse events include: injection site reactions; the use of ustekinumab, significant gaps still exist in the literature, infusion reactions; and, cutaneous reactions.39 Additionally, an including information regarding optimal dosing, the impact on increased incidence of tuberculosis, neutropenia, demyelinating extraintestinal manifestations, and the extent of mucosal healing.50 disease, and malignancy (lymphoma, leukaemia and melanoma) have been associated with infliximab use.12,40,41 There are thus several Conclusion limitations to the use of combination therapy with infliximab, despite Currently, 322 individuals per 100,000 are living with Crohn’s disease research showing advantageous outcomes; further studies may be in Europe, with the majority of cases reported in Northern warranted. Europe.2,11,22 As Crohn’s disease is highly prevalent, a number of novel, targeted therapeutic agents have recently been incorporated Ustekinumab into the treatment regime. At present, infliximab and ustekinumab Ustekinumab is a monoclonal antibody that has recently been are two biologic agents used for patients with moderate to severe approved by the US Food and Drug Administration (FDA) and NICE Crohn’s disease who have failed to respond to conventional first-line for patients with moderate to severe Crohn’s disease.42,43 Ustekinumab treatment.50 The majority of clinical trials investigating biologics have is also approved for use in patients who have experienced either an focused primarily on adult patients with moderate to severe disease. inadequate response or intolerance to conventional first-line Promising results have been shown with a variety of biologic agents; treatments and TNFa inhibitors.12,42,43 This antibody binds to p40, a to date, however, the use of combination therapy with azathioprine subunit of pro-inflammatory interleukins 12 and 23. IL-12 and IL-23 and infliximab has shown the highest remission rates in this patient have been identified in the underlying pathophysiology of Crohn’s population.51 The addition of TNFa inhibitors to the Crohn’s disease disease; however, the relationship with Th1 and Th17 cells is not treatment plan has also been shown to reduce signs and symptoms, completely understood.44 IL-23 has been hypothesised to aid in the and improve QoL by reducing hospitalisations and the need for differentiation of Th1 and Th17; therefore, by inhibiting IL-12 and surgeries.31,52 Introducing a biologic agent may thus be a powerful, IL-23, T cells and pro-inflammatory cytokines are inhibited.44,45 feasible tool in certain patient populations to target the underlying According to NICE guidelines, induction treatment with ustekinumab immunopathogenesis of Crohn’s disease and improve QoL.

References 1. Farrell RJ, Rutgeerts P, Robson KM. Overview of the medical management 2. Kumar V, Abbas A, Aster J. Robbins Basic Pathology. Philadelphia: Elsevier Saunders, 2013.

of severe or refractory Crohn disease in adults. Pubmed. 2016. [Internet]. 3. Ha F, Khalil H. Crohn’s disease: a clinical update. Therap Adv

[cited 2017 Sept 16]. Available from: Gastroenterol. 2015;8(6):352-9.

https://www-uptodate-com.proxy.library.rcsi.ie/contents/overview-of-the- 4. Lashner B. Cleveland Clinic. Crohn’s Disease. 2013. [Internet]. [updated

medical-management-of-severe-or-refractory-crohn-disease-in-adults?sourc January 2013; cited 2017 Sept 16]. Available from:

e=machineLearning&search=crohns&selectedTitle=3~150§ionRank=1 http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/

&anchor=H11188279#H11188279. gastroenterology/crohns-disease/.

Page 56 | Volume 11: Number 1. 2018 RCSIsmjstaff review

5. US National Library of Medicine. Crohn’s disease. [Internet]. [undated; Crohn’s disease? 2017. [Internet]. [undated; cited 2017 Sept 17]. Available

cited 2017 Sept 16]. Available from: from:

https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022801/. http://www.bidmc.org/Centers-and-Departments/Departments/Digestive-

6. Peppercorn MA, Putgeerts, Robson KM. Clinical manifestations, diagnosis Disease-Center/Services/Inflammatory-Bowel-Disease-Program/Crohns-Dise

and prognosis of Crohn disease in adults. 2017. [Internet]. [cited 2017 ase/What-are-the-goals-in-treating-Crohns-disease.aspx.

Sept 16]. Available from: 20. National Institute for Health Care and Excellence. Crohn’s disease overview

https://www-uptodate-com.proxy.library.rcsi.ie/contents/clinical-manifestat 2016. [Internet]. [updated 2016; cited 2017 Sept 17]. Available from:

ions-diagnosis-and-prognosis-of-crohn-disease-in-adults?source=search_res https://pathways.nice.org.uk/pathways/crohns-disease/inducing-remission-

ult&search=crohns&selectedTitle=2~150#H12689022. in-crohns-disease#path=view%3A/pathways/crohns-disease/crohns-disease-

7. National Clinical Guideline Centre. Crohn’s disease: Management in overview.xml&content=view-index.

adults, children and young people. 2012. [Internet]. [updated 2012 21. Longmore M, Wilkinson I, Baldwin A, Wallin E. Oxford Handbook of

October; cited 2017 Sept 16]. Available from: Clinical Medicine (9th ed.). Oxford: Oxford University Press, 2014.

https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0079977/#ch1.s3. 22. A-Rahim Y, Rutgeerts P, Robson KM. Azathioprine and 6-mercaptopurine in

8. Walfish AE, Companioni RAC. Crohn Disease: Regional Enteritis: inflammatory bowel disease. UptoDate. 2015. [Internet]. [cited 2017 Sept

Granulomatous Ileitis: Granulomatous Ileocolitis. 2016. [Internet]. 17]. Available from:

[updated 2016 January; cited 2017 Sept 16]. Available from: https://www-uptodate-com.proxy.library.rcsi.ie/contents/azathioprine-and-

http://www.merckmanuals.com/professional/gastrointestinal-disorders/infla 6-mercaptopurine-in-inflammatory-bowel-disease?source=search_result&se

mmatory-bowel-disease-ibd/crohn-disease. arch=Azathioprine%20and%206-mercaptopurine%20in%20inflammatory

9. Wilkins T, Jarvis K, Patel J. Diagnosis and management of Crohn’s disease. %20bowel%20disease&selectedTitle=1~150#H13.

Am Fam Physician. 2011;84(12):1365-75. 23. Randall CW, Vizuete JA, Martinez N, Alvarez JJ, Garapati KV, Malajouti M et

10. Merali Z, Woodfine J. Toronto Notes 2016. (32nd ed.). Toronto: Toronto al. From historical perspectives to modern therapy: a review of current and

Review Notes, 2016. future biological treatments for Crohn’s disease. Therap Adv Gastroenterol.

11. M’Koma AE. Inflammatory bowel disease: an expanding global health 2015; 8(3):143-59.

problem. Clin Med Insights Gastroentol. 2013;6:33-47. 24. Crohn’s and Colitis Foundation. Biologic Therapies. 2014. [Internet].

12. Feuerstein JD, Cheifetz AS. Crohn disease: epidemiology, diagnosis and [updated 2014 Feb 6; cited 2017 Sept 17]. Available from:

management. Mayo Clin Proc. 2017;92(7):1088-103. http://www.crohnscolitisfoundation.org/resources/biologic-therapies.html.

13. Boyapati R, Satsangi J, Ho G-T. Pathogenesis of Crohn’s disease. 25. MacDermott RP, Rutgeerts P, Robson KM. Infliximab in Crohn disease.

F1000Prime Rep. 2015;7:44. UptoDate. 2015. [Internet]. [updated 2015 July 9]. Available from:

14. Park JH, Peyrin-Biroulet L, Eisenhut M, Shin J. IBD immunopathogenesis: a https://www-uptodate-com.proxy.library.rcsi.ie/contents/infliximab-in-croh

comprehensive review of inflammatory molecules. Autoimmun Rev. n-disease?source=related_link.

2017;16(4):416-26. 26. Elliot MJ, Maini RV, Feldmann M, Long-Fox A, Charles P, Katsikis P et al.

15. Ng SC, Benjamin JL, McCarthy NE, Hedin CR, Koutsoumpas A, Palmondon Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to

S et al. Relationship between human intestinal dendritic cells, gut tumor necrosis factor a. Arthritis Rheum. 1993;36(2):1681-90.

microbiota, and disease activity in Crohn’s disease. Inflam Bowel Dis. 27. Singh S, Heien HC, Sangaralingham LR, Schilz SR, Kappelman MD, Shah

2011;17(10):2027-37. ND et al. Comparative effectiveness and safety of anti-tumor necrosis

16. Philpott DJ, Sorbara MT, Robertson SJ, Croitoru K, Girardin SE. NOD factor agents in biologic-naïve patients with Crohn’s disease. Clin

proteins: regulators of inflammation in health and disease. Nat Rev Gastroenterol Hepatol. 2016;14(8):1120-9.

Immunol. 2013;14:9-23. 28. Danese S, Colombel JF, Reinisch W, Rutgeerts PJ. Review article: infliximab

17. Feldman PA, Wolfson D, Barkin JS. Medical management of Crohn’s for Crohn’s disease treatment – shifting therapeutic strategies after 10

disease. Clin Colon Rectal Surg. 2007;20(4):269-81. years of clinical experience. Aliment Pharmacol Ther. 2011;33(8):857-69.

18. Rutgeerts PJ. Conventional treatment of Crohn’s disease: objectives and 29. Poggioli G, Laureti S, Campieri M, Pierangeli F, Gionchetti P, Ugolini F et al.

outcomes. Inflamm Bowel Dis. 2001;7(Suppl. 1):S2-8. Infliximab in the treatment of Crohn’s disease. Ther Clin Risk Manag.

19. Beth Israel Deaconess Medical Centre. What are the goals in treating 2007;3(2):301-8.

Volume 11: Number 1. 2018 | Page 57 RCSIsmjstaff review

30. Paychaudhuri SB, Raychaudhuri SK. Biologics: target-specific treatment of https://www.uptodate.com/contents/tumor-necrosis-factor-alpha-inhibitors

systemic and cutaneous autoimmune diseases. Indian J Dermatol. -risk-of-malignancy?source=related_link.

2009;54(2):100-9. 42. National Institute for Health Care and Excellence. Ustekinumab for

31. National Institute for Health Care and Excellence. Crohn’s disease: moderately to severely active Crohn’s disease after previous treatment:

management. 2016. [Internet]. [updated May 2016; cited 2017 Sept 17]. Recommendations. 2017. [Internet]. [updated 2017 July 12; cited 2017

Available from: Sept 17]. Available from:

https://www.nice.org.uk/guidance/cg152/chapter/Recommendations#ind https://www.nice.org.uk/guidance/ta456/chapter/1-Recommendations.

ucing-remission-in-crohns-disease. 43. Johnson and Johnson. FDA approves STELARA (ustekinumab) for treatment

32. Bendtzen K, Maini RN, Romain PL. Tumour necrosis factor-alpha inhibitors: of adults with moderately to severely active Crohn’s disease. 2016.

induction of antibodies, autoantibodies, and autoimmune diseases. [Internet]. [updated 2016 Sept 26; cited 2017 Sept 17]. Available from:

UptoDate, 2017. [Internet]. [updated 2017 Sept; cited 2017 Sept 17]. https://www.jnj.com/media-center/press-releases/fda-approves-stelara-uste

Available from: kinumab-for-treatment-of-adults-with-moderately-to-severely-active-crohns

https://www.uptodate.com/contents/tumor-necrosis-factor-alpha-inhibitors -disease.

-induction-of-antibodies-autoantibodies-and-autoimmune-diseases?source= 44. Koutruba N, Emer J, Lebwohl M. Review of ustekinumab, an interleukin-12

search_result&search=infliximab%20crohn&selectedTitle=10~150. and interleukin-23 inhibitor used for the treatment of plaque psoriasis.

33. Billmeier U, Dieterich W, Neurath MF, Atreya R. Molecular mechanism of Ther Clin Risk Manag. 2010;6:123-41.

action of anti-tumor necrosis antibodies in inflammatory bowel disease. 45. Simon EG, Ghosh S, Lacucci M, Moran GW. Ustekinumab for the

World J Gastroenterol. 2016;22(42):9300-13. treatment of Crohn’s disease: can it find its niche? Therap Adv

34. Nguyen DL, Flores S, Sassi K, Bechtold ML, Nguyen ET, Parekh NK. Gastroenterol. 2016;9(1):26-36.

Optimizing the use of anti-tumor necrosis factor in the management of 46. National Institute for Health Care and Excellence. Ustekinumab for

patients with Crohn’s disease. Ther Adv Chronic Dis. 2015;6(3):147-54. moderately to severely active Crohn’s disease after pervious treatment: The

35. Crohn’s Colitis Foundation. Diagnosing and managing IBD. 2011. Technology. 2017. [Internet]. [updated 2017 July 12; cited 2017 Sept 17].

[Internet]. [updated 2011 April 30; cited 2017 Sept 17]. Available from: Available from:

http://www.crohnscolitisfoundation.org/resources/diagnosing-and-managi https://www.nice.org.uk/guidance/ta456/chapter/2-The-technology.

ng-ibd.html. 47. Deepak P, Loftus EV. Ustekinumab in the treatment of Crohn’s disease:

36. Kim DH, Cheon JH. Pathogenesis of inflammatory bowel disease and design, development, and potential place in therapy. Drugs Des Devel

recent advances in biologic therapies. Immune Netw. 2017;17(1):25-40. Ther. 2016;10:3685-98.

37. Magro F, Portela F. Management of inflammatory bowel disease with 48. National Institute for Health Care and Excellence. Ustekinumab for

infliximab and other anti-tumor necrosis factor alpha therapies. BioDrugs. moderately to severely active Crohn’s disease after pervious treatment:

2010;24(Suppl. 1):3-1.4. Committee discussion. 2017. [Internet]. [updated 2017 July 12; cited 2017

38. Colombel JF. When should combination therapy for patients with Crohn’s Sept 17]. Available from:

disease be discontinued? Gastroenterol Hepatol (NY). 2012;8(4):259-62. https://www.nice.org.uk/guidance/ta456/chapter/4-Committee-discussion.

39. Kirkham B, Furst DE, Romain PL. Tumor necrosis factor-alpha inhibitors: an 49. Sandborn WJ, Gasink C, Gao L, Blank MA, Johanns J, Guzzo C et al.

overview of adverse effects. UptoDate. 2017. [Internet]. [cited 2017 Sept Ustekinumab induction and maintenance therapy in refractory

17]. Available from: Crohn’s disease. N Engl J Med. 2012;367:1519-28.

https://www-uptodate-com.proxy.library.rcsi.ie/contents/tumor-necrosis-fa 50. Engel T, Kopylov U. Ustekinumab in Crohn’s disease: evidence to date and

ctor-alpha-inhibitors-an-overview-of-adverse-effects?source=see_link. place in therapy. Ther Adv Chronic Dis. 2016;7(4):208-14.

40. University of Maryland Medical Centre. Crohn’s disease. 2012. [Internet]. 51. Ghazi LJ. Crohn disease treatment & Management. 2017. [Internet].

[updated 2012 Dec 21; cited 2017 Dec 21]. Available from: [updated 2017 Jan 6; cited 2017 Sept 17]. Available from:

http://www.umm.edu/health/medical/reports/articles/crohns-disease. http://emedicine.medscape.com/article/172940-treatment.

41. Hyrich K, Furst DE, Romain PL. Tumor necrosis factor-alpha inhibitors: risk 52. Smart C, Sellinger CP. The cost-effectiveness of infliximab in Crohn’s

of malignancy. UptoDate, 2017. [Internet]. [cited 2017 Sept 17]. Available disease. Expert Rev Pharmacoecon Outcomes Res. 2014;14(5):589-98.

from:

Page 58 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Out of Africa into a genetic bottleneck: how evolution has shaped modern disease

Abstract Two hundred million years ago, humans shared a common ancestor with worms; Homo sapiens have come a long way since then. Steady changes in the environment, due to migration patterns and climatic changes, have caused humans to become increasingly genetically distinct. These changes have affected a range of physiological aspects, from differential metabolisms tailored to available sustenance, to population-specific immune responses to dissimilar threats. Fragments of ancestral DNA live on in the present human genome, with chance encounters between anatomically modern humans and ancestral populations having resulted in the introgression of ancestral DNA fragments. This is, in part, responsible for the current expression, downregulation, or complete loss of certain alleles and Sumara Jaimungal phenotypic traits, and has significant health implications. These ancestral genes have RCSI medical student impacted modern medicine, disease, and human nature immensely.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 59-66.

Volume 11: Number 1. 2018 | Page 59 RCSIsmjstaff review

~ 15-35 kya Arrival to the Americas

~ 40-80 kya Out of Africa Trans-Atlantic slave trade ~ 1-4 kya

Arrival to ~ 5 kya Polynesia Bantu expansion

~ 400 yrs

FIGURE 1: Migration patterns following the exodus from Africa. Adapted from Quach and Quintana-Murci.3

Introduction Homo heidelbergensis left Africa 400,000 years ago.1 Upon An understanding of the relationship exodus, H. heidelbergensis split into two groups: one moved between populations’ genetic variation northwestward into West Asia and Europe and became the and differences in disease susceptibility Neanderthals, while the other moved east, becoming Denisovans has set the stage for therapeutic (Figure 1).1 innovations. The H. heidelbergensis remaining in Africa eventually became anatomically modern humans (AMHs).1 Stark climatic and environmental differences in these regions prompted subtle Bottlenecking: how the founders may have maladapted genetic changes in these populations for the purpose of survival. During migration, when a small portion of a population leaves to Between 50,000 and 72,000 years ago, AMHs left Africa and bred colonise new land, these individuals are known as founders.10 with humans in Eurasia.2 As such, all contemporary non-Africans These founders carry, in their DNA, a random portion of the are descended from a single population that left Africa genetic variation that was present in the original population.6,10 approximately 60,000 years ago.3 The smaller number of individuals in the founder population, Today, roughly 2.5% of the DNA carried by modern humans compared to the original population, is referred to as a living outside of Africa comes from Neanderthals, whereas ‘population bottleneck’.6,8,10 Australasians carry approximately 5% Denisovan DNA (Figure Novel selection pressures in the new geographic area result in 2).4-7 adaptations that differentiate the founders from their ancestors.8 These small portions of ancestral DNA within different However, genetic diversity is decreased as a consequence of populations worldwide have notable physiological consequences. genetic drift, which results in random selection of alleles.8 In For instance, the immune systems of Africans and non-Africans small populations, genetic drift can overwhelm the effects of evolved distinctly to cope with the different pathogenic pressures natural selection, mutation and migration; thus, an allele that is of Europe and Africa.7-9 Pathologies related to metabolism, being positively selected for its evolutionary advantage might in immune responses and susceptibility to disease have thus been fact decrease in frequency.9-10 Consequently, genetic drift can found to differ between populations, and research into these result in non-adaptive evolution.10,11 The predecessors of AMH variations provides the framework for novel disease treatments. had a tendency to accumulate mutations resulting in altered

Page 60 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Genes* I African I Unknown archaic 2% 2.5% 2.5% 5% African source I Neanderthal I Denisovan

98% 97.5% 92.5% *Figures are approximate, and for Africa, based on limited data.6

Sub-Saharan Eurasia and Australia and Africa Americas New Guinea

FIGURE 2: Percentages of archaic DNA introgression in specific populations.3-7 Adapted from Stringer.7

protein structure, often leading to changes in function (known as Small populations such as this experience increased deleterious non-synonymous deletions).10 While some changes were variation, since natural selection is less effective as a result of genetic beneficial, other variants were genetically damaging.4,8,11 Genetic drift.7 This led to an extreme distribution of allele frequencies among drift, an impressively powerful selective force, thus favoured the the Inuit compared to other populations, resulting in propagation of persistence of certain deleterious alleles.4 weakly deleterious alleles.8 Genes involved in phospholipid transporter activity, fat metabolism, and trace amine receptor activity, are Denisovan ancestry has been significantly enriched in Denisovan ancestry, including the Inuit, with somewhat deleterious on a modern notable consequences.11 genetic scale. Common alleles that were advantageous in ancestral environments, Classical CPT1A deficiency: an energy crisis Carnitine palmitoyltransferase 1 (CPT1) is an enzyme on the such as certain genes regulating outer mitochondrial membrane.16 During periods of fasting, CPT1 metabolism, are in fact deleterious in catalyses the rate-limiting step in the import of long-chain fatty current environments. acids (LCFAs) into the mitochondrion, for use in fatty acid oxidation.4,17 During the fed state, CPT1 isoforms (CPT1A, B and The Inuit bottleneck C) are allosterically inhibited by malonyl CoA, the first Denisovan ancestry has been somewhat deleterious on a modern intermediate of fatty acid synthesis. genetic scale.8,11 Common alleles that were advantageous in ancestral environments, such as certain genes regulating metabolism, are in fact Following the exodus from Africa, deleterious in current environments.12-15 Conversely, some formerly populations developed significant maladaptive alleles are now selected for.12,13,15 The Inuit population, variation in appearance, behaviour, with its Denisovan ancestry, provides a notable example of this unusual metabolism, and immune responses. inheritance pattern.8 The Inuit population underwent a prolonged Historic bottlenecks played a key role in bottleneck of roughly 20,000 years, making it one of the smallest and shaping the present genetic landscape. most isolated human populations to exist.13,14

Volume 11: Number 1. 2018 | Page 61 RCSIsmjstaff review

Plasma FFA

(-) (-) Insulin Cytostolic LCFA- + CPT 1 Glucose LCFA CoA Carnitine

Triglyceride (-) hydrolysis in muscle Malonyl CoA

(+)

ACC

FIGURE 3: Metabolic pathway illustrating the increase in malonoyl CoA levels during the fed state, resulting in CPT1 inhibition. Adapted from Chien et al.19

This inhibition appropriately results in decreased LCFA 4).22,25,26 Consequences of the CPT1A mutation counter this metabolism in the fed state (Figure 3).16,17 In contrast, during overactivity, preventing excessive oxidation of LCFA.24 That is, fasting, lipolysis of adipose tissue is increased to provide free fatty while beta-oxidation takes place constantly, it does so on a acids for beta-oxidation; malonyl CoA production is inhibited, smaller scale, effectively preventing overproduction of and thus CPT1 activity increases.17,18 ketones.22,25 Increased CPT1 activity results in greater acetyl CoA production, Thus, individuals with the mutation are able to subsist on high-fat which is used to synthesise ketone bodies.19-21 Ketones provide diets without suffering from ketoacidosis.16,23,24 energy to extrahepatic tissues during periods of starvation, However, over the past five decades, Euro-Canadian influence has allowing glucose to be spared for use by red blood cells and resulted in cultural and dietary shifts among the Inuit.22,27 There nervous tissue, as these tissues cannot utilise ketones.17,20,22 has been a dramatic reduction in hunting and gathering, as more However, excessive ketone production may result in ketoacidosis; food is shop bought.25,27 Metabolism has thus shifted from this causes acidification of the blood, impairing the ability of lipocentric to glucocentric, matching the Western world. The haemoglobin to bind oxygen, and is a medical emergency.21 modern Inuit diet largely lacks unsaturated LCFA, meaning that CPT1A deficiency is an autosomal recessive disorder resulting individuals with the CPT1A mutation rely almost entirely on from mutation in the CPT1A gene.23 glucose for fuel.25,27 This mutation also decreases the sensitivity of CPT1A for During periods of fasting or illness, individuals with classical inhibition by malonyl CoA.16 Classical CPT1A deficiency is CPT1A deficiency often become hypoketotic and hypoglycaemic, common among the Aboriginals of Alaska and the Greenlandic due to a reduced capacity for LCFA beta-oxidation.25-29 Inuit.23 Historically, these populations’ diets consisted primarily of marine animals, with little or no carbohydrates or saturated Genetic diversity conferred significant fats.22-24 The CPT1A mutation was thus advantageous in these advantages for ancestral populations, populations, as their high-fat diet meant metabolism needed to yet, in modern times, some of 21 be lipocentric, without causing ketosis. A diet rich in LCFA these inherited differences have results in upregulation of CPT1A through activation of pathological implications. peroxisome proliferator activated receptor alpha (PPAR) (Figure

Page 62 | Volume 11: Number 1. 2018 RCSIsmjstaff review

PUFA

+-

SREBP1 PPAR Sp1 NF-Y

PPRE FA-oxidation Lipogenic genes genes

Peroxisome Mitochondria Fatty acid Triglyceride β-oxidation β-oxidation synthesis synthesis

VLDL-TG

FIGURE 4: Role of polyunsaturated fats (PUFAs) in activating peroxisome proliferator-activated receptor (PPAR), and relationship with PPAR response element (PPRE). Adapted from Clarke.26 Sterol regulatory element binding protein-1 (SREBP1); Very low density lipoprotein (VLDL); Triglyceride (TG).

This can result in general malaise, loss of consciousness, or and acetyl CoA then enters the Krebs cycle, but in some cancer neurological damage from prolonged hypoglycaemia.28-30 cells, the glycolytic and Krebs cycles are uncoupled.31,32 This Saturated fats, which were previously foreign to Inuit populations, results in increased glucose uptake and consumption due to lack do not result in CPT1A upregulation; as such, these fats may of downstream oxidative phosphorylation; there is a metabolic accumulate in the liver, resulting in hepatic encephalopathy and shift, in cancerous cells, toward fatty acid oxidation (FAO) rather liver failure.28-30 Classical CPT1A deficiency is commonly linked to than pyruvate oxidation.31-33 An understanding of this the high prevalence of sudden infant death syndrome (SIDS) phenomenon, known as the Warburg Effect, is key to developing among Alaskan and Greenlandic Inuit infants.29 It is suggested innovative cancer therapies.33,34 that SIDS may result from prolonged periods of fasting in babies By inhibiting FAO through blockage of CPT1A, malignant cells with the mutation, as their fasting tolerance is markedly are unable to thrive due to reduced capacity to generate reduced.29 Treatment is centred on dietary changes, with energy.35 In addition, inhibiting FAO halts the production of increased complex carbohydrates and frequent feedings to nicotinamide adenine dinucleotide phosphate (NADPH), an prevent hypoglycaemia.30 important molecule for eliminating reactive oxygen species (ROS).35 Without NADPH, toxic ROS accumulate within cancer Saturated fats, which were previously cells, triggering apoptosis.35 foreign to Inuit populations, do not The Inuit have historically had lower cancer rates, including result in CPT1A upregulation; as such, prostate, breast, bladder and leukaemia.36 these fats may accumulate in the liver, This may likely be due to the higher prevalence of CPT1A deficiency in this population. resulting in hepatic encephalopathy Fatty acid oxidation takes place on a smaller scale, meaning that and liver failure. the tumour’s primary bioenergetic pathway is diminished. In addition, tumours have shown a critical dependence on glucose CPT1A in cancer for growth and metastasis.37 The Inuit’s traditional ketogenic diet Fatty acids (FAs) are essential for cell proliferation in many was devoid of carbohydrates, making glucose largely unavailable cancers.31 In normal cells, glucose enters the glycolytic pathway, to the cell.37

Volume 11: Number 1. 2018 | Page 63 RCSIsmjstaff review

Consequently, Africans developed prevalence of lupus compared to Caucasians.47 SLE is a complex immune systems that are considered autoimmune disorder, characterised by immunologic abnormalities that lead to disrupted self-tolerance and ‘more active’ than non-Africans, due to production of autoantibodies targeting nucleic acids and increased pathogenic pressures. proteins.48 Patients with SLE exhibit defects in clearance of dead cells, Evolution of the immune system normally removed by phagocytes.49 Autoantibodies produced by Owing to its tropical location, Africa has a rich biodiversity, with hyperactive B-cells form immune complexes with the uncleared an impressive range of species and pathogens thriving.1,38 genetic debris.50 Plasmacytoid dendritic cells (pDCs), a Pathogenic microorganisms are among the strongest selective specialised subset of DCs, then internalise the immune pressures encountered by humans, and genes associated with complexes, triggering activation of TLR7 and TLR9.51 A cascade immune responses, particularly the Toll-like receptors (TLRs), of events results in nuclear factor (NF)-κB activation and evolve faster than any others in the genome.9,39 Consequently, transcription of pro-inflammatory cytokines; depending on the Africans developed immune systems that are considered ‘more site of immune complex deposition, SLE may affect the skin, active’ than non-Africans, due to increased pathogenic 52 pressures.40,41 Comparatively, Eurasia lacked predators that renal, musculoskeletal, and/or haematologic systems. posed a significant threat to hominins; Neanderthals in Europe Generally, genetic diversity has been shown to decrease with thus developed a reduced immune response compared to increasing distance from Africa; however, TLR1 is nearly twice as Africans.1,9 diverse in non-African populations compared to Africans.29 The TLR1 1805G (602S) variant, common among non-Africans, Inappropriate activation of TLR blocks NF-κB activation, resulting in decreased expression of signalling contributes to autoimmunity, inflammatory response genes.29 This variant was likely lost in and diseases such as systemic lupus African populations, as it is linked to a decreased immune response and would not have conferred a survival advantage in erythematosus (SLE), inflammatory Africa’s diverse pathogenic environment.51 bowel disease, psoriasis, multiple For this reason, it has been suggested that SLE and other sclerosis and rheumatoid arthritis are autoimmune diseases are less prevalent among non-Africans known to arise from such immune who were, historically, exposed to a less pathogenic overactivity. environment and developed a diminished immune response.34,46,49 Indeed, studies conducted in Georgia and Michigan revealed Polymorphisms in TLRs are directly related to resistance or that SLE was two to three times more prevalent in African susceptibility to infectious and autoimmune diseases.9 Americans than Caucasians, though socioeconomic disparities TLRs are a family of pattern recognition receptors that recognise also play a role.53 Additionally, the Saharawi population within pathogen-associated molecular patterns on microbial molecules West Africa has the highest prevalence worldwide of coeliac and mount a host immune response.42 TLRs are expressed on disease, another autoimmune disease, which may support the many immune cells, including macrophages, dendritic cells above hypothesis.54 (DCs), B cells, T cells, and some non-immune cells such as fibroblasts and epithelial cells.43 Inappropriate activation of TLR Conclusion signalling contributes to autoimmunity, and diseases such as Following the exodus from Africa, populations developed systemic lupus erythematosus (SLE), inflammatory bowel significant variation in appearance, behaviour, metabolism, and disease, psoriasis, multiple sclerosis and rheumatoid arthritis are immune responses. Historic bottlenecks played a key role in known to arise from such immune overactivity.8,44,45 shaping the present genetic landscape. Genetic diversity conferred significant advantages for ancestral populations, yet, Is decreased immune responsiveness the key to in modern times, some of these inherited differences have surviving lupus? pathological implications. An understanding of the relationship Individuals from different populations vary considerably in their between populations’ genetic variation and differences in susceptibility to inflammatory and autoimmune diseases.46 disease susceptibility has set the stage for therapeutic African Americans, Hispanics and Asians have a higher innovations.

Page 64 | Volume 11: Number 1. 2018 RCSIsmjstaff review

As a consequence of ketogenic metabolism and CPT1A By targeting the TLRs responsible for mounting harmful deficiency, Inuit populations face a number of health issues, and inflammatory responses, it may be possible to treat autoimmune yet appear to have been historically protected from malignancy. diseases such as SLE and rheumatoid arthritis, which affect Research into CPT1A deficiency thus led to great strides in millions worldwide. cancer therapy. Additionally, within non-African populations, Evidently, understanding evolutionary genetics is, in many ways, autoimmune diseases seem to be less prevalent, due to a the foundation for novel treatments and targeted disease diminished immune response. management.

References 1. Ko KH. Hominin interbreeding and the evolution of human variation. J 13. Crespi BJ. The emergence of human-evolutionary medical genomics.

Biol Res (Thessalon). 2016;23:17. Evol Appl. 2011;4(2):292-314.

2. Bottinger E, Carrell DS, Chisholm RL et al. The phenotypic legacy of 14. Choi JS, Yoo HW, Lee KJ, Ko JM, Moon JS, Ko JS. Novel mutations in

admixture between modern humans and Neandertals. Science. the CPT1A gene identified in the patient presenting jaundice as the

2016;351(6274):737-41. first manifestation of carnitine palmitoyltransferase 1A deficiency.

3. Quach H, Quintana-Murci L. Living in an adaptive world: genomic Pediatr Gastroenterol Hepatol Nutr. 2016;19(1):76-81.

dissection of the genus Homo and its immune response. J Exp Med. 15. Wakil SJ, Abu-Elheiga LA. Fatty acid metabolism: target for metabolic

2017;214(4):877-94. syndrome. J Lipid Res. 2009;50(Suppl.):S138-S143.

4. Harris K, Nielsen R. The genetic cost of Neanderthal introgression. 16. Faye A, Esnous C, Price NT, Onfray MA, Girard J, Prip-Buus C. Rat liver

Genetics. 2016;203(2):881-91. carnitine palmitoyltransferase 1 forms an oligomeric complex within

5. Sams AJ, Dumaine A, Nedelec Y, Yotova V, Alfieri C, Tanner JE et al. the outer mitochondrial membrane. J Biol Chem.

Adaptively introgressed Neandertal haplotype at the OAS locus 2007;282(37):26908-1.

functionally impacts innate immune responses in humans. Genome 17. Berg JM, Tymoczko JL, Stryer L. Biochemistry (5th ed.). New York: W

Biol. 2016;17(1):246. H Freeman; 2002. Section 30.3: Food Intake and Starvation Induce

6. Simonti CN, Vernot B, Bastarache L, Bottinger E, Carrell DS, Chisholm Metabolic Changes. Available from:

RL et al. The phenotypic legacy of admixture between modern https://www.ncbi.nlm.nih.gov/books/NBK22414/.

humans and Neandertals. Science. 2016;351(6274):737-41. 18. Csatho BM, Schenk AF, van der Veen CJ, Babonis G, Duncan K,

7. Stringer C. Evolution: what makes a modern human. Nature. Rezvanbehbahani S et al. Laser altimetry reveals complex pattern of

2012;485(7396):33-5. Greenland ice sheet dynamics. Proc Natl Acad Sci USA.

8. Pedersen CET, Lohmueller KE, Grarup N, Bjerregaard P, Hansen T, 2014;111(52):18478-83.

Siegismund H et al. The effect of an extreme and prolonged 19. Chien D, Dean D, Saha AK, Flatt JP, Ruderman NB. Malonyl-CoA

population bottleneck on patterns of deleterious variation: insights content and fatty acid oxidation in rat muscle and liver in vivo. Am J

from the Greenlandic Inuit. Genetics. 2017;205(2):787-801. Physiol Endocrinol Metab. 2000;279(2):E259-65.

9. Quach H, Rotival M, Pothlichet J, Loh Y-HE, Dannemann M, Zidane N 20. Manninen AH. Metabolic effects of the very-low-carbohydrate diets:

et al. Genetic adaptation and Neandertal admixture shaped the misunderstood “villains” of human metabolism. J Int Soc Sports Nutr.

immune system of human populations. Cell. 2016;167(3):643-56. 2004;1(2):7-11.

10. Pievani T. The final wave. Homo sapiens biogeography and the 21. King M. Lipolysis and the oxidation of fatty acids. The Medical

evolution of language. Rivista Italiana di Filosofia del Linguaggio. Biochemistry Page. [Internet]. [updated 2017, cited 2017 August].

2012b. Numero Speciale SFL:203-16. Available from:

11. Sankararaman S, Mallick S, Patterson N, Reich D. The combined https://themedicalbiochemistrypage.org/fatty-acid-oxidation.php –

landscape of Denisovan and Neanderthal ancestry in present-day clinical.

humans. Curr Biol. 2016;26(9):1241-7. 22. Grabacka M, Pierzchalska M, Dean M, Reiss K. Regulation of ketone

12. O’Reilly D. The evolutionary basis of human disease. Royal College of body metabolism and the role of PPARalpha. Int J Mol Sci.

Surgeons of Ireland Student Medical Journal. 2014;7(1):52-5. 2016;17(12).

Volume 11: Number 1. 2018 | Page 65 RCSIsmjstaff review

23. Clemente FJ, Cardona A, Inchley CE, Peter M, Jacobs G, Pagani L et al. 38. Barreiro LB, Ben-Ali M, Quach H, Laval G, Patin E, Pickrell JK et al. A selective sweep on a deleterious mutation in CPT1A in Arctic Evolutionary dynamics of human Toll-like receptors and their different populations. Am J Hum Genet. 2014;95(5):584-9. contributions to host defense. PLoS Genet. 2009;5(7):e1000562. 24. Collins SA, Sinclair G, McIntosh S, Bamforth F, Thompson R, Sobol I et 39. Medvedev AE. Toll-like receptor polymorphisms, inflammatory and al. Carnitine palmitoyltransferase 1A (CPT1A) P479L prevalence in live infectious diseases, allergies, and cancer. J Interferon Cytokine Res. newborns in Yukon, Northwest Territories, and Nunavut. Mol Genet 2013;33(9):467-84. Metab. 2010;101(2-3):200-4. 40. Campbell MC, Tishkoff SA. African genetic diversity: implications for 25. Koeller D. Diet and the CPT1A Arctic variant: impact on the health of human demographic history, modern human origins, and complex Alaska native children. [presentation] Oregon Health and Science disease mapping. Annu Rev Genomics Hum Genet. 2008;9:403-33. University. Available From: 41. Prugnolle F, Manica A, Charpentier M, Guégan JF, Guernier V, Balloux https://www.nbstrn.org/sites/default/files/nbstrn_6.1.17_koeller.pdf. F. Pathogen-driven selection and worldwide HLA class I diversity. Curr 26. Clarke SD. I. Molecular mechanism for polyunsaturated fatty acid Biol.15(11):1022-7. regulation of gene transcription. Am J Physiol Gastrointest Liver 42. Brightbill HD, Modlin RL. Toll-like receptors: molecular mechanisms Physiol. 2001;281(4):G865-G9. of the mammalian immune response. Immunology. 27. Akande VO, Hendriks AM, Ruiter RA, Kremers SP. Determinants of 2000;101(1):1-10. dietary behavior and physical activity among Canadian Inuit: a 43. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate systematic review. Int J Behav Nutr Phys Act. 2015;12(1):84. immunity. Cell. 2006;124(4):783-801. 28. Bennett MJ, Santani AB. Carnitine palmitoyltransferase 1A deficiency. 44. Ongen H, Dermitzakis ET. Alternative splicing QTLs in European and In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean African populations. Am J Hum Genet. 2015;97(4):567-75. LJH et al. (eds.). GeneReviews(R). Seattle (WA), 1993. 45. Lee J, Sohn JW, Zhang Y, Leong KW, Pisetsky D, Sullenger BA. Nucleic 29. Bennet M. Carnitine palmitoyltransferase IA deficiency. San Diego: acid-binding polymers as anti-inflammatory agents. Proc Natl Acad MedLink Corporation; c2001-2017. [Internet]. [Updated 2017 May; Sci USA. 2011;108(34):14055-60. Accessed 2017 August]. Available from: 46. Nédélec Y, Sanz J, Baharian G, Szpiech ZA, Pacis A, Dumaine A et al. http://www.medlink.com/scripts/mpdf/print_friendly.php?title=carniti Genetic ancestry and natural selection drive population differences in ne_palmitoyltransferase_1a_deficiency&action=print&channel=public_ immune responses to pathogens. Cell. 2016;167(3):657-69. content&entryid=12719. 47. Zervou MI, Dorschner JM, Ghodke-Puranik Y, Boumpas DT, Niewold 30. National Organization For Rare Diseases. Carnitine palmitoyltransferase TB, Goulielmos GN. Association of IRF5 polymorphisms with 1A deficiency. Danbury, CT: NORD, Inc; c2017. [Internet]. [updated increased risk for systemic lupus erythematosus in population of 2017; cited 2017 August]. Available From: Crete, a southern-eastern European Greek island. Gene. https://rarediseases.org/rare-diseases/carnitine-palmitoyltransferase-1a 2017;610:9-14. -deficiency/. 48. Stone RC, Feng D, Deng J, Singh S, Yang L, Fitzgerald-Bocarsly P et 31. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr. Cellular fatty al. Interferon regulatory factor 5 activation in monocytes of systemic acid metabolism and cancer. Cell Metab. 2013;18(2):153-61. lupus erythematosus patients is triggered by circulating autoantigens 32. Ricciardi MR, Mirabilii S, Allegretti M, Licchetta R, Calarco A, Torrisi independent of type I interferons. Arthritis Rheum. MR et al. Targeting the leukemia cell metabolism by the CPT1a 2012;64(3):788-98. inhibition: functional preclinical effects in leukemias. Blood. 49. Wu YW, Tang W, Zuo JP. Toll-like receptors: potential targets for lupus 2015;126(16):1925-9. treatment. Acta Pharmacol Sin. 2015;36(12):1395-407. 33. Warburg O. On the origin of cancer cells. Science. 50. Duffy L, O’Reilly SC. Toll-like receptors in the pathogenesis of 1956;123(3191):309-14. autoimmune diseases: recent and emerging translational 34. Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin developments. Immunotargets Ther. 2016;5:69-80. B et al. Pharmacologic inhibition of fatty acid oxidation sensitizes 51. Saito K, Kukita K, Kutomi G, Okuya K, Asanuma H, Tabeya T et al. human leukemia cells to apoptosis induction. J Clin Invest. Heat shock protein 90 associates with Toll-like receptors 7/9 and 2010;120(1):142-56. mediates self-nucleic acid recognition in SLE. Eur J Immunol. 35. Carracedo A, Cantley LC, Pandolfi PP. Cancer metabolism: fatty acid 2015;45(7):2028-41. oxidation in the limelight. Nat Rev Cancer. 2013;13(4):227-32. 52. Shrivastav M, Niewold T. Nucleic acid sensors and type I interferon 36. Friborg JT, Melbye M. Cancer patterns in Inuit populations. Lancet production in systemic lupus erythematosus. Front Immunol. Oncol. 2008;9(9):892-900. 2013;4:319. 37. Allen BG, Bhatia SK, Anderson CM, Eichenberger-Gilmore JM, 53. Lim SS, Drenkard C. Epidemiology of lupus: an update. Curr Opin Sibenaller ZA, Mapuskar KA et al. Ketogenic diets as an adjuvant Rheumatol. 2015;27(5):427-32. cancer therapy: history and potential mechanism. Redox Biol. 54. Ramakrishna BS. Celiac disease: can we avert the impending 2014;2:963-70. epidemic in India? Indian J Med Res. 2011;133:5-8.

Page 66 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Are emerging treatments in Parkinson’s disease curative or just buying time?

Abstract Parkinson’s disease is a neurodegenerative disorder that varies in disease progression and severity, and currently affects roughly one in 500 people. The main cause of Parkinson’s disease is still unclear. However, both Lewy bodies (LB) and Lewy neurites (LN) have been discovered in brain areas, and contain the protein alpha synuclein (aSyn), an accumulation of which leads to protein misfolding. Aggregates of misfolded aSyn generate a proteinopathy that results in progressive neuronal loss. Levodopa, dopamine receptor agonists, monoamine oxidase inhibitors, and catechol-O-methyltransferase inhibitors remain the mainstay of symptomatic treatment; however, a curative option is yet to be discovered, necessitating a renaissance in Parkinson’s disease research. This niche, in the literature and market alike, led to the development of a Parkinson’s disease vaccine that aims to inhibit aSyn accumulation, ultimately inhibiting neurodegeneration. Hence, this agent is suspected to be a disease-modifying treatment. The vaccine successfully passed preclinical studies and animal testing, where vaccinated animals showed superior cognitive functions compared to unvaccinated controls when assessed in the Morris water maze test. The vaccine then passed Phase I clinical trials assessing safety and tolerability (at doses of 15-75µg), and was found to elicit an immune response in 86% of patients. Further phase II trials were undertaken for multiple system atrophy (MSA), which exhibits a similar phenomenon of aSyn accumulation in oligodendrocytes. These recent findings

Scientific Author’sJessica nameMillar1 continue to educate scientists with respect to Parkinson’s disease and the process of safe,

1ScientificRCSI pharmacy Author’s Collegestudent effective vaccination, and suggest that active vaccination has potential therapeutic advantages for Parkinson’s disease.

Royal College of Surgeons in Ireland Student Medical Journal 2018; 1: 67-72.

Volume 11: Number 1. 2018 | Page 67 RCSIsmjstaff review

Introduction Current treatments for symptomatic Parkinson’s disease Parkinson’s disease is a neurodegenerative disorder, which varies in Levodopa is a dopamine precursor, given orally, with the ability to disease progression and severity. It is currently thought that cross the blood-brain barrier (BBB) after a rapid decarboxylation. approximately one in 500 people are affected by Parkinson’s disease, Levodopa is then converted to dopamine, directly replacing the with many developing symptoms over the age of 50.1 Nearly 8,000 deficient neurotransmitter.7 George Cotzias first introduced its people are currently affected in Ireland, and statistics show that men clinical utility in 1967; this was followed by FDA approval in 1970.5,8 are more susceptible than women.2,3 The timing for initiation of levodopa therapy strongly depends on The main cause of Parkinson’s disease is still unclear; however, both the stage of Parkinson’s disease progression, the patient’s age, and Lewy bodies (LB) and Lewy neurites (LN) have been discovered in disease characteristics.9 For example, a younger patient who wishes the cortical and subcortical areas of the brain. These Lewy species to remain mobile and employable may begin treatment at an earlier are composed of a protein known as alpha synuclein (aSyn), linking stage of disease progression.10 them as hallmarks of the disease. An accumulation of aSyn leads to Levodopa remains the gold standard of Parkinson’s disease protein misfolding and aggregation, creating a proteinopathy that treatment, and is the most efficacious and potent therapy results in progressive neuronal loss.2 Other causes of Parkinson’s available.4,6 The dose of levodopa varies widely from patient to disease are thought to include exposure to industrial chemicals, patient, with 300-600mg daily showing the best response and pollutants, pesticides, heavy metals, and well water containing these tolerability.9 Dose increases should be carried out gradually due to toxins.1 Despite this, many Parkinson’s disease cases are idiopathic, the concomitant increase in dopaminergic side effects (Table 1).7 with affected patients having minimal exposure to such causative In addition to the various side effects outlined in Table 1, agents. And, although many may carry the susceptible genes [PARK2 fluctuations in response to levodopa are common. This is thought to (Parkin), LRRK2 (leucine-rich repeat kinase 2), and GBA be due to the drug’s short half-life (less than 90 minutes) and erratic (glucocerebrosidase)], genetic development of Parkinson’s disease gastric emptying, which reduces the absorption time in the only occurs in approximately 10-15% of the population.3 It is stomach, giving rise to sub-therapeutic doses.7 Intermittent therefore crucial not to confuse Parkinson’s disease, a stimulation of dopamine receptors also occurs as a result of the neurodegenerative illness, with a process of ageing. short half-life, resulting in ‘on’ and ‘off’ periods, or fluctuations The aforementioned pathophysiology gives rise to both motor and between treatment effectiveness and inactivity.7 These side effects non-motor symptoms, such as bradykinesia, rigidity, resting tremor, are often overcome through drug monitoring with steady state postural instability, impaired olfaction, gastrointestinal dysfunction, plasma levels, repeated drug administration or, more recently, and neuropsychiatric disturbances.4,5 Significant loss of dopamine is through the addition of peripheral dopamine decarboxylase also a hallmark of Parkinson’s disease, with an 80% depletion inhibitors (PDDIs) such as carbidopa or benserazide.5,9 These PDDIs becoming symptomatic.1 In response to this dopamine deficiency, not only help to reduce side effects, but also increase the half-life of many current treatments focus on replenishing dopamine stores, levodopa by preventing its degradation prior to reaching the brain. using agents such as levodopa, dopamine receptor agonists, With the addition of a PDDI, levodopa’s bioavailability in the brain is monoamine oxidase (MAO) inhibitors, and thus increased.9 catechol-O-methyltransferase (COMT) inhibitors. With this spectrum Combination therapies also include COMT inhibitors, which inhibit of therapies, however, patients receive symptomatic relief alone; an enzyme involved in the peripheral metabolism of levodopa. they are neither curative nor disease modifying. This led to a call for Entacapone is a COMT inhibitor used to prevent the breakdown of a renaissance in Parkinson’s disease research and, ultimately, to the levodopa once through the BBB.11-13 However, with its short half-life, development of a Parkinson’s disease vaccine. This agent aims to entacapone requires multiple daily doses, to a maximum of eight inhibit aSyn accumulation and prevent neurodegeneration. Through per day.14 these mechanisms, the vaccine is suspected to be a The greatest bioavailability of oral levodopa has been achieved disease-modifying treatment, and could prevent development and through co-administration with both a COMT inhibitor and a PDDI; progression of Parkinson’s disease.6 this combination significantly improves efficacy, with increased daily This review aims to examine the current treatments for Parkinson’s ‘on’ time being reported.9,15-17 However, the addition of COMT disease, as well as the therapeutic prospects of the emerging inhibitors or PDDIs does not prevent the development of dyskinesias vaccine. associated with Parkinson’s disease treatment.18

Page 68 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Table 1. Side effects associated with pharmacologic The main drawbacks to levodopa therapy are the development of 6,31-34 treatments for Parkinson’s disease. dyskinesias, and reduced efficacy in 40% of the population after five to six years of use.9,19 All in all, it is clear that levodopa should not be considered a Drug name Side effects long-term therapeutic option for many patients, nor is it a disease-modifying agent. Hence, the search for a disease-modifying Levodopa Nausea, orthostatic hypotension, therapy, which provides safe and consistent drug delivery to the dyskinesia, hallucinations. brain, continues.

Apomorphine Nausea, vomiting, hypotension, syncope, sedation, Dopamine agonists hallucinations, impulse control disorders (ICDs). The dopamine agonists bromocriptine and pergolide have been

Entacapone Dark-coloured urine and enhanced levodopa side effects. widely employed for symptomatic relief in Parkinson’s disease. They are often prescribed so as to delay the initiation of levodopa Bromocriptine Constipation, nausea, vomiting, asthenia, headache, treatment by several months to years.6 These agents, when used as dizziness, rhinitis, pericardial or pleural effusion, monotherapy, show a reduced risk of developing motor myocardial infarction, heart valve disorder, complications compared to levodopa monotherapy, which has retroperitoneal and pulmonary fibrosis, gastrointestinal further increased their use.20,21 However, despite the many ulcers, psychosis, hallucinations. Parkinson’s disease treatments available, monotherapy is not always appropriate, and has not been shown to be of superior efficacy Cabergoline Constipation, nausea, headache, dizziness, fatigue, congestive heart failure, heart valve disorder, pericardial compared to combination therapy. Clinical trials have shown that disease, pleural effusion or fibrosis, pulmonary or dopamine agonists will require the addition of levodopa within two retroperitoneal fibrosis, peripheral oedema. years of initiation, to maintain the same level of control.22 Trials also demonstrated, however, that co-prescribing levodopa with a Pergolide Constipation, diarrhoea, nausea, orthostatic dopamine agonist did not reduce the risk of developing motor hypotension, sedation, tachycardia, dizziness, complications, despite the aforementioned findings related to dyspnoea, confusion, hallucinations, psychosis, visual dopamine agonist monotherapy.7,9,23 disorders, cardiac valvulopathy, pleural fibrosis, Dopamine agonists exert their pharmacological effect through cardiac failure, ICDs. direct activation of dopamine receptors, bypassing the synaptic

Lisuride Orthostatic hypotension, nausea, headache, fatigue, synthesis of dopamine. Evidence shows that D2 dopamine dyskinesia, vertigo, dizziness, peripheral oedema, receptors are important targets for the drugs’ anti-Parkinsonian sweating, erythromelalgia, somnolence, sleep effects; however, D1 dopamine receptors must also be stimulated disorders, ICDs, cardiac, pulmonary or pleural fibrosis, for optimal physiological and behavioural effects within patients pleural effusion, retroperitoneal fibrosis. with Parkinson’s disease.24 Non-traditional dopamine agonists such as pramipexole and Pramipexole Nausea, orthostatic hypotension, oedema, increased ropinirole are thought to have a lower risk of peptic ulcers, sleepiness, hallucinations, ICDs. vasoconstriction, erythromelalgia, and pulmonary and respiratory

Ropinirole Same as pramipexole. fibrosis, compared to traditional dopamine agonists (pergolide and bromocriptine).7,9,25 Pramipexole is a safe and effective drug when

Rotigotone Same as pramipexole. used as monotherapy, and has a possible neuroprotective effect; it is thought to enhance neurotrophic activity in mesencephalic Selegiline Stimulatory effects, dizziness, headache, confusion, dopaminergic regions.26 enhanced levodopa-like side effects. Apomorphine is a water-soluble dopamine agonist, and can be delivered intravenously, subcutaneously, sublingually, or Rasagiline Headache, dyspepsia, depression, constipation, intranasally.9,27 Subcutaneous and continuous infusions have proven arthralgia, enhanced levodopa-like side effects. effective in the advanced stages of Parkinson’s disease, without

Volume 11: Number 1. 2018 | Page 69 RCSIsmjstaff review

increasing dyskinesias.28 With regard to adverse effects, when aSyn associated with neuronal membranes, and promoted the compared to levodopa, dopamine agonists showed no significant degradation of aSyn aggregates.42 These ‘vaccine-derived’ difference in risk of hypotension, nausea, or dizziness.29 However, antibodies thus appeared to serve a significant therapeutic role.42 ropinirole demonstrated a higher risk of hypotension when The first aSyn vaccine developed for human use is AFFITOPE PD01, compared to pramipexole, and a lower risk of hallucinations.30 and is used to target synucleopathies such as those found in While no appreciable difference in side effects has been noted Parkinson’s disease.2 It targets aSyn aggregates by inducing between these two treatment classes, further research should still production of antibodies that recognise aSyn, but spare the family be undertaken in an effort to overcome existing side effects and member protein bSyn, which is known to be neuroprotective.2 develop a safer symptomatic treatment or, ideally, to develop a The Parkinson’s disease vaccine consists of a peptide carrier disease-modifying option. conjugated with aluminium hydroxide, an immunological adjuvant. As the peptides used are seven amino acids in length, this prevents Novel therapies for Parkinson’s disease unwanted aSyn-specific T cell responses, as the peptides are too Previous studies investigating immunotherapy to treat certain short to induce an immune response; this effectively avoids T cell neurological diseases have sparked an interest in its use for autoimmunity.2 Parkinson’s disease. Studies have shown that cerebral proteins can The vaccine successfully passed preclinical studies, and advanced to be safely targeted in humans; however, immunological responses animal studies. Vaccinated animals showed superior cognitive such as T cell activation should be avoided to prevent development functions compared to unvaccinated controls when assessed in the of complications such as T cell autoimmunity.6 Another challenge Morris water maze test.2 This was followed by Phase I clinical trials presented by immunotherapy is crossing the BBB while maintaining assessing safety and tolerability in patients with early-stage the agent’s bioactivity and bioavailability.9 Parkinson’s disease. Doses of 15-75µg were tolerated in patients To date, immunotherapy in Parkinson’s disease has focused on with early Parkinson’s disease, and elicited dose-dependent aSyn, a major component of Lewy bodies that plays a causative role production of antibodies.43 No further adverse events were in Parkinson’s disease. The first experimental indication of aSyn’s observed during or after the trial. A booster vaccine was assessed in causative role was observed in autosomal dominant forms of another trial, completed in June 2017.44 Parkinson’s disease, where point mutations in the aSyn gene (SNCA) Following this Phase I trial, the immune response was observed in gave rise to misfolded proteins.24 Higher amounts of mutant SNCA 86% of patients.42 Booster vaccinations help to maintain prolonged also led to increased aSyn production.24 Through these protective immunity when the vaccine used is not live attenuated, observations, it has been postulated that aSyn is responsible for as is the case for AFFITOPE PD01.45,46 However, further trials Parkinson’s disease at a level as low as a two-fold elevation in investigating the potential depletion of these newly generated aSyn.2,35-37 Alongside this phenomenon, a gradual increase in aSyn antibodies are needed; trial AFF008AA is one such trial, and is is seen throughout the normal ageing process in neurons awaiting publication.47 susceptible to Parkinson’s disease.38 The exact mechanism of The vaccine has only been tested on patients with early-stage toxicity is yet to be determined, but it is thought that aggregations Parkinson’s disease; its efficacy in other patient groups is yet to be of aSyn lead to progressive neurotoxicity and determined.43,48 Additional Phase II trials have also been undertaken neurodegeneration.2,39,40 Thus, therapeutic mechanisms to reduce for multiple system atrophy (MSA), which exhibits a similar aSyn levels present a novel treatment strategy that targets phenomenon of aSyn accumulation in oligodendrocytes as Parkinson’s disease causation, rather than providing purely cytoplasmic inclusions.49,50 symptomatic relief. Despite these ongoing advances, variable responses to the E. Masliah et al. produced evidence to support this concept by antibodies have been noted across patients, perhaps due to over-expressing aSyn in mice, with administration of either a age-related immune deficiencies or a reduced ability to generate full-length aSyn-based vaccine, or aSyn-specific monoclonal adequate numbers of antibodies.6 Notwithstanding these potential antibodies.41,42 Those given the full-length aSyn vaccine developed red flags, active vaccination does have potential therapeutic antibodies with a high relative affinity for aSyn, and showed advantages, and is continuing to educate scientists with respect to reduced accumulation of aggregated aSyn in both neuronal cells Parkinson’s disease pathophysiology and the use of novel, safe, and synapses.2,42 The antibodies were shown to recognise abnormal effective vaccinations.51

Page 70 | Volume 11: Number 1. 2018 RCSIsmjstaff review

Conclusion Many symptomatic treatment options are available for patients with treatment. This is not ideal for a population afflicted with Parkinson’s disease, including levodopa, PDDIs, COMT inhibitors, neurodegenerative disease, as compliance can be challenging. In and dopamine agonists. response to these challenges, researchers sought to develop a Research in each of these domains continues to strive for improved Parkinson’s disease vaccine targeting aSyn. This potentially symptom management. However, the persistent issues of tolerance disease-modifying regimen is currently being trialed, and has shown and challenging, unpleasant side effects, make a strong argument promising results in both animal testing and initial human trials. for the need for novel Parkinson’s disease treatments. Many patients With encouraging early results, it is hoped that this work will require polypharmacy, with a long regimen of medications to not continue to progress toward what could be the first curative and only treat the disease, but also to manage the side effects of potentially preventive treatment for Parkinson’s disease.

References 1. Parkinson’s Association of Ireland. What is Parkinson’s? 2011. [Internet]. decarboxylase on the half-life and other pharmacokinetic parameters of

[updated 2011; accessed 2017 June 21]. Available from: oral L-3,4-dihydroxyphenylalanine. Drug Metab Dispos.

http://parkinsons.ie/aboutparkinsons_whatisparkinsons. 1983;11(3):195-200.

2. Schneeberger A, Mandler M, Mattner F et al. Vaccination for Parkinson’s 13. Kaakkola S, Teravainen H, Ahtila S et al. Effect of entacapone, a COMT

disease. Parkinsonism Relat Disord. 2012;18(Suppl.1):S11-S13. inhibitor, on clinical disability and levodopa metabolism in parkinsonian

3. Parkinson’s Foundation. Genetics and Parkinson’s disease. 2017. [Internet]. patients. Neurology. 1994;44(1):77-80.

[Accessed 2017 October 5]. Available from: 14. Gordin A, Kaakkola S, Teravainen H. Clinical advantages of COMT

http://www.parkinson.org/understanding-parkinsons/what-is-parkinsons/G inhibition with entacapone – a review. J Neural Transm (Vienna).

enetics-and-Parkinsons-Disease. 2004;111(10-11):1343-63.

4. Poirier AA, Aube B, Cote M et al. Gastrointestinal dysfunctions in 15. Dong J, Cui Y, Li S et al. Current pharmaceutical treatments and alternative

Parkinson’s disease: symptoms and treatments. Parkinsons Dis. therapies of Parkinson’s disease. Curr Neuropharmacol. 2016;14(4):339-55.

2016;2016:6762528. 16. Entacapone improves motor fluctuations in levodopa-treated Parkinson’s

5. DeMaagd G, Philip A. Parkinson’s disease and its management: Part 5: disease patients. Parkinson Study Group. Ann Neurol. 1997;42(5):747-55.

treatment of nonmotor complications. P T 2015;40(12):838-46. 17. Rinne UK, Larsen JP, Siden A et al. Entacapone enhances the response to

6. George S, Brundin P. Immunotherapy in Parkinson’s disease: levodopa in parkinsonian patients with motor fluctuations. Nomecomt

micromanaging alpha-synuclein aggregation. J Parkinsons Dis. Study Group. Neurology. 1998;51(5):1309-14.

2015;5(3):413-24. 18. Brooks DJ, Sagar H, UK-Irish Entacapone Study Group. Entacapone is

7. Salat D, Tolosa E. Levodopa in the treatment of Parkinson’s disease: current beneficial in both fluctuating and non-fluctuating patients with Parkinson’s

status and new developments. J Parkinsons Dis. 2013;3(3):255-69. disease: a randomised, placebo controlled, double blind, six month study.

8. Fahn S, Parkinson Study Group. Does levodopa slow or hasten the rate of J Neurol Neurosurg Psychiatry. 2003;74(8):1071-9.

progression of Parkinson’s disease? J Neurol. 19. Stocchi F, Rascol O, Kieburtz K et al. Initiating levodopa/carbidopa therapy

2005;252(Suppl.4):IV37-IV42. with and without entacapone in early Parkinson disease: the STRIDE-PD

9. Jankovic J, Aguilar LG. Current approaches to the treatment of Parkinson’s study. Ann Neurol. 2010;68(1):18-27.

disease. Neuropsychiatr Dis Treat. 2008;4(4):743-57. 20. Ahlskog JE, Muenter MD. Frequency of levodopa-related dyskinesias and

10. Gershanik OS. Clinical problems in late-stage Parkinson’s disease. J Neurol. motor fluctuations as estimated from the cumulative literature. Mov

2010;257(Suppl.2):S288-91. Disord. 2001;16(3):448-58.

11. Rinne UK, Molsa P. Levodopa with benserazide or carbidopa in Parkinson 21. Chondrogiorgi M, Tatsioni A, Reichmann H et al. Dopamine agonist

disease. Neurology. 1979;29(12):1584-9. monotherapy in Parkinson’s disease and potential risk factors for

12. Huebert ND, Palfreyman MG, Haegele KD. A comparison of the effects of dyskinesia: a meta-analysis of levodopa-controlled trials. Eur J Neurol.

reversible and irreversible inhibitors of aromatic L-amino acid 2014;21(3):433-40.

Volume 11: Number 1. 2018 | Page 71 RCSIsmjstaff review

22. Poewe W, Antonini A, Zijlmans JC et al. Levodopa in the treatment of 2009;65(5):610-4.

Parkinson’s disease: an old drug still going strong. Clin Interv Aging. 38. Simon-Sanchez J, Scholz S, Matarin Mdel M et al. Genomewide SNP

2010;5:229-38. assay reveals mutations underlying Parkinson disease. Hum Mutat.

23. Hauser RA, Rascol O, Korczyn AD et al. Ten-year follow-up of 2008;29(2):315-22.

Parkinson’s disease patients randomized to initial therapy with 39. Singleton AB, Farrer M, Johnson J et al. alpha-synuclein locus

ropinirole or levodopa. Mov Disord. 2007;22(16):2409-17. triplication causes Parkinson’s disease. Science. 2003;302(5646):841.

24. Lees AJ, Katzenschlager R, Head J et al. Ten-year follow-up of three 40. Danzer KM, Haasen D, Karow AR et al. Different species of

different initial treatments in de-novo PD: a randomized trial. alpha-synuclein oligomers induce calcium influx and seeding. J

Neurology. 2001;57(9):1687-94. Neurosci. 2007;27(34):9220-32.

25. Tintner R, Manian P, Gauthier P et al. Pleuropulmonary fibrosis after 41. Savitt JM, Dawson VL, Dawson TM. Diagnosis and treatment of

long-term treatment with the dopamine agonist pergolide for Parkinson disease: molecules to medicine. J Clin Invest.

Parkinson disease. Arch Neurol. 2005;62(8):1290-5. 2006;116(7):1744-54.

26. Zanettini R, Antonini A, Gatto G et al. Valvular heart disease and the 42. Masliah E, Rockenstein E, Adame A et al. Effects of alpha-synuclein

use of dopamine agonists for Parkinson’s disease. N Engl J Med. immunization in a mouse model of Parkinson’s disease. Neuron.

2007;356(1):39-46. 2005;46(6):857-68.

27. LeWitt PA, Lyons KE, Pahwa R et al. Advanced Parkinson disease treated 43. Affiris. Boost vaccination data encourage continued development of

with rotigotine transdermal system: PREFER Study. Neurology. AFFiRiS therapeutic Parkinson’s disease vaccine against alpha-synuclein.

2007;68(16):1262-7. 2017. [Internet]. Available from:

28. Ondo W, Hunter C, Almaguer M et al. Efficacy and tolerability of a http://www.affiris.com/news/boost-vaccination-data-encourage-continu

novel sublingual apomorphine preparation in patients with fluctuating ed-development-of-affiris-therapeutic-parkinsons-disease-vaccine-agains

Parkinson’s disease. Clin Neuropharmacol. 1999;22(1):1-4. t-alpha-synuclein/.

29. Antonini A, Tolosa E, Mizuno Y et al. A reassessment of risks and 44. Masliah E, Rockenstein E, Mante M et al. Passive immunization reduces

benefits of dopamine agonists in Parkinson’s disease. Lancet Neurol. behavioral and neuropathological deficits in an alpha-synuclein

2009;8(10):929-37. transgenic model of Lewy body disease. PLoS One. 2011;6(4):e19338.

30. Hickey P, Stacy M. Available and emerging treatments for Parkinson’s 45. Pulendran B, Ahmed R. Immunological mechanisms of vaccination. Nat

disease: a review. Drug Des Devel Ther. 2011;5:241-54. Immunol. 2011;12(6):509-17.

31. Boyle A, Ondo W. Role of apomorphine in the treatment of Parkinson’s 46. Clem AS. Fundamentals of vaccine immunology. J Glob Infect Dis.

disease. CNS Drugs. 2015;29(2):83-9. 2011;3(1):73-8.

32. Poewe W, Wenning GK. Apomorphine: an underutilized therapy for 47. The Science of Parkinson’s Disease. Vaccine for Parkinson’s – AFFiRiS

Parkinson’s disease. Mov Disord. 2000;15(5):789-94. update. [Internet]. [Accessed 2017 October 23] Available from:

33. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: https://scienceofparkinsons.com/2016/09/11/vaccine-for-parkinsons-affi

a review. JAMA. 2014;311(16):1670-83. ris-update/2016.

34. Borovac JA. Side effects of a dopamine agonist therapy for Parkinson’s 48. Affiris. Vaccine candidate based on proprietary technology by AFFiRiS

disease: a mini-review of clinical pharmacology. Yale J Biol Med. AG, 2014.

2016;89(1):37-47. 49. Affiris AG. Follow-up study to assess a second boost immunization with

35. Lansbury PT Jr, Brice A. Genetics of Parkinson’s disease and biochemical AFFITOPE® PD01A with regard to safety and clinical activity

studies of implicated gene products. Curr Opin Genet Dev. (AFF008AA). [Internet]. [updated 2017 June 2; accessed 2017 July 13].

2002;12(3):299-306. Available from: https://clinicaltrials.gov/ct2/show/NCT02618941.

36. Ross OA, Braithwaite AT, Skipper LM et al. Genomic investigation of 50. Marques O, Outeiro TF. Alpha-synuclein: from secretion to dysfunction

alpha-synuclein multiplication and parkinsonism. Ann Neurol. and death. Cell Death Dis. 2012;3:e350.

2008;63(6):743-50. 51. Valera E, Masliah E. Immunotherapy for neurodegenerative diseases:

37. Scholz SW, Houlden H, Schulte C et al. SNCA variants are associated focus on alpha-synucleinopathies. Pharmacol Ther.

with increased risk for multiple system atrophy. Ann Neurol. 2013;138(3):311-22.

Page 72 | Volume 11: Number 1. 2018 RCSIsmjperspective

HPV VACCINATION: facts versus fears

LAURA STAUNTON discusses vaccination against human papilloma virus, and the prevalence of misinformation regarding side effects of the vaccine.

Introduction Numerous cancers have been attributed to the human papilloma virus recommended for young girls in the first year of second-level school, (HPV), including cervical, vaginal, vulvar, penile, anorectal, and to provide protection against HPV prior to expected sexual exposure, oropharyngeal.1,2 The incidence of HPV-related cancers in Ireland is thereby reducing the risk of HPV infection.3 420 cases annually, resulting in 130 deaths.1 HPV is most frequently There are a number of different HPV vaccines available; the two main associated with cervical cancer; globally, over half a million women are types are Cervarix and Gardasil. Cervarix is a bivalent vaccine diagnosed with this cancer each year.1,2 Serotypes HPV16 and HPV18 protecting against cancer-associated serotypes HPV16 and HPV18.4 are associated with the highest cancer risk.1 Gardasil is a quadrivalent vaccine protecting against HPV16 and The Irish prevention strategies include a national screening HPV18, as well as the genital warts-associated strains HPV6 and programme to detect cervical pre-cancer and cancerous lesions HPV11.3 The Gardasil vaccine was first introduced to Ireland’s national (namely cervical intraepithelial neoplasia; CIN) in women aged 25-60, screening programme in 2011, but this has not been without as well as a national HPV vaccination programme.3 The HPV vaccine is contention.3

Volume 11: Number 1. 2018 | Page 73 RCSIsmjperspective

Irish media, adding greater influence to the anti-vaccination movement.11 As yet, no evidence has been offered to support the hypothesis of molecular mimicry, use of an aluminium adjuvant, or exposure time between doses as mechanisms for generating autoimmunity and adverse reactions to the vaccine.8,9 Meta-analyses (large cohort and case-controlled research studies over prolonged time periods) agree; there is no evidence to link autoimmune or neurological conditions to the HPV vaccine.7,8,14-16 A study conducted in Sweden and Denmark initially observed an association between the HPV vaccine and Raynaud’s disease, Behcet’s syndrome and type 1 diabetes.8 However, further analysis of the purported associations dismissed the findings as weak and not related to HPV vaccine exposure.8 An increase in CFS/ME was recorded in Norway from 2009-2014; however, no link could be found with the HPV vaccine.16 Currently, no laboratory diagnosis exists for CFS/ME, and an Public opinion vs medical research increased awareness has been suggested as a likely reason for this As with any medical intervention, there are side effects associated rise in numbers.16 In the UK, in spite of a high rate of uptake of with the HPV vaccine.5,6 It is the association of chronic adverse the bivalent vaccine, there has been no increase in CFS/ME events, such as autoimmune and neurological conditions, incidence.4 including chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), with the HPV vaccination, that has led to speculation Unmasking the truth behind misinformation regarding the vaccine’s safety.4,7-10 Research has suggested various The concept of an unmasking phenomenon has been suggested mechanisms of autoimmunity in an effort to explain this, as an explanation for the proposed link between these adverse including: molecular mimicry (the cross-reactivity of foreign and effects and the HPV vaccine.8 The unmasking phenomenon self antigens); hyper-responsive immune reactions to the occurs when, during a medical visit, symptoms that the patient aluminium component used as an adjuvant in the vaccine; or, the suspects may be associated with the HPV vaccine are discussed short exposure time between vaccine doses.8,9 with the healthcare practitioner. Clinical history and examination subsequently leads to the discovery of an underlying, pre-existing Groups such as REGRET often use condition.8 This especially applies to conditions with vague, generalised symptoms, such as Raynaud’s disease or CFS/ME, unsubstantiated allegations and scare which can make accurate diagnosis challenging.8 Bias occurs tactics, offering only dubious research when the patient or her family considers these symptoms to be articles, opinion pieces, and media adverse effects of the HPV vaccine and, consequently, the newly diagnosed condition may be mistakenly attributed to the vaccine links as ‘evidence’ to support an itself.8 association between adverse events In the UK, there is no increased incidence of CFS/ME following and the HPV vaccine. HPV vaccination when compared to expected rates of the disorder.4 The mislabelling of CFS/ME as an adverse effect of the HPV vaccine could be explained by the unmasking phenomenon, The association between chronic side effects and HPV vaccination or may be due to a naturally increased prevalence of has led to increasing media publicity. Easily accessible, non autoimmune and neurological disorders in the vaccine target evidence-based social media, blogs, and websites for supporters population.4 One study reported that some patients presented to of ‘anti-vaccination’ add to the public’s growing speculation and their general practitioner with symptoms of fatigue and weakness concern regarding the vaccine’s safety.11,12 One such example is a prior to administration of the vaccine, and a subsequent website that exaggerates the rate of Gardasil’s adverse side diagnosis of CFS/ME was made in a specialist centre.16 Obtaining effects; it reports an incidence rate of 2.5%, when in fact the true a full and accurate medical history prior to vaccination is thus rate of adverse events is 0.03% (4 per 15,705 individuals).12,13 vitally important. Additionally, an anti-vaccination support group, REGRET (Reactions and Effects of Gardasil Resulting in Extreme Trauma) Risk vs benefit – weighing the evidence has been established by parents who believe their daughters have Parents or guardians of young girls may decide that the risk of suffered from chronic adverse effects of the Gardasil vaccine.11 adverse side effects outweighs the benefit of protection against This group has attained a significant amount of exposure in the HPV, and consequently choose to opt out of vaccination.

Page 74 | Volume 11: Number 1. 2018 RCSIsmjperspective

Increased media speculation, anti-vaccination groups, and groups to opt out of vaccination can lead to an increased risk of such as REGRET make it challenging for parents to make an preventable cancer and death due to HPV infection.15 This is not informed decision regarding vaccination.11,12 National screening the first time that unconfirmed allegations about a vaccine’s programmes for cervical cancer may also influence parents to safety have affected long-term public health outcomes and refuse vaccination for their children, as they assume any placed society at risk of increasing cases of a disease. When the irregularities will simply be detected by screening.3 measles, mumps, and rubella (MMR) vaccine was incorrectly When parents are faced with deciding whether or not to associated with autism in 1998 by Andrew Wakefield, this led to a vaccinate their child against HPV, evidence-based medicine must significant decrease in MMR vaccine uptake, and a dangerous rise be accessible and considered, to help inform their decision and in measles cases.17 Wakefield’s research paper has since been allay their fears. Existing evidence that suggests an association widely discredited, and numerous large case-controlled and between the HPV vaccine and the aforementioned adverse effects epidemiological studies have proven that there is in fact no link has largely come from case-based analyses without proper between the MMR vaccine and autism.17 controls.8,9 Large cohort and case-controlled studies, on the other hand, provide no evidence for such a link.7,8,14-16 Due to low vaccine uptake in Ireland, as Healthcare providers have a duty to ensure that patients and their families are accurately informed prior to medical decision making; revealed by recent data, both girls and this is especially important in the present climate, where boys are at risk of HPV infection and its impassioned non evidence-based public opinion about vaccine associated cancers in the future. risks can become widespread on the internet, and thereby influence others. Like any medical intervention, no vaccination or medication is The Health Products Regulatory Authority (HPRA), which governs entirely without risk. Adverse side effects have been medication safety in Ireland, has received 1,115 reports of demonstrated with other vaccines; for example, the 2009 suspected side effects from the HPV vaccine over the last 11 influenza vaccination has been linked with narcolepsy and years, of which approximately 650 were deemed serious.6 These Guillain-Barré syndrome.18,19 However, prolonged research studies included fainting, injection site reactions, and gastrointestinal have continued to show that there is no association between issues. The majority of these ‘serious’ cases were not chronic chronic side effects and the HPV vaccine.7,8,14-16 conditions, and required minimal medical intervention.6 As The best way to prevent HPV infection is through vaccination.2 previously mentioned, the HPRA also notes that suspected side Screening can identify precancerous changes and malignant effects may be coincidental or due to an undiagnosed underlying lesions in the cervix, but it does not prevent HPV infection.3 condition.6 Furthermore, there are no screening programmes in place for non-cervical cancers caused by HPV. The HPV vaccination One study reported that some programmes worldwide, most of which have high rates of uptake, have proven to be successful, showing a decrease in HPV patients presented to their general incidence for the serotypes that are vaccinated against, as well as practitioner with symptoms of fatigue a reduction in precancerous lesions.20,21 Cross-protection against and weakness prior to administration of other HPV low-risk strains has also been achieved.20 Countries such as Japan, which do not have a national HPV vaccination the vaccine, and a subsequent diagnosis programme, have experienced a rise in cervical cancer cases.15 of CFS/ME was made in a specialist centre. Obtaining a full and accurate Conclusion HPV has been shown to cause numerous cancers, including medical history prior to vaccination is cervical, vaginal, vulvar, penile, anorectal, and oropharyngeal. thus vitally important. The strongest way to protect individuals against such HPV-associated cancers is through vaccination.2 Various adverse Groups such as REGRET often use unsubstantiated allegations and events thought to be linked to the HPV vaccine have been scare tactics, offering only dubious research articles, opinion reported worldwide, including some autoimmune and pieces, and media links as ‘evidence’ to support an association neurological conditions.4,7-10 These reports, along with between adverse events and the HPV vaccine.11 These biased, anti-vaccination campaigns, have led to reduced uptake of the uncorroborated views, along with media speculation, have led to HPV vaccine in Ireland.5 The unmasking phenomenon and decreased uptake of the HPV vaccine.5 In 2015-2016, the general prevalence of these conditions in the vaccine target vaccination rate was 72.3%, compared to 86.9% in the previous population should be considered as explanations for these year.5 Data for HPV vaccine uptake in Ireland in 2016-2017 observed adverse events, when determining whether they should (released in January 2018) revealed a shockingly low uptake of in fact be reported as side effects of HPV vaccination.8,16 Due to only 51%, which is likely due to ongoing controversy.5 Choosing low vaccine uptake in Ireland, as revealed by recent data, both

Volume 11: Number 1. 2018 | Page 75 RCSIsmjperspective

girls and boys are at risk of HPV infection and its associated review the reported adverse events linked to the HPV vaccine. cancers in the future.6 Reassuringly, it persistently reports that the results of large-scale, The Global Advisory Committee on Vaccine Safety (GACVS), high-quality, evidence-based studies continue to demonstrate that which directly advises the World Health Organisation, continues to the HPV vaccine is safe and effective.15

References 1. National Cancer Registry Ireland. HPV-associated cancers in Ireland: 12. SaneVax, Inc. FDA approved Gardasil 9: Malfeasance or Stupidity. 2014. report from the National Cancer Registry. 2017. [Internet]. [updated [Internet]. [updated 2014 Dec 17; cited 2018 January 21]. Available 2017 May 4; cited 2017 October 14]. Available from: from: https://www.ncri.ie/news/article/hpv-associated-cancers-ireland-report- http://sanevax.org/fda-approved-gardasil-9-malfeasance-or-stupidity/. nation al-cancer-registry. 13. FDA. Package Insert – Gardasil 9. United States: Merck & Co.,Inc. 2016. 2. HPV Information Centre. Human Papillomavirus and Related Diseases [Internet]. [updated 2016 October; cited 2018 January 21]. Available Report. 2017. [Internet]. [updated 2017 July 27; cited 2017 October from: 18]. Available from: https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/Appr http://www.hpvcentre.net/statistics/reports/XWX.pdf. ovedProducts/UCM426457.pdf. 3. Health Service Executive. Human Papillomavirus (HPV) Vaccine. 2017. 14. Chao C, Klein NP, Velicer CM, Sy LS, Slezak JM, Takhar H et al. [Internet]. [updated 2017 September 6; cited 2017 October 25]. Surveillance of autoimmune conditions following routine use of Available from: quadrivalent human papillomavirus vaccine. J Intern Med. http://www.hse.ie/eng/health/Immunisation/pubinfo/schoolprog/HPV/. 2012;271(2):193-203. 4. Donegan K, Beau-Lejdstrom R, King B, Seabroke S, Thomson A, Bryan 15. World Heath Organisation. Safety update of HPV vaccines. 2017. P. Bivalent human papillomavirus vaccine and the risk of fatigue [Internet]. [updated 2017 July 14; cited 2017 October 18]. Available syndromes in girls in the UK. Vaccine. 2013;31:4961-7. from: 5. Health Protection Surveillance Centre. HPV Immunisation Uptake http://www.who.int/vaccine_safety/committee/topics/hpv/June_2017/e Statistics. 2017. [Internet]. [updated 2017 February 7; cited 2017 n/. October 14]. Available from: 16. Feiring B, Laake I, Bakken IJ, Greve-Isdahl M, Wyller VB, Haberg SE et al. http://www.hpsc.ie/a-z/vaccinepreventable/vaccination/immunisationu HPV vaccination and risk of chronic fatigue syndrome/myalgic ptakestatistics/hpvimmunisationuptakestatistics/. encephalomyelitis: a nationwide register-based study from Norway. 6. Health Products Regulatory Authority. Adverse Reaction (side effects) Vaccine. 2017;35(33):4203-12. Reports. 2017. [Internet]. [updated 2017 August 31; cited 2017 17. Gerber JS, Offit PA. Vaccines and autism: a tale of shifting hypotheses. October 17]. Available from: Clin Infect Dis. 2009;48(4):456-61. https://www.hpra.ie/homepage/medicines/special-topics/hpv-school-im 18. Nohynek H, Jokinen J, Partinen M, Vaarala O, Kirjavainen T, Sundman J munisation/national-monitoring-experience. et al. ASO3 adjuvanted AH1NI vaccine associated with an abrupt 7. Grimaldi-Bensouda L, Rossignol M, Koné-Paut I, Krivitzky A, increase in the incidence of childhood narcolepsy in Finland. PLoS One. Lebrun-Frenay C, Clet J et al. Risk of autoimmune diseases and human 2012;7(3):e33536. papilloma virus (HPV) vaccines: six years of case-referent surveillance. J 19. Salmon DA, Proschan M, Forshee R, Gargiullo P, Bleser W, Burwen DR Autoimmun. 2017;79:84-90. et al. Association between Guillain-Barré syndrome and influenza A 8. Arnheim-Dahlström L, Pasternak B, Svanström H, Sparén P, Hviid A. (H1N1) 2009 monovalent inactivated vaccines in the USA: a Autoimmune, neurological, and venous thromboembolic adverse meta-analysis. Lancet. 2013;381(9876):1461-8. events after immunisation of adolescent girls with quadrivalent human 20. Kavanagh K, Pollock KG, Potts A, Love J, Cuschieri K, Cubie H et al. papillomavirus vaccine in Denmark and Sweden: cohort study. BMJ. Introduction and sustained high coverage of the HPV bivalent vaccine 2013;347:5906-17. leads to a reduction in prevalence of HPV 16/18 and closely related 9. Baker B, Eca Guimarães L, Tomljenovic L, Agmon-Levin N, Shoenfeld Y. HPV types. Br J Cancer. 2014;110(11):2804-11. The safety of human papilloma virus-blockers and the risk of triggering 21. Hariri S, Bennett NM, Niccolai LM, Schafer S, Park IU, Block KC et al. autoimmune diseases. Expert Opin Drug Saf. 2015;14(9):1387-94. Reduction in HPV 16/18-associated high grade cervical lesions following 10. Gatto M, Agmon-Levin N, Soriano A, Manna R, Maoz-Segal R, Kivity S HPV vaccine introduction in the United States – 2008-2012. Vaccine. et al. Human papillomavirus vaccine and systemic lupus erythematosus. 2015;33(13):1608-13. Clin Rheumatol. 2013;32(9):1301-7. 11. REGRET. Reactions and Effects of Gardasil Resulting in Extreme Trauma. 2015. [Internet]. [updated 2015 May 23; cited 2017 October 15]. Available from: https://www.regret.ie/index.html.

Page 76 | Volume 11: Number 1. 2018 RCSIsmjperspective

CLAIRE GALLIBOIS, DEENA SHAH, NATASHA JAWA and DAMIEN NOONE look at the issues facing Canadian international medical graduates who wish to return to practise in Canada. Making the match

Introduction Over time there has been a steady increase in the number of Ireland.1 The challenge for the future will be for Irish medical schools Canadians studying medicine outside of Canada, and especially in to maintain these successful match rates in order to continue to Ireland.1 These Canadians now find themselves classified as attract North American students. international medical graduates (IMGs), and face substantial IMGs are physicians who have graduated from a medical school challenges in matching back to Canadian residency programmes. outside of the country in which they intend to practise. In Canada, Preparing for this increasingly competitive match is extremely this means any medical school not accredited by the Committee on daunting, and there is limited data on how to ensure success. The Accreditation of Canadian Medical Schools (CACMS) or the Liaison Irish medical schools have a reputation for training competent Committee on Medical Education (LCME).2 Compared to Canadian physicians who successfully match back to Canada or the United medical graduates (CMGs), IMGs face substantial barriers when States,1 and in some ways are now a victim of their own success, attempting to match to residency programmes in Canada. In 2017 with an increasing number of Canadians choosing to study in alone, 411 (22.7%) IMGs matched to a Canadian residency

Volume 11: Number 1. 2018 | Page 77 RCSIsmjperspective

programme, compared to 2,714 (96.5%) CMGs, amounting to numbers of IMGs going unmatched.1 Of the 1,811 IMG an almost seven-fold difference in matching rates.1 candidates who applied in the 2017 match year, 411 matched An IMG must apply through the Canadian Resident Matching successfully. A total of 157 were from European medical schools, Service (CaRMS) to the small amount of designated IMG 79 from the Caribbean, and 58 from Asia.1 In an informal positions, which is much lower than the number that CMGs are snowball survey conducted at the Hospital for Sick Children, of applying to, in order to be considered for the match. CaRMS uses 54 respondents (45 from Irish medical schools), 31 (57.4%) a specialised system – the Roth-Peranson algorithm – to match all participants overall had matched back to Canada at some point prospective residents with postgraduate medical residency between 2009 and 2017; 13 (24.1%) matched to the United programmes throughout the country.3 The process of matching is States through the National Residency Matching Program two sided: prospective residents assign rank orders to their (NRMP); and 10 (18.5%) did not match to either Canada or the preferred programmes, while programmes simultaneously rank United States. their preferred residents, based on written application and interview scores.3 The algorithm then compares the rank order Preparing for match day lists of applicants and programmes, and determines the match Upon entering medical school, all IMGs must plan their outcome.4 experiences strategically for the upcoming years, in order to arm themselves with the best possible chances for success during the Canadian residency programme matching trends match. Anecdotally, research involvement, observerships, electives While the first half of the past decade saw a marginal increase in at prospective schools in the desired subspecialty, and the overall number of applicants, and consequently a slight competitive board exam scores play an important role in increase in IMG Canadian matches, in the last five years these determining the probability of a successful match; however, this rates have plateaued, while the relative proportion of IMG has yet to be formally studied. applications has continued to increase.1 From 2006 to 2011 From anecdotal experience, there are two types of medical alone, this amounted to a six-fold increase in CaRMS applications programmes in Ireland: direct-entry six-year programmes from Canadian citizens who studied abroad,5 resulting in growing (immediately after high school, known as secondary school) and

Page 78 | Volume 11: Number 1. 2018 RCSIsmjperspective

the graduate entry, North American-style four-year programme which is both very competitive and not well known; thus, (for students with prior degrees). A CaRMS study in 2010 international schools became a viable option. Ireland, the UK, revealed that among the main reasons for Canadians to study and the United States all have six-year programmes and costs medicine abroad was inability to secure a seat in a Canadian among the three countries are relatively similar. school (77.6%).6 Upon coming to Ireland, challenges IMGs face and the stigma associated with going to an international medical school were Anecdotally, research involvement, known, this stigma being that IMGs are not as well educated as observerships, electives at prospective their CMG peers. However, we were not aware of the exact statistics associated with attempting the match. schools in the desired subspecialty, Essentially, statistics are not in favour of travelling internationally and competitive board exam scores for medical school if one’s goal is to end up practising in Canada. play an important role in determining With this in mind, realising that IMGs have matched and will continue to match to Canada is the key to having resilience in the probability of a successful match; this daunting process. however, this has yet to be formally studied. What are the factors and determinants of a As international students, six-year medical programmes abroad successful match? can be very attractive due to the possibility of entering directly Board scores into medical school after secondary school. According to the According to data collected from the CaRMS database, as of informal Hospital for Sick Kids study, knowing prior to graduating 2013 the average Medical Council of Canada Evaluating Exam high school that medicine was the career path on which a (MCCEE) score among Canadians studying abroad that matched student wanted to embark, played a very large role in deciding was 343, and among those that did not match the average score where to apply. Canada has one six-year medical programme, was 311.7

Volume 11: Number 1. 2018 | Page 79 RCSIsmjperspective

Interestingly, the average National Assessment Collaboration Furthermore, a study by the University of Arkansas’ Department Objective Structured Clinical Examination (NAC OSCE) score of Radiology found that residents who cited location as a reason among those that matched and those that did not match in the for choosing their programme were more likely to match; hence, same year (2013) was the same: 78.7 For this match year, the the importance of completing electives in the intended match mean was 70, with a standard deviation of 8 and a pass score of city.9 65.8 The informal 2017 study found that both the average NAC and MCCEE score among those who matched and those who did Letters of recommendation not match was essentially the same, ranging from 70-80 (p=0.41) A study conducted at the University of Minnesota Medical School and 325-350 (p=0.31), respectively. The mean score for the found that candidates applying to its psychiatry residency match year 2017 was 271, with a standard deviation of 50 and a programme garnered more positive overall scores if their passing score of 261.8 application was accompanied by clinical letters of reference that The scores clearly vary from year to year and, while board scores included the descriptors “hard-working”, “responsible”, are important, they may not be the determining factor for those “diligent”, and/or “team member”. who match to Canada. This resulted in applicants with better board examination scores This leads to speculation that once board scores reach a certain ranking similarly to those with average board exam scores and a ‘cut-off’, the probability of matching or not matching plateaus positive clinical letter of reference.10 Interestingly, through and other factors, like electives and reference letters, play a more correspondence with a matched Canadian IMG, they felt that pivotal role. their strong letter of reference from a summer elective was pivotal in their successful match. IMGs who have recently IMGs who have recently matched to matched to a Canadian programme highlighted the importance of “being true to who you are” and the importance of a Canadian programme highlighted demonstrating fulfillment of the CanMed roles11 (collaborator, the importance of “being true to who communicator, medical expert, manager, health advocate, you are” and the importance of scholar and professional) in interviews, personal statements, and electives. demonstrating fulfillment of the CanMed roles. The strength of the IMG There is a stigma that IMGs are inferior to graduates from the Research experience matching country, since the schools IMGs are matching from are Having research experience and publications is felt to be often smaller or lesser known. In two recent studies comparing important. Of surveyed IMGs currently practising in Canada, a CMGs and IMGs, however, IMG residents were on par with their large percentage (69.5%) felt that research and/or publications CMG colleagues with respect to in-training evaluation reports.12 A were an important part of a candidate’s residency application; subsequent study conducted in Alberta looked at programme however, after reviewing the research and publications of those directors’ perceived benefits of having IMG residents as part of same IMGs, it was found that there was no significant difference their resident class; IMG residents were noted to possess strong in the number of summer research positions held (p=0.46) or clinical knowledge, varied cultural perspectives, and positive publications during medical school (p=0.70) between those who personal attributes.13 One main downfall of IMGs in Canada is matched and those who did not. that they are not fully aware of the Canadian healthcare system, This would lend credence to the idea that both research and as the bulk of the student’s clinical teaching takes place in the publications, which can be highly variable between candidates in country the student is graduating from. Therefore, learning about terms of the time dedicated to them and the general preference the Canadian (or other) healthcare system could be done prior to of research format (one long project versus several small matching, such as during electives. projects), though not pivotal in matching, seem to be unwritten Recent evidence has shown that around one-quarter of physicians requirements that all candidates should have. practising in Canada are IMGs, lending credence to the idea that IMGs represent a vital and continuing source of physicians across Electives – location, location, location the country.14,15 A study published in 2014 of Canadians studying abroad who matched to Canada found the following: (i) a 55% increase in The role of the Irish medical schools, specifically RCSI the chances of matching if an elective was completed in the Irish medical schools are renowned for training medical students province of the intended match school; (ii) a 47% increase if an to a high standard that is accepted and recognised worldwide. elective was completed in the same discipline; and, (iii) a 32% The Royal College of Surgeons in Ireland (RCSI) was ranked in the increase if an elective was completed at the intended match top 2% by the Times Higher Education World University Rankings university.7 2018.16 The RCSI has established connections with numerous

Page 80 | Volume 11: Number 1. 2018 RCSIsmjperspective

schools across North America, including the University of step might be to survey the programme directors who accept Toronto, to ensure successful repatriation of its students. With these IMGs into their programmes, as they are likely to hold the this, the RCSI continues to receive an influx of Canadian students, key. What successful IMGs claim to be the secret to their success further maintaining these ever-growing connections with North may be fundamentally biased and flawed. America. The RCSI prides itself on the comprehensive training of It is likely to be multifactorial and, in some ways, a je ne sais quoi. its students, and provides many opportunities for continued In conclusion, matching will remain a very personal process, as growth, such as compulsory research time and links to electives candidates all note different aspects of their application as strong. abroad. The RCSI and other medical schools now plan the There is currently no definitive algorithm that will guarantee a curriculum such that students applying to North American successful match to Canada, as factors like location, availability of residency programmes have time to complete both board exams positions, and competitiveness of other applicants all play pivotal and electives, ensuring a competitive CV. roles, and are both out of the applicant’s control and year dependent. Future challenges and studies However, by arming oneself with strong letters of The challenge in future will lie in maintaining this symbiotic recommendation, gaining clinical experience in the specialty and relationship between North American and Irish medical schools. at the school to which one intends to match, preparing for More formal studies should be conducted to attempt to discover interviews, and having faith in the process, one can increase the the secret to a successful North American match. Perhaps a next chances of a successful match.

References 1. Canadian Resident Matching Service. R-1. Main Residency Match 9. Deloney LA, Rozenshtein A, Deitte LA et al. What program directors Outcomes and insights. April 30, 2017. [Internet]. Available from: think: results of the 2011 annual survey of the Association of Program https://www.carms.ca/wp-content/uploads/2017/04/2017-CaRMS-For Directors in Radiology. Acad Radiol. 2012;19(12):1583-8. um-web-deck-EN.pdf. 10. Shiroma PR, Alarcon RD. Selection factors among international 2. Canadian Resident Matching Service. Ontario. November 21, 2017 medical graduates and psychiatric residency performance. Acad [Internet]. [Accessed 2017 October 26]. Available from: Psychiatry. 2010;34(2):128-31. https://www.carms.ca/en/residency/r-1/eligibility-criteria/provincial-cri 11. The Royal College of Physicians and Surgeons of Canada. CanMEDS teria/ontario/. 2005 Physician Competency Framework: Better standards, better 3. Canadian Resident Matching Service. The Match Algorithm. physicians, better care. 2011. [Internet]. Available from: [Internet]. [Accessed 2017 October 26]. Available from: http://www.royalcollege.ca/rcsite/canmeds/canmeds-framework-e201 https://www.carms.ca/en/residency/match-algorithm/. 8. 4. Alvin Roth EP. The redesign of the matching market for American 12. Andrew RF. How do IMGs compare with Canadian medical school physicians: some engineering aspects of economic design. American graduates in a family practice residency program? Can Fam Physician. Economic Review 1999; 89. [Internet]. Available from: 2010;56(9):e318-22. https://web.stanford.edu/~alroth/papers/rothperansonaer.PDF. 13. Triscott JA, Szafran O, Waugh EH et al. Cultural transition of 5. Watts E, Davies J, Metcalfe D. The Canadian International Medical international medical graduate residents into family practice in Graduate Bottleneck: A New Problem for New Doctors. CMEJ. Canada. Int J Med Educ. 2016;7:132-41. 2011;2(2):86-90. 14. Canadian Task Force on Licensure of International Medical Graduates. 6. Banner S, McKiver A, Rattanasithy S, Cassie J, Woodward C, Ford R. Federal/Provincial/Territorial Advisory Committee on Health Delivery Canadian Students Studying Medicine Abroad. CaRMS Report. 2010. and Human Resources. 2004. A Framework for Collaborative [Internet]. Available from: Pan-Canadian Health Human Resources Planning. [Internet]. Available http://www.carms.ca/pdfs/2010_CSA_Report/CaRMS_2010_CSA_Repo from: rt.pdf. https://www.canada.ca/en/health-canada/services/health-care-system/ 7. Banner S, Bowmer I. Selecting IMGs for residency programs: myths reports-publications/health-human-resources/framework-collaborative- and shibboleths. The International Conference on Residency canadian-health-human-resources-planning-health-canada-2007.html. Education. 2014. [Internet]. Available from: 15. Audas R, Ross A, Vardy D. The use of provisionally licensed http://www.royalcollege.ca/portal/page/portal/rc/common/document international medical graduates in Canada. CMAJ. s/events/icre/2014proceedings/slides/Health_Policy_and_Residency_Ed 2005;173(11):1315-6. ucation/Selecting_IMGs_for_residency_programs.pdf. 16. Royal College of Surgeons in Ireland. RCSI ranks among top 2% of 8. Medical Council of Canada. Score interpretation guidelines. 2018. universities in Times Higher Education World University Rankings. [Internet]. Available from: 2017. [Internet]. Available from: http://mcc.ca/research-and-development/score-interpretation/2018. http://www.rcsi.ie/index.jsp?p=100&n=110&a=11058.

Volume 11: Number 1. 2018 | Page 81 RCSIsmjperspective

IS A ROBOT READING my x-rays?

SRI SANNIHITA VATTURI and LAN-LINH TRUONG look at the impact of AI on the specialty of radiology.

Introduction For nearly 30 years, radiology has been an appealing specialty for I healthcare moving out of hospitals, causing decreased many medical students. The number of applicants to radiology demand for imaging; residency programmes increased throughout the 1990s and 2000s, I payment reform, whereby imaging becomes a cost for and peaked in 2009, when nearly 7% of US senior medical hospitals rather than a profit; and, students applied to radiology for residency.1 Since then, interest in I increased use of machine learning and/or artificial intelligence radiology has declined.1 This decline is attributed to three causes: (AI).

Page 82 | Volume 11: Number 1. 2018 RCSIsmjperspective

Of all these causes, AI is the only one that threatens radiology as scans or large volumes of data, a computer will not.2 It is a medical specialty, while the others only cause declines in estimated that the error rate among radiologic examinations is terms of numbers and pay.2 AI is algorithm-driven learning by approximately 30% and approximately 4% of real-time daily computers. It relies on application of algorithms that are able to interpretations by radiologists contain errors.5,8 Historically, up learn and improve based on the amount of data that they to 19% of lung nodules seen on chest radiographs were missed interpret, and make predictions to reduce occurrence of and misdiagnosis of breast cancer occurs in up to 30% of diagnostic errors.2 The purpose of this piece is to explore and mammography studies.9,10 In a summary of literature on the use demonstrate the advantages and disadvantages of AI in of AI in diagnosis of breast cancer, Birdwell11 reported that using radiology and how it may affect the future of radiology. AI to screen mammograms increased detection of breast cancer by 7-20%, with an increase in recall rate of 9-18%. Another study In a summary of literature on the use of demonstrated that in a cohort of 110 patients where a breast tumour was missed, AI was able to identify 73% of missed AI in diagnosis of breast cancer, Birdwell masses.12 These figures suggest that AI is already performing just reported that using AI to screen as well, if not better, than experienced radiologists. mammograms increased detection of breast cancer by 7-20%, with an Another important factor driving AI is increase in recall rate of 9-18%. the cost of healthcare. When used as a diagnostic tool, AI can aid in reducing Traditional radiology the need for unnecessary testing, Radiology was once confined to projectional images such as chest x-rays, although with the advancement to cross-sectional through recommending the most imaging (including CT/MRI) the amount of data requiring appropriate test given a specific set of interpretation has increased substantially. For example, a patient symptoms. radiologist may need to view 4,000 images in a CT scan of multiple body parts in patients with multiple trauma.3 The Integrating AI into radiology increased workload causes radiologists to alter their approach in Computer-aided detection (CAD) is a computer algorithm that interpreting these images,3 for example, using pattern integrates multiple image processing steps to compare and recognition given clinical context. AI has the potential to identify the abnormalities using various diagnostic modalities. identify the same features as a physician, and with the Computer-aided diagnosis (CADx) marks these regions and increasing amount of data, it can aid in reducing errors and bias assesses disease, severity, stage, and progression or regression. caused by physician fatigue.4 CAD can improve sensitivity of a single reader, but is associated Nearly 75% of all medical malpractice claims against with reduced specificity, potentially leading to overdiagnosis.13 radiologists are related to diagnostic errors linked to problems Evidence also shows that CAD does not perform as well as with visual perception (scanning, recognition or image image interpretation by two independent physicians in the interpretation) and system errors (such as failure to context of breast mammography and CT detection of communicate).5 In other words, errors are mostly attributable to pulmonary nodules.13 A further study showed similar outcomes human factors. Compare that to diagnostic errors in internal in identifying malignant thyroid nodules.14 The sensitivity of the medicine, which are usually associated with multiple factors and CAD was comparable to a physician; however, the specificity secondary to a combination of cognitive and system factors.5,6 and accuracy were reduced.14 In internal medicine many more factors come into play when IBM Watson is a new AI system that shows great promise; it is a making an error, making misdiagnosis more complex. However, processing system that analyses information in a similar way to in radiology the diagnosis is highly dependent on the humans, by understanding natural language and analysing physician’s ability to identify abnormalities. A study by Graber et unstructured data. When given a problem, Watson generates a al.6 estimated that nearly 75% of diagnostic errors were related hypothesis and analyses evidence. Through repeated use, the to cognitive factors such as poor perception and use of short system ‘gets smarter’ by tracking feedback from its users and cuts. Radiologists rely on mental short cuts during reasoning to learning from correct and incorrect analyses.15 The system uses minimise delay and costs, but failure in these methods and patient data to create suggestions that physicians can then use processes leads to bias.4 AI is less susceptible to biases, and and refer to. The system also takes feedback from the therefore reduces the likelihood of diagnostic error when used physicians, which contributes to its constant learning.16 to complement decision-making by a physician.7 AI can also The Watson system has been shown to be particularly effective handle more complex datasets than humans can. Where in managing cancer diagnoses and even treatment.17 When humans can easily become overwhelmed reading complicated used in a clinical setting with a cohort of 400 patients, the

Volume 11: Number 1. 2018 | Page 83 RCSIsmjperspective

accuracy of the system was shown to be 82.6%, with a false those will be false positives, as previously mentioned, in which positive rate of 2.9% and false negative rate of only 0.4%.17 This case it is recommended that a physician would need to review displays the ability of the system to suggest options with a high the positive scans in order to exclude or confirm these false accuracy rate. positives. AI is also occurring at a time where the amount of Given the success of Watson thus far, it is evident that data needed to be processed is increasing. Incorporating AI integrating AI into everyday practice will be beneficial, though it would result in more efficient data processing and help to would still require testing on a larger scale. If shown to be reduce the workload on physicians, but would in turn reduce beneficial there, the system could be considered a reasonable the number of physicians needed.12 This will result in fewer investment to healthcare. If a single AI unit were able to do the residency spots, potentially making radiology a less desirable same amount of work as several radiologists, and in a more and even more competitive specialty.18 time-efficient manner, it would negate the need for multiple Another important factor driving AI is the cost of healthcare. radiologists. When used as a diagnostic tool, AI can aid in reducing the need for unnecessary testing, through recommending the most AI has been proven to be an effective appropriate test given a specific set of patient symptoms.7 This in turn will reduce healthcare expenditure and also help method not only for detection of physicians to adhere to constantly changing guidelines.7,12 abnormalities but also in the diagnosis Increased cost of health spending affects both private and and treatment of disease. government payers. In 2016, it is estimated that nearly 20% of the US economy was spent on healthcare, compared to 16% in 2007 and only 8% in 1975.19 An AI-based system would cost a Implications of AI in radiology hospital less than the conventional method of having a large Currently the issue with AI is specificity, not sensitivity. AI team of radiologists and, on top of that, would be more detects a larger amount of ‘positives’. However, a proportion of efficient.3

Page 84 | Volume 11: Number 1. 2018 RCSIsmjperspective

A disadvantage to consider is whether or not patients would be time? AI is already being incorporated into healthcare now; the willing to accept a diagnosis made solely by a computer system. uncertainty is how it will affect us in 15 to 20 years. Would patients be able to trust the decision made by a robot? Or would they prefer a decision made by a physician? This Conclusion comes into effect when discussing who is responsible for the AI has been proven to be an effective method not only for actions of the system. If the system makes an error in diagnosis detection of abnormalities but also in the diagnosis and or treatment, who is liable for the mistake: the hospital, the treatment of disease. Given its success to date, its potential to physician, or the company who made the machine? This opens grow in the future and the current interest in improving AI, it is up an important conversation about liability and the legal evident that it can greatly augment the field of radiology. implications of incorporating machines into healthcare.2,7 A By combining the work of physicians and AI, we allow both to computer system also lacks empathy, which a radiologist would do what they do best and, in the end, maximise the potential of be able to provide. The pressing question is how fast will these both. As Krittanawong says: “AI in medicine remains very technological advancements happen? Will they happen in our promising, although still in its infancy”.20

References 1. Chen JY, Heller MT. How competitive is the match for radiology residency? 12. Birdwell RL, Ikeda DM, O’Shaughnessy KF, Sickles EA. Mammographic

Present view and historical perspective. J Am Coll Radiol. characteristics of 115 missed cancers later detected with screening

2014;11(5):501-6. mammography and the potential utility of computer-aided detection.

2. Chockley K, Emanuel E. The end of radiology? Three threats to the future Radiology. 2001;219(1):192-202.

practice of radiology. J Am Coll Radiol. 2016;13(12 Pt A):1415-20. 13. Saba L, Caddeo G, Mallarini G. Computer-aided detection of pulmonary

3. Jha S, Topol EJ. Adapting to artificial intelligence: radiologists and nodules in computed tomography: analysis and review of the literature. J

pathologists as information specialists. JAMA. 2016;316(22):2353-4. Comput Assist Tomogr. 2007;31(4):611-9.

4. Croskerry P, Nimmo GR. Better clinical decision making and reducing 14. Choi YJ, Baek JH, Park HS, Shim WH, Kim TY, Shong YK et al. A

diagnostic error. J R Coll Physicians Edinb. 2011;41(2):155-62. computer-aided diagnosis system using artificial intelligence for the

5. Lee CS, Nagy PG, Weaver SJ, Newman-Toker DE. Cognitive and system diagnosis and characterization of thyroid nodules on ultrasound: initial

factors contributing to diagnostic errors in radiology. AJR Am J Roentgenol. clinical assessment. Thyroid. 2017;27(4):546-52.

2013;201(3):611-7. 15. Doyle-Lindrud S. Watson will see you now: a supercomputer to help

6. Graber ML, Franklin N, Gordon R. Diagnostic error in internal medicine. clinicians make informed treatment decisions. Clin J Oncol Nurs.

Arch Intern Med. 2005;165(13):1493-9. 2015;19(1):31-2.

7. Dilsizian SE, Siegel EL. Artificial intelligence in medicine and cardiac imaging: 16. Jiang F, Jiang Y, Zhi H, Dong Y, Li H, Ma S et al. Artificial intelligence in

harnessing big data and advanced computing to provide personalized medical healthcare: past, present and future. Stroke and Vascular Neurology.

diagnosis and treatment. Curr Cardiol Rep. 2014;16(1):441. 2017;2(4). Available from: http://svn.bmj.com/content/2/4/230.

8. Borgstede JP, Lewis RS, Bhargavan M, Sunshine JH. RADPEER quality 17. Takahashi K, Kantarjian HM, Garcia-Manero G, Stevens RJ, Dinardo CD,

assurance program: a multifacility study of interpretive disagreement rates. Allen J et al. MD Anderson’s Oncology Expert Advisor powered by IBM

J Am Coll Radiol. 2004;1(1):59-65. Watson: a web-based cognitive clinical decision support tool. J Clin Oncol.

9. Giess CS, Frost EP, Birdwell RL. Difficulties and errors in diagnosis of breast 2014;32(15).

neoplasms. Semin Ultrasound CT MR. 2012;33(4):288-99. 18. Recht M, Bryan RN. Artificial intelligence: threat or boon to radiologists? J

10. Quekel LG, Kessels AG, Goei R, van Engelshoven JM. Miss rate of lung Am Coll Radiol. 2017;14(11):1476-80.

cancer on the chest radiograph in clinical practice. Chest. 19. Orszag PR, Ellis P. The challenge of rising health care costs – a view from

1999;115(3):720-4. the Congressional Budget Office. N Engl J Med. 2007;357(18):1793-5.

11. Birdwell RL. The preponderance of evidence supports computer-aided 20. Krittanawong C. The rise of artificial intelligence and the uncertain future

detection for screening mammography. Radiology. 2009;253(1):9-16. for physicians. Eur J Intern Med. 2017.

Volume 11: Number 1. 2018 | Page 85 RCSIsmjperspective

BIG BUDGET brain projects

ANUJ RASTOGI explores the importance of large-scale collaboration in neuroscience, neurology and psychiatry.

Introduction The brain is a machine of staggering complexity. As a result, our to systems, and the field can be stymied and fragmented by a lack understanding of basic neuroscience and translatable clinical insights of collaboration between investigators from different levels. These is far from complete – a point made obvious by the increasing initiatives make a concerted effort to unify the field by bringing prevalence and economic costs of brain diseases. The global together the entire gamut of investigative tools and expertise. economic burden of mental, neurological, and substance use Currently, neuroscience is primed to answer grand questions: What disorders was estimated at $8.5 trillion USD in 2010, equivalent to are the basic principles governing neural structure and function? 13.5% of the global gross domestic product (GDP) that year, and is What triggers neurodegeneration? expected to reach $16.1 trillion by 2030.1 Additionally, the most What are the biomarkers for neurological and psychiatric disorders? recent Global Burden of Disease Study (2015) found an increase in To answer such questions, one must first evaluate how best to deal the global prevalence of nearly every major neurological and with the copious amounts of data generated from these ‘big brain’ psychiatric disorder, including Alzheimer’s disease, Parkinson’s projects and from neuroscience labs across the world. Sharing the disease, epilepsy, schizophrenia, and depression.2 data load may be the answer. The rising economic burden of brain Recognising that combating brain disease relies primarily on diseases demands a shift in traditionally independent neuroscience neuroscience research, governments and institutions have recently research towards more collaborative initiatives worldwide. As such, devised ambitious global research initiatives (Table 1). These big neuroscience must foster a culture of shared investigation to budget consortia aim to change the way neuroscience is largely confront existing vast, complex datasets and fully realise their conducted. Neuroscience has many levels of analysis, from synapses therapeutic potential.

Page 86 | Volume 11: Number 1. 2018 RCSIsmjperspective

Table 1: Collaborative brain projects.

Project name Origin and year Aims Budget Funding sources

Brain Research USA; 2013 Census: brain cell types Federal Federal: NIH, through Create new technologies for projection: NSF, DARPA, Advancing analysing microcircuitry, $4.5 billion IARPA, FDA, Innovative recording large-scale neural over 12 DOE Neurotechnologies activity, and neuromodulation years; $434 Foundations, (BRAIN) (clinical and non-clinical) million for research Initiative18 Neuro-ethics: ethical implications 2017 institutions, of neuroscience companies: HHMI, Allen Institute for Brain Science, the Kavli Foundation, the Simons Foundation, GE, GSK

Allen Institute USA; 2003 “Periodic Table of Cell Types”: Founded with Diverse public for Brain Science categorise brain cell types based $100 million (including NIH) (multiple on structural and functional by Paul Allen and private (philanthropic, projects)19 properties (in mouse and human (Microsoft Co-founder) Paul Allen) cortex) Allen contribution: organisations “Brain Observatories”: Observe $500 million to date co-ordinated activity of neurons in real-time (dynamics) in mouse visual cortex

Human USA, UK, Map the macroscopic structural Federal: Federal: NIH Connectome Italy, and functional connections of the $40 million Project20 Germany; human brain using functional 2009 magnetic resonance imaging, diffusion tensor imaging, magnetic encephalography

Human Brain European Theoretical/mathematical €1 billion European Project21 Union (main modelling (~$1.07 Commission: hub in Reconstruct and simulate the billion USD) €500 million Switzerland), mouse and human brain projected National, public, UK; 2013 Investigate cognitive processes: Planned EU and private learning, memory, sleep contribution: organisations: Neuroinformatics: new tools for €89 million €500 million analysis of large data sets from April Neurorobotics: using neural 2016 to processes to control machines March 2018 Neuro-ethics

China Brain China; 2016 Investigate neural architecture of Unknown Ministry of Project (brain macaque monkey Timeline: Science and science and brain- New approaches in the early diagnosis 2016-2030 Technology inspired and intervention of brain disorders Natural Science intelligence)22 Brain machine intelligence Foundation of technologies China

Brain/Mapping Japan; 2014 Structural and functional mapping ¥40 billion (~ Ministry of by Integrated of marmoset monkey brain $360 million Education, Neurotechnologies Develop new high-resolution, USD) Culture, Sports, for Disease wide-field, fast imaging technologies projected Science, and Studies (MINDS) Use data from marmoset disease over ten Technology of Programme23 models to inform clinical years Japan biomarkers for the diagnosis and Japan Agency for treatment of human brain diseases Medical Research Neuroinformatics and Development

Australian Brain Australia; Encoding information in synapses $500 million Government, Initiative24 2016 and circuits AUD (~$380 philanthropic, Neural basis of learning, million USD) public, and cognition, and behaviour projected private Create technologies to optimise over five organisations and restore brain health, spur years innovation in new industries, and educate the public

Volume 11: Number 1. 2018 | Page 87 RCSIsmjperspective

Neuroinformatics: big data sharing One key aim is to build large databases Neuroinformatics links neuroscience with information science to of anonymised patient information accumulate, manage, analyse and, most importantly, share data for to help identify imaging biomarkers the validation of computational and theoretical models of the brain.3 Recognising its significance, most big brain projects have an explicit for use in the diagnosis and focus on neuroinformatics. But ‘open’ neuroscience must further management of disease. incentivise and sustain data-sharing efforts. First and foremost, change must start with attitudes at the individual level. Career By combining patient information from multiple internal hospital incentives for data sharing are currently dwarfed by the yearning for databases, data sets can grow sufficiently to run large-scale data intellectual autonomy and more traditional metrics upon which analytics. The Alzheimer’s Disease Neuroimaging Initiative researchers are judged, such as publication in high-impact journals, (ADNI) leads by example, with healthcare and research maximising citations, and attaining grants.4 Proponents of open institutions around the world contributing patient imaging data neuroscience have suggested various credit attribution systems to to identify biomarkers and, ultimately, develop personalised combat this, including a sharing index (S-index), increased treatments.10 In this sense, the future of clinical neuroinformatics publication in ‘data journals’, and mandatory data sharing in order to may parallel that of precision genomics, and may one day enable secure funding.4 Sustainability in this field refers to the maintenance the implementation of tailored therapeutic protocols for of data repositories and cataloguing new data, which is of paramount individual patients. importance. This will likely require a digital content marketplace, increased funding, and the training of young neuroscientists in open Ethical implications access practices. Organisations that deliver such analytic tools, Regulatory barriers regarding data sharing and patient privacy resources, and funding for networked cyber-infrastructure will also can be difficult to navigate; at the personal level, many patients facilitate the re-use and reproducibility of shared data. For example, fear the disclosure of personal health information due to the International Neuroinformatics Coordinating Facility (INCF) negative employment or insurance consequences.11 However, partners with clinical, industrial, and technological organizations to when patients are given a voice and are asked whether their fund and marshal data-sharing initiatives across four continents.5 The data may be shared for research purposes, they are more likely INCF also offers a training committee to educate the research to give consent.11 Furthermore, using novel encryption software community about neuroinformatics. and anonymisation algorithms on patient information uploaded into research databases has been shown to be effective.12 This Data sharing in clinical neuroscience and other ethical issues of data sharing must be addressed The application of neuroinformatics to medicine, known as clinical responsibly in neuroscience. At the healthcare agency level, neuroinformatics, takes advantage of the current work being done in however, legal specifics make patient data sharing more clinical neuroimaging. One key aim is to build large databases of uncertain. For example, the 1996 Health Insurance Portability anonymised patient information to help identify imaging biomarkers for and Accountability Act of the United States does allow for the use in the diagnosis and management of disease. Functional magnetic non-consented sharing of patient data for clinical trial research, resonance imaging (fMRI) data from the Human Connectome Project6 but stipulates that the data cannot leave the healthcare site, can be used to identify abnormal connectivity biomarkers, i.e., which makes little sense and provides little security in this abnormal connections between different brain areas, in different patient modern age of ‘cloud-based’ services for electronic patient populations, such as those with depression and anxiety.7 Indeed, many records.11 Outdated regulations such as this, and comparable brain disorders including Parkinson’s disease, Alzheimer’s dementia, legislation in other nations, need to be modernised to enable epilepsy, depression, and even chronic pain are now being thought of multi-site clinical data sharing. Interactions between healthcare, as “connectopathies”, or connectivity aberrations.8 Functional MRI can legislative, and ethics agencies must also ensure consistent also be used as a prognostic biomarker to assess the systems-level policies on patient data sharing and privacy, keeping potential pharmacodynamic effects of central nervous system (CNS) drugs.9 future gains in mind; it is likely that the pooling and analysis of Therefore, connectomics, an important aim of nearly all big brain shared data would expedite drug development and improve projects, has direct clinical implications. public health.

Page 88 | Volume 11: Number 1. 2018 RCSIsmjperspective

For example, the 1996 Health Insurance heterogeneous data, and varying animal model efficacy are three major reasons why CNS drug discovery lags behind that of other Portability and Accountability Act of the areas in medicine.13 These factors are not kind to pharmaceutical United States does allow for the companies, and have resulted in profit draining and the evanescing non-consented sharing of patient data for of industry resources within CNS drug research.14 In the most recent comprehensive report of 7,455 drug programmes between 2006 clinical trial research, but stipulates that and 2015, the success rate of progression from Phase I trials to the data cannot leave the healthcare site, market approval was a combined 9.6%.12 However, out of 16 areas which makes little sense and provides of medicine, neurology and psychiatry ranked among the four lowest, with drug success rates of 8.4% and 6.2%, respectively.15 little security in this modern age of Analysing pooled multi-site patient data repositories may help to ‘cloud-based’ services for electronic identify common, reliable biomarkers and could drastically reduce patient records. the number of candidate CNS drugs, most of which tend to fail after considerable investment. A quicker and more cost-effective progression of CNS drugs in the pharmaceutical pipeline could result from analysing amalgamated data, through improvements in Neurological biomarkers and CNS drug development patient selection for clinical trials, risk assessment, and outcome The identification of disease-specific biomarkers will aid targeted measurement. Interestingly, when biomarkers were used in drug CNS drug development. The current scarcity of reliable biomarkers development, the success rate for advancement from Phase I trial to is largely due to the inherent pathophysiological complexity of CNS market approval improved from 9.6% to 25.9%.15 This underscores disorders, which impedes drug discovery. Neurological complexity, the clinical utility of biomarkers, but research must first begin with

Volume 11: Number 1. 2018 | Page 89 RCSIsmjperspective

how to properly analyse them. The Biomarkers Consortium, brain diseases show no signs of plateauing. We must not let clinical launched in the United States, now has numerous programmes to insights become lost in the scattered deluge of data. identify biomarkers and translate findings into effective treatments, There are now ways to manage large, complex datasets using the as with the Autism Biomarkers Consortium for Clinical Trials principles of neuroinformatics. Integrating patient data repositories (ABC-CT).16 The ABC-CT is currently building a repository for may help to identify clinical biomarkers and hasten CNS drug electroencephalographic (EEG) and eye tracking data, to evaluate its development. There are, however, uncertainties surrounding utility as a biomarker for visual attention and behaviour in autism collaborative neuroscience, such as regulatory oversight, patient spectrum disorder.17 privacy, how best to allocate funds in multi-site projects, and incentivising data sharing for researchers at a personal level. Conclusion Nevertheless, a major swing in data sharing attitudes has seen Neuroscience is going where genomics has been; it is in the midst consortia arise worldwide, which have the capacity to revolutionise of an open, transparent, data-sharing zeitgeist. Discovery in our current understanding of the brain and associated diseases. neuroscience is time sensitive, as the economic and social costs of Open neuroscience is afoot.

References 1. Bloom DE, Cafiero ET, Jané-Llopis E et al. The global economic burden of 12. Kohlmayer F, Prasser F, Eckert C, Kuhn KA. A flexible approach to non-communicable diseases. Geneva: World Economic Forum. distributed data anonymization. J Biomed Inform. 2014;50:62-76. 2011;1-46. [Internet] Available from: 13. Hyman SE. Revolution stalled. Sci Transl Med. 2012;4(155):155cm11. http://apps.who.int/medicinedocs/documents/s18806en/s18806en.pdf. 14. Miller G. Is pharma running out of brainy ideas? Science. 2. Vos T, Allen C, Arora M et al. Global, regional, and national incidence, 2010;329(5991):502-4. prevalence, and years lived with disability for 310 diseases and injuries, 15. Thomas DW, Burns J, Audette J, Carroll A, Dow-Hygelund C, Hay M. 1990-2015: a systematic analysis for the Global Burden of Disease Study Biotechnology Innovation Organization (BIO). Biomedtracker, Amplion 2015. Lancet. 2016;388(10053):1545-1602. Report. 2016. [Internet]. Available from: 3. Bjaalie JG. Understanding the brain through neuroinformatics. Front https://www.bio.org/sites/default/files/Clinical%20Development%20Succ Neurosci. 2008;2:19-21. ess%20Rates%202006-2015%20-%20BIO,%20Biomedtracker,%20Ampli 4. Ferguson AR, Nielson JL, Cragin MH, Bandrowski AE, Martone ME. Big on%202016.pdf. data from small data: data-sharing in the “long tail” of neuroscience. Nat 16. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT). Neurosci. 2014;17(11):1442-7. [Internet]. Available from: 5. The International Neuroinformatics Coordinating Facility. [Internet]. https://fnih.org/what-we-do/biomarkers-consortium/programs/autism-bi Available from: https://incf.org/. omarkers. 6. Smith SM, Beckmann CF, Andersson J et al. Resting-state fMRI in the 17. McPartland JC. Developing clinically practicable biomarkers for autism human connectome project. Neuroimage. 2013;80:144-68. spectrum disorder. J Autism Dev Disord. 2017;47(9):2935-7. 7. De Witte NAJ, Mueller SC. White matter integrity in brain networks 18. The United States BRAIN Initiative. [Internet]. Available from: relevant to anxiety and depression: evidence from the human https://www.braininitiative.nih.gov/. connectome project dataset. Brain Imaging and Behav. 19. The Allen Institute for Brain Science Projects. [Internet]. Available from: 2017;11(6):1604-15. https://www.alleninstitute.org/what-we-do/brain-science/research/progra 8. Fox MD, Buckner RL, Liu H, Chakravarty MM, Lozano AM, Pascual-Leone ms/. A. Resting-state networks link invasive and noninvasive brain stimulation 20. Van Essen DC, Smith SM, Barch DM et al. The Wu-Minn Human across diverse psychiatric and neurological diseases. Proc Natl Acad Sci Connectome Project: an overview. Neuroimage. 2013;80:62-79. USA. 2014;111(41):4367-75. 21. The European Union Human Brain Project. [Internet]. Available from: 9. Duff EP, Vennart W, Wise RG et al. Learning to identify CNS drug action https://www.humanbrainproject.eu/documents/10180/538356/FPA++An and efficacy using multistudy fMRI data. Sci Transl Med. nex+1+Part+B/41c4da2e-0e69-4295-8e98-3484677d661f. 2015;7(274):274ra16. 22. Poo MM, Du JL, Ip NY, Xiong ZQ, Xu B, Tan T. China Brain Project: basic 10. Shaw LM, Vanderstichele H, Knapik-Czajka M et al. Cerebrospinal fluid neuroscience, brain diseases, and brain-inspired computing. Neuron. biomarker signature in Alzheimer’s disease neuroimaging initiative. Ann 2016;92(3):591-6. Neurol. 2009;65(4):403-13. 23. Okano H, Sasaki E, Yamamori T et al. A Japanese national brain project 11. Institute of Medicine (US). Sharing clinical research data: workshop for marmoset neuroscience. Neuron. 2016:92(3):582-90. summary. Washington (DC): National Academies Press. 2013. [Internet]. 24. Richards LR, Michie PT, Badcock DR et al. Australian Brain Alliance. Available from: https://www.ncbi.nlm.nih.gov/books/NBK131772. Neuron. 2016;92(3):597-600.

Page 90 | Volume 11: Number 1. 2018 RCSIsmjperspective ‘What’s in a name?’ CAROL RIZKALLA examines the weighty consequences of semantics in human genome editing.

Introduction A recent announcement from Oregon Health & Science been suggested.3 Each potential target gene would need to be University stated that their scientists have eliminated the cause of evaluated carefully, on both scientific and ethical grounds, in a deadly genetic disease by editing the genes of a human order to be considered a suitable candidate for heritable genome embryo.1 This has raised the prospect of a powerful new tool in editing.3 The semantics behind the National Academy of the physician’s toolbox.2 Sciences’ suggested considerations regarding human genome At present, the National Academy of Science does not specify a editing will be explored here. prohibition on human genome editing; rather, it stipulates certain The terms ‘deadly’, ‘fatal’, and ‘serious disease’ will be used considerations and parameters that must be met in any project interchangeably, as is presently done in the literature on this proposal regarding this type of work. topic. As well, the implications of other generally accepted terms To eliminate the prospect of ‘designer babies’, the use of such to support gene editing, such as ‘disability’ and ‘disease’, will genome-altering technology only for ‘deadly’ genetic diseases has be explored.

Volume 11: Number 1. 2018 | Page 91 RCSIsmjperspective

Setting the scene – insight into eugenics In order to better understand the ethical context of human cochlear implant to be a loss of culture, and yet such a device genome editing, one must first grasp the concept of eugenics. may be perceived by those who can hear (e.g., parents) as an Eugenics is the selection of desired heritable characteristics in opportunity for improvement.8 Why, then, do science and order to improve future generations; it is inherently society aim to target and prevent disability through human discriminatory.4 However, precisely which characteristics are genome editing, when many of these individuals do not, in fact, deemed suitable within a society is based on unique societal consider themselves to be disabled? values.5 While we assume that parents and guardians have their child’s Williamson (1998) suggested that the basis of eugenic best interests at heart, they may often base such clinical decision-making lies in the social, economic, personal, and decisions on current societal norms.5 Is it sufficient to rely on family circumstances of the parents, rather than the details of terms widely accepted by society today (e.g., deadly or developmental or cognitive impairment in the offspring.5 As a disability) as determinants for human genome editing? consequence, certain ‘undesirable characteristics’ become We must consider the future implications; by blindly abiding by justifiable targets of eugenics, simply by being labelled with a current social labels and beliefs, we fail to respect a child’s term that musters public support, a term such as ‘deadly’ or individuality. ‘disability’. A dangerous discrepancy Words such as deadly and disability are When one types ‘deadly genetic disease’ into the Google search bar, conditions such as cystic fibrosis, sickle cell disease, and inherently emotive; they do not define Tay-Sachs disease appear. Tay-Sachs is a fatal disease, with death clinical timelines, nor do they have typically occurring between ages two and four years.9 Cystic precise definitions. Instead, fibrosis is also fatal, with a life expectancy of approximately 30 years.10 Sickle cell disease is also life limiting, with an average such terms are often used within the lifespan of 50 years.11 field of human genome editing in an It is clear, however, that there is a discrepancy in the precise attempt to maximise public support for definition and prognosis of the term ‘deadly’, as evidenced by the vast variability in affected individuals’ life expectancy. If a technological developments, and to disease takes months to cause an individual’s death, it is deemed minimise opposition. fatal. If a disease takes half a century to cause death, it is also deemed fatal. This begs the question: how is a deadly genetic Today, the primary targets for eugenic practices are these disease defined, and why is this term so often, and so loosely, so-called ‘unwanted characteristics’ of disease and disability; used? society deems these attributes to be medical problems in need of a corrective, eugenic solution.5 The importance of oversight Until children are of age and acquire autonomy and It can be argued that using a single, general term, such as ‘fatal’, decision-making capacity, parents or guardians remain the sole might be beneficial for the human germline editing movement. medical decision makers. With ever-advancing technologies such For instance, research could be conducted and implemented as prenatal testing, which can detect foetal abnormalities in without ethical roadblocks. If there is no clear boundary or utero, we are faced with scenarios in which a mother may be definition when it comes to enforcing guidelines, and a broad stigmatised or deemed immoral for choosing to maintain a over-arching term is used instead, this leaves much room for pregnancy that will lead to the birth of a child with a disability, scientists to interpret guidelines for their own benefit. due to the negative connotations associated with the term.6 And Proponents of biomedical technology rarely acknowledge the yet, there are many reports from patients who feel strongly that, distributional inequities, ramifications, and lack of constraints if given the choice, they would not wish to change or ‘correct’ within their research proposals, and are thus afforded greater their existing medical condition or disability.7 freedom in their work.5 At present, there is a strong movement towards embracing In the absence of further clarification on the semantics of human disability, led primarily by those who are directly affected, for genome editing, scientists would have, arguably, too much example, individuals in the Deaf community (a capital “D” is freedom in choosing which embryos receive genetic therapy. This used to indicate reference to a group of people sharing a may make it difficult for individuals to challenge scientists for common language, whereas a lower case “d” is used to refer to providing genetic therapy, especially when said therapy targets a the medical condition of not hearing).8 disease that is universally deemed ‘fatal’. Many individuals who are Deaf view the acquisition of a Further ethical discussions must take place at the level of national

Page 92 | Volume 11: Number 1. 2018 RCSIsmjperspective

and international regulatory authorities as a sort of anticipatory If there is no clear boundary or governance; we cannot have stagnation in technological advancement in the near future due to a lack of dialogue in the definition when it comes to enforcing present time.12 guidelines, and a broad over-arching This will be especially relevant as new biomedical technologies term is used instead, this leaves much continue to arise. Currently, there is a promising new technology, the CRISPR/Cas9 system, which allows for fast and inexpensive room for scientists to interpret gene editing (as low as US $30).13,14 There has been a large guidelines for their own benefit. increase (from US $0 in 2010, to over US $80 million in 2014) in the US National Institute of Health’s funding for projects In 2012, researchers from the biotechnology firm Amgen set out involving this technology, which may be an indicator of further to reproduce 53 landmark studies in cancer research; only six advances to come.14 However, with any new technology comes were successful.17 Even when flawed research does not result in associated glitches, and CRISPR has been shown to have loss of life, it continues to use valuable resources and funding. ‘off-target’ effects.15 One lab engineered an inhaled virus to However, as scientists continually seek new discoveries, little of introduce the CRISPR technology into mice, to generate a model their time is devoted to verifying results from existing studies, to for human lung cancer.16 ensure safety and reproducibility.18 This technique was shocking to many individuals, as a simple Accordingly, it is the public’s duty to remain diligent and oversight could have resulted in this technology having continue to challenge scientists when new technological dangerous effects on humans. In order to address bioethical advancements arise; we must hold medical researchers concerns raised by these potentially harmful adverse events, accountable to the highest ethical standard. Intellectual honesty various culturing strategies and chemical techniques have been thus necessitates the use of descriptively accurate terms that implemented to improve the safety and efficiency of CRISPR, in clarify relevant ethical issues, to ensure that they may be hopes of continuing to develop and implement this technology addressed head on.19 One example of such oversight is provided for genome editing.16,17 by bioethics committees, which aim to monitor progressions in It is imperative to anticipate the risks involved with such study the life sciences field and supervise their application, in order to designs; alongside rapid scientific developments, there ought to ensure respect for human dignity and freedom.20 The scope of be parallel discussions and advancements within the ethical such committees has expanded in the last few years to include sphere, to ensure safe, compatible progression in the field of areas of public opinion, policy making, and medical genomic editing. decision-making.21

Volume 11: Number 1. 2018 | Page 93 RCSIsmjperspective

Bioethics committees have the unique, vital responsibility to ask Conclusion tough questions, challenge scientists, and seek sensible, Words such as deadly and disability are inherently emotive; they equitable, and safe policies. do not define clinical timelines, nor do they have precise Accordingly, they must take the lead in navigating the semantics definitions. Instead, such terms are often used within the field of of eugenics, by facilitating open, informed dialogues regarding human genome editing in an attempt to maximise public support genetic engineering. for technological developments, and to minimise opposition. Such discussions must also include members of the affected However, to ensure transparency, safety, and further progress communities (i.e., persons with disabilities), in order to ensure within the biomedical community, it is crucial that terms relating that such individuals are accurately represented and heard. This to disability, morbidity and mortality be accurately defined and would enable persons with disabilities to inform governmental universally understood, especially when it comes to the ethically decisions and influence biomedical policies.5 challenging cases of gene editing and eugenics.

References 1. Servick K. First U.S.-based group to edit human embryos brings practice 11. Sandhu MK, Cohen A. Aging in sickle cell disease: co-morbidities and new

closer to clinic. 2017. [Internet]. Available from: issues in management. Hemoglobin. 2015;39(4):221-4.

http://www.sciencemag.org/news/2017/08/first-us-based-group-edit-hum 12. Wolbring G, Diep L. The discussions around precision genetic engineering:

an-embryos-brings-practice-closer-clinic. role of and impact on disabled people. Laws. 2016;5(3):37.

2. Powell A. Seeing promise, and limits, in embryo edit. The Harvard Gazette. 13. Vassena R, Heindryckx B, Peco R, Pennings G, Raya A, Sermon K et al.

2017. Genome engineering through CRISPR/Cas9 technology in the human

3. National Academies of Sciences, Engineering and Medicine; National germline and pluripotent stem cells. Hum Reprod Update.

Academy of Medicine; National Academy of Science; Committee on 2016;22(4):411-9.

Human Gene Editing: Scientific Medical, and Ethical Considerations. 14. Ledford H. CRISPR, the disruptor. Nature. 2015;522(7554):20-4.

Human Genome Editing: Science, Ethics, and Governance. Washington 15. Miller JC, Tan S, Qiao G, Barlow KA, Wang J, Xia DF et al. A TALE nuclease

(DC): National Academies Press (US). 2017. architecture for efficient genome editing. Nat Biotechnol. 2011;29(2):143-8.

4. Sharrer GT. Personalized medicine: ethical aspects. Methods Mol Biol. 16. Maddalo D, Manchado E, Concepcion CP, Bonetti C, Vidigal JA, Han YC et

2017;1606:37-50. al. In vivo engineering of oncogenic chromosomal rearrangements with

5. Wolbring G. Where do we draw the line? Surviving eugenics in a the CRISPR/Cas9 system. Nature. 2014;516(7531):423-7.

technological world. Disability and the life course: global perspectives. 17. Problems with scientific research: How science goes wrong. The

2001:38-49. Economist. 2013. [Internet]. Available from:

6. Terzo S. Parents of unborn babies with disabilities often experience great https://www.economist.com/news/leaders/21588069-scientific-research-ha

pressure to abort. Live Action. 2013. [Internet]. Available from: s-changed-world-now-it-needs-change-itself-how-science-goes-wrong.

https://www.liveaction.org/news/parents-of-unborn-babies-with-disabilities 18. Kendall G. Why you should care about the rise of fake journals and the bad

-often-experience-great-pressure-to-abort/. science they publish. The Conversation. 2017. [Internet]. Available from:

7. Check Hayden E. Should you edit your children’s genes? Nature. http://theconversation.com/why-you-should-care-about-the-rise-of-fake-jou

2016;530(7591):402-5. rnals-and-the-bad-science-they-publish-72130.

8. Ringo A. Understanding Deafness: Not Everyone Wants to Be ‘Fixed’. The 19. Baylis F. Human nuclear genome transfer (so-called mitochondrial

Atlantic. 2013. [Internet]. Available from: replacement): clearing the underbrush. Bioethics. 2017;31(1):7-19.

https://www.theatlantic.com/health/archive/2013/08/understanding-deafn 20. International Bioethics Committee. United Nations Educational, Scientific

ess-not-everyone-wants-to-be-fixed/278527/. and Cultural Organisation. 2017. [Internet]. Available from:

9. Jalal K, Carter RL. Mortality incidence estimation using federal death http://www.unesco.org/new/en/social-and-human-sciences/themes/bioet

certificate and natality data with an application to Tay–Sachs disease. Biom hics/international-bioethics-committee/.

J. 2015;57(5):885-96. 21. World Health Organization. The Global Summit of National Bioethics

10. Fajac I, Wainwright CE. New treatments targeting the basic defects in Committees. 2017. [Internet]. Available from:

cystic fibrosis. Presse Med. 2017;46(6 Pt 2):e165-e175. http://www.who.int/ethics/partnerships/globalsummit/en/.

Page 94 | Volume 11: Number 1. 2018 RCSIsmjbook review

Fitting in Colin Thompson’s memoir on life with Asperger’s and depression has a lot to teach us all about empathy and what it’s like to feel ‘different’, says ALEXANDRA MITCHAM.

Fitting In Empathy Colin Thompson As the reader becomes familiar with Colin, they gain empathy for Hardcover: 232 pages the challenges he faces on a daily basis. Such empathy is a quality Publisher: Jessica Kingsley Publishers that should be adopted in those who strive to be not only a good Published: 2016 person, but a good doctor. Compassionate understanding of ISBN-13: 978-1785920462 patients’ hardships is essential to holistic care, and is a skill future physicians would benefit from gaining early. Fitting in. It’s an elusive and fruitless undertaking, that everyone Thompson describes: “They always say ‘Everyone is different’, which desires, and no one achieves. Add obscure fixations and difficulty isn’t true because most of the Them are all the same as each other picking up on the nuances of human conversation and body and the last thing they actually want is to be different. They all want language, and you have the recipe for a lifetime of ‘different’. to be exactly the same as each other, but with a bit more money. Fitting In is a memoir by Colin Thompson, which paints a And it’s because we are different that they have a problem with us. comprehensive picture of his ‘different’ life, both as a human being They cannot understand us and they cannot control or change us and a person with Asperger’s syndrome and depression. even though they keep trying…” Asperger’s sits on the an autism spectrum, and is defined by This proclamation is striking; perhaps we as future physicians should difficulty in social interaction, and repetitive behavioural patterns focus less on trying to help individuals with mental health problems and interests.1 This memoir is an in-depth, frenzied description of ‘fit in’, and more on working to encourage the rest of the world to Thompson’s ups and downs from childhood to adult life, ranging accept that each of us is different, and that, in itself, is common from pottery and divorce, to benzodiazepine addiction, and the ground. We should take note of our position of leadership in the discovery of Bob Dylan. healthcare setting, and use it as a means to destigmatise mental health so that fewer people are burdened with feeling like eternal No filter outliers. It is human to fear what we do not understand, but This book successfully serves as a lens through which the reader can medical professionals are in a position to help others understand envision the world from the perspective of someone with and accept. We have a duty to advocate for the mental well-being Asperger’s; it allows us to see the invisible. The reader witnesses of patients and colleagues alike. Colin Thompson’s memoir is an Thompson’s thought processes, reasoning, and reflections on his life outstanding depiction of what going through life ‘different’ entails, experiences. He describes his life with a level of candour and and provides a moving perspective on how we can appreciate such sarcasm that is both hilarious and respectable. He volunteers his differences in a way that makes each person feel they belong, just as life’s trials and tribulations without filter; the reader quickly comes to much as the next person. appreciate his blunt retellings of circumstances most others would omit to save face. Thompson gives a voice to his internal struggle, Reference going through the motions of growing up (“When I was a child, I 1. National Institute of Mental Health. Autism Spectrum Disorder. 2015. fitted in perfectly. Then I got bigger, but the box stayed the same [Internet]. Available from: size.”) This feeling speaks to the ignorant bliss that fades in the face https://www.nimh.nih.gov/health/publications/autism-spectrum-disorder/ of the complex and often disheartening awareness of life’s realities qf-15-5511_152236.pdf. as we grow older. For the author, this transition was further complicated by mental illness.

Volume 11: Number 1. 2018 | Page 95 RCSIsmjabstract

Investigating the impact of enhancer methylation on gene expression in metastatic colorectal cancer

Joshua Ramjohn

Camille Hurley

Ian Miller

Annette Byrne

Darran O’Connor

Sudipto Das

Royal College of Surgeons in Ireland

Introduction DNA methylation has a suggested role in regulating genes Animal model-derived tumours were treated with FOLFOX, Avastin, or involved in the development of metastatic colorectal cancer combination (FOLFOX + Avastin); this was followed by quantitative (mCRC). polymerase chain reaction (qPCR) to estimate CCAT1 and FOXD2 However, the impact of enhancer methylation on gene expression mRNA levels, compared to control. In a second experiment, the remains to be elucidated. This study aimed to ascertain the gene tumours were treated with 5-aza-2’-deoxycytidine (5-aza), a DNA expression levels of two potentially enhancer-regulated genes: demethylating agent, followed by qPCR to determine CCAT1 and colon cancer associated transcript 1 (CCAT1)1 and forkhead box FOXD2 expression levels. D2 (FOXD2),2 in both in vitro and in vivo models developed using CRC cell lines. Results Endogenous mRNA levels of FOXD2 and CCAT1 were significantly Methods lower in SW620 compared to SW480 cell lines (Figure 1). An Complementary DNA (cDNA) synthesis was performed using RNA increase in FOXD2 and CCAT1 mRNA levels was observed in both extracted from two CRC cell lines: SW480 (primary cell lines following 5-aza treatment (Figure 2), suggesting DNA tumour-derived: Dukes’ type B colorectal adenocarcinoma); and, hypermethylation as a potential regulatory mechanism for these SW620 (metastasis-derived: Dukes’ type C colorectal genes in CRC cell lines. In orthotopic mouse models developed adenocarcinoma), grown in vitro and used to generate in vivo using SW620 cells, mRNA levels were higher for FOXD2 and lower mouse models. for CCAT1 in tumours treated with FOLFOX, Avastin, and combination, compared to vehicle (dimethylsulfoxide) (Figures 3 Further studies, such as targeted bisulfite and 4). sequencing and in vitro and in vivo This suggests that FOXD2 and CCAT1 may serve as a tumour suppressor gene (increased in chemotherapeutically treated cells) assays, would help to determine and a tumour oncogene (decreased in chemotherapeutically the therapeutic potential of targeting treated cells), respectively, in mCRC. For the SW480 orthotopic methylation-sensitive genes in counterpart, mRNA levels were higher for both genes in FOLFOX-, mCRC treatment. Avastin-, and combination-treated tumours, compared to vehicle (Figures 3 and 4).

Page 96 | Volume 11: Number 1. 2018 RCSIsmjabstract

Endogenous mRNA levels of CCAT1 and FOXD2 are mRNA levels of CCAT1 and FOXD2 are increased in 5-aza higher in the SW480 cell lines compared to the SW620 cell lines (n=3) treated SW480 and SW620 cell lines compared to vehicle (n=3) * p=0.0141 * p=0.0250 40 35 ** p=0.0088 35

30 30

25 CCAT1 25 SW480 FOXD2 SW620 20 20 15

15 Fold expression p<0.05 * p<0.05 *

Fold Fold expression 10 10 p<0.001** p<0.001** p<0.0001 *** 5 p<0.0001 *** 5 0 0 SW480 SW620 Untreated Vehicle Untreated Vehicle 5-aza treated 5-aza treated SW480 SW620

FIGURE 1: Endogenous mRNA levels of CCAT1 and FOXD2. FIGURE 2: mRNA levels of CCAT1 and FOXD2 in 5-aza-treated SW480 and SW620 cell lines.

mRNA levels of CCAT1 are lower in treated SW620 orthotopic xenograft mRNA levels of FOXD2 are in treated SW480 and cell lines compared to vehicle and higher in treated SW480 orthotopic SW620 orthotopic xenograft cell lines compared to vehicle xenograft cell lines compared to vehicle

** p=0.0028 * p=0.0287 10 * p=0.0449 125

8 100 SW480 SW480 SW620 SW620 6 75

4 p<0.05 * 50 p<0.05 * p<0.001** p<0.001** Fold Fold expression Fold Fold expression p<0.0001 *** p<0.0001 *** 2 25

0 0

Avastin Folfox Vehicle Avastin Folfox Vehicle Combination Combination

FIGURE 3: mRNA levels of CCAT1 in SW480 and SW620 orthotopic FIGURE 4: mRNA levels of FOXD2 in SW480 and SW620 orthotopic mouse models. mouse models.

Discussion References We suggest that CCAT1 and FOXD2 mRNA levels are potentially 1. McCleland ML, Mesh K, Lorenzana E, Chopra VS, Segal E, Watanabe C et al. influenced by DNA methylation alterations within the associated CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in enhancers. colorectal cancer. J Clin Invest. 2016;126(2);639-52. Further studies, such as targeted bisulfite sequencing and in vitro 2. Conesa-Zamora P, García-Solano J, del Carmen Turpin M, Sebastián-León P, and in vivo assays, would help to determine the therapeutic Torres-Moreno D, Estrado E et al. Methylome profiling reveals functions and potential of targeting methylation-sensitive genes in mCRC genes which are differentially methylated in serrated compared to treatment. conventional colorectal carcinoma. Clin Epigenetics. 2015;7:101.

Volume 11: Number 1. 2018 | Page 97 RCSIsmjabstract

Implications of stroke for informal caregivers: a five-year follow-up

Orla Conway1

Prof. Anne Hickey2

1RCSI medical student

2Department of Psychology, RCSI

Introduction cognitive impairment five years post stroke. Some 50% of caregivers of Informal caregivers are fundamental in the aftercare of stroke survivors. stroke patients with evidence of cognitive decline were categorised as In one study, it was found that informal caregivers are present in up to anxious according to HADS-A scores of 8+ (n=9), compared to 8.9% 20% of households for different reasons, including stroke.1 Unfortunately (n=4) of carers of patients without evidence of cognitive decline. This they can experience anxiety and depressive symptoms due to the strain difference is statistically significant [p=0.001, OR (95% CI): 10.250 of caregiving.2 This study’s aim was to explore the link between cognitive (2.576, 40.792)], indicating potential evidence linking cognitive decline impairment in stroke survivors and anxious or depressive symptoms in and psychological well-being of carers. Due to our small sample size we caregivers, five years post stroke. were unable to draw definitive conclusions about the effects of caregiving on the psychological well-being of caregivers of stroke Methods survivors. This was a five-year follow-up of the Action on Rehabilitation and Secondary Prevention Interventions in Stroke cohort of stroke patients Conclusion and their carers. The original study assessed 256 stroke patients and their These results indicate that not only stroke survivors, but also caregivers, 162 caregivers six months post stroke.3 Data collection for this follow-up suffer as a result of a stroke. This suggests a need for more formal care is ongoing; at the time of writing, 71 carers had completed the carer for patients, to prevent such effects on the psychological well-being of questionnaire. This was posted to caregivers of the stroke patients caregivers. identified in the original study between October 2011 and September 2012 from three large hospitals in the north Dublin area. Consent was References obtained from the next of kin in patients unable to provide consent.4 1. Schofield HL, Herrman HE, Bloch S, Howe A, Singh B. A profile of Australian This postal questionnaire included the anxiety subscale of the Hospital family caregivers: diversity of roles and circumstances. Aust N Z J Public Anxiety and Depression Scale (HADS-A), the Center for Epidemiologic Health. 1997;21:59-66. Studies Depression Scale (CES-D), and the Informant Questionnaire on 2. Greenwald & Associates for the National Alliance of Caregiving (NAC) and the Cognitive Decline in the Elderly (IQCODE).5 AARP Public Policy Institute. Caregiving in the US. 2018. [Internet]. Available from: Cognitive decline was defined as an IQCODE score of 3.4 or higher. http://www.caregiving.org/wp-content/uploads/2015/05/2015_Caregivingint HADS-A scores of 8+ and CES-D scores of 16+ were considered indicative heUS_Executive-Summary-June-4_WEB.pdf. of anxiety and depressive symptoms, respectively. Fisher’s exact test was 3. Atteih S, Mellon L, Hall P, Brewer L, Horgan F, Williams D et al. Implications of used to investigate associations between cognitive decline in stroke stroke for caregiver outcomes: findings from the ASPIRE-S study. Int J Stroke. patients and anxiety or depressive symptoms in caregivers. Results are 2015;10(6):918-23. presented below as odds ratios (ORs) and 95% confidence intervals 4. Mellon L, Brewer L, Hall P, Horgan F, Williams D, Hickey A. Cognitive (CIs). Statistical significance was set at p<0.05. impairment six months after ischaemic stroke: a profile from the ASPIRE-S

study. BMC Neurol. 2015;15:31. Results 5. Rohde D, Williams D, Gaynor E, Bennett K, Dolan E, Callaly E et al. Secondary We identified substantial levels of depressive symptoms in informal prevention and cognitive function after stroke: a study protocol for a 5-year caregivers. This is shown by the CES-D results, where 22.5% of carers follow-up of the ASPIRE-S cohort. BMJ Open. 2017;7(3):e014819. exhibited these symptoms. Similarly, 27.9% of our sample of stroke survivors scored above 3.3 on the IQCODE, indicating significant

Page 98 | Volume 11: Number 1. 2018

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

www.rcsismj.com. Th!nkMedia