RCSIsmj2016 by RCSIsmj

Inside: The artificial womb: bridging the gap between embryo culture and the incubator

RCSI

Watch this space: bringing medicine beyond Earthâ&#x20AC;&#x2122;s boundaries

Volume 9: Number 1. 2016 ISSN 2009-0838

smj Royal College of Surgeons in Ireland Student Medical Journal

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 Professor 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, Professor 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: Doctor Mark Murphy Doctor Afif El-Khuffash Professor Kieran Murphy Professor Seamus Sreenan Professor Noel G. McElvaney Professor Arnold Hill Professor Fergal Malone

RCSIsmjcontents Royal College of Surgeons in Ireland Student Medical Journal Executive Committee Director Editor-in-Chief Peer Review Director Senior Editor Assistant Peer Review Director Senior Staff Writer

Natalie Achamallah Mohit Butaney Ian Elliott Jenna Geers Corey Nixon Daniel O’Reilly

Staff Writers Samar Atteih Vincent Healy Naomi O’Sullivan Stephanie Tung Peer Review Team Anu Ananth Lindsay Cheskes Carling Cheung Alice Fox Elise Halpern Alex Kasman David Maj Maria Mikail Andrew Mikhail Simraaj Powar Sarah Pradhan Fiona Rawat Lorna Sampson Dexter Seow Renuka Sitram Sunny Vig Zac Wikerd Matt Wong Executive Secretary Simran Ohson Education Director Stephen Tsoukas Education Officers Ruth Carey Katie Dunleavy Public Relations Monika Cieslak Hayley Spurr Tessa Weinberg Webmaster Gemma Ballester

Editorial

Director’s welcome

RCSI Ethics Challenge 5

RCSIsmj Ethics Challenge 2016/2017

RCSIsmj Ethics Challenge winner 2015/2016

Case reports 10

A rare case of post-gastric bypass hypoglycaemia

Kicking up a cytokine storm: an unusual presentation of Castleman's disease

Toxic shock syndrome complicated by necrotising fasciitis: back to basics

A missed coarctation

Original articles 27

Exploring the views of healthcare professionals on increasing smoking cessation advice for patients

An investigation of responsiveness to PI3K inhibition in breast cancer cells expressing high levels of androgen receptor

Review articles 39

Epidemiological evaluation of rotavirus burden and potential impact of vaccination in Uganda

The history, mystery, and management of fibromyalgia

The road to the gold standard: whole genome sequencing in the clinic

Staff reviews 57

Continuous glucose monitoring: a sweet deal for paediatric type 1 diabetics

I eat, therefore I am: the gut–brain axis and appetite control

The artificial womb: bridging the gap between embryo culture and the incubator

Antibiotics in the 21st century: a fight against a familiar foe

Watch this space: bringing medicine beyond Earth's boundaries

Perspectives 85

Sharing and caring? Open access vs closed doors

Empathy is the new black

A global responsibility

The future of surgery or a robotic waste of money?

A future for anaesthesia?

100

The blunt truth: can marijuana fund better healthcare?

Interview 104

Senior staff writer Daniel O'Reilly interviews Dr Michael Webb, Medical Director of Ulster Rugby

Travel briefs 106

Nepal: a country shaken

107

Fostering hope

108

The mass approach

JOURNALISM CONTENT DESIGN

The Malthouse, 537 NCR, Dublin 1. T: 01-856 1166 F: 01-856 1169 www.thinkmedia.ie Design: Tony Byrne, Tom Cullen, Ruth O’Sullivan and Niamh Short Editorial: Ann-Marie Hardiman, Paul O’Grady and Colm Quinn

Book reviews 109

Do No Harm: Stories of Life, Death and Brain Surgery by Henry Marsh and When the Air Hits Your Brain: Tales from Neurosurgery by Frank Vertosick Jr.

Abstracts 110

Oestrogen receptor gene mutations in endocrine-resistant breast cancer

Please email comments to editorsmj@rcsi.ie, join our Facebook page, or follow us on Twitter @RCSIsmj to discuss journal articles. Submissions to submissionssmj@rcsi.ie Volume 9: Number 1. 2016 | Page 3

RCSIsmjeditorial and director’s welcome Medicine: science or art? As we wade through electronic journals, PowerPoint presentations, and modern mobile applications in the course of our medical education, the increased influence of modern science and technology makes it all too easy to think of medicine as a pure science. In this issue of the RCSIsmj, Vincent Healy’s review of the quest to build an ‘artificial womb’ and Jenna Geers’ discussion of incorporating whole genomic sequencing in the clinic exemplify how modern technology and science have changed the face of medicine. Reviews of relatively well-studied topics such as fibromyalgia by Ghaleb Halaseh, diabetes by Samar Atteih, and antibiotics by Stephanie Tung highlight how our approach to diseases that are well understood continues to be moulded as our knowledge grows. In addition to discussing advances in science, in this issue we also reflect the other side – that is, the art – of medicine. Travel briefs by Luke Gin and Amenah Dhanoon illustrate the true essence of medicine in nations dealing with difficult situations (such as Nepal and Syria, respectively), while Danielle Wuebbolt’s visit to Shanghai demonstrates how culture affects medicine. Jessica Suddaby examines the challenges and opportunities facing refugee and migrant healthcare in Europe, Katie Dunleavy et al. discuss the rotavirus burden and impact of vaccination in Uganda, and Naomi O’Sullivan takes us beyond our shrinking world to discuss medicine in space! The concepts of medicine as an art and science collide as Amelia Reid explores changing attitudes to communication, Michael

Bravo argues for ‘sharing and caring’ in the world of scientific and medical literature, and Deirdre Harford, in her prize winning essay, deliberates on the ethics associated with the use of untested drugs in the treatment of the Ebola virus. Apart from reflecting how the world continues to evolve, they also serve as a reminder that humanity and the art of medicine are still very much alive and well, and not merely romantic rhetoric. There is something to learn from every patient and every moment in medicine, and (we hope) in every page of this Journal. The pieces within exemplify the need to constantly evaluate our actions and motivations, particularly in how we balance science and art. Though our world continues to evolve, and science continues to advance, medicine desperately requires both and has since the time of Hippocrates. After all, “wherever the art of medicine is loved, there is also a love of humanity.”

Mohit Butaney Editor-in-Chief, RCSIsmj 2015-2016

Director’s welcome “If we knew what it was we were doing, it would not be called research, would it?” Attributed to Albert Einstein I am delighted to welcome you to the ninth edition of the RCSIsmj. This year we received an unprecedented number of fabulous submissions from the RCSI student body, and as a result were able to fill a larger issue than ever before with high-quality pieces. I am confident that you will enjoy their work and learn a great deal from it. Our training has deeply instilled in us the concept of evidence-based decision-making, and we are introduced to research as an educational tool from the very beginning of medical school. Still, participation in the ‘publish or perish’ world of medical research can be extremely daunting for young scientists. The RCSIsmj aims to ease students at all levels of their training into the research and publication process in a collaborative, collegial environment. The result is the Journal you hold in your hands, but also (we hope) the initiation of several early physician-scientist careers. The RCSIsmj is a student-run organisation; all of the content published within is written, reviewed, selected, and edited by students, and our journal clubs are organised and presented by Page 4 | Volume 9: Number 1. 2016

students for discussion with our peers. We are extraordinarily grateful for the support and assistance we receive from the Dean’s office in the RCSI, and from the faculty who take time out of their busy schedules to participate in journal activities. This publication would not be possible without any of them. Though my involvement with the RCSIsmj has come to an end, I am excited to watch the Journal continue to grow and evolve under the guidance of the next generations of students. I hope that through their involvement they find, as I have, the confidence to dive head first into the challenging and rewarding world of medical research.

Natalie Achamallah Director, RCSIsmj 2015-2016

RCSIsmjprize

Ethics Challenge 2016/2017 GENE EDITING Gene editing allows sections of DNA from a genome to be precisely replaced or removed using ‘molecular scissors’. Techniques such as CRISPR-Cas9 can modify genomes of living organisms at precise locations in more specific and more cost-effective ways than were previously possible.1 In the future, these tools also hold the potential to be applied clinically to prevent or treat lethal and/or seriously debilitating genetic diseases. Gene editing of somatic cells is currently in clinical development for a variety of conditions, including HIV and leukaemia.2 Human germline editing, which involves altering genes in sperm, eggs or embryos, holds the possibility of not only correcting genes that cause disease, but also of passing those genetic fixes on to future generations. In April 2015, researchers in China announced that they had attempted to use CRISPR-Cas9 to edit non-viable human embryos with a debilitating disease. The experiment was partially successful, but the team concluded that there are still hurdles to overcome before CRISPR is safe for clinical use.3 The announcement was welcomed by some in the scientific community as a major step forward in eradicating debilitating human disease. Although these embryos were non-viable – they could not result in a pregnancy – a public outcry

arose that the scientists had taken an alarming step towards the creation of ‘designer babies’.4 Then, in February 2016, the Human Fertilisation and Embryo Authority (HFEA) in the United Kingdom approved an application from Dr Kathy Niakan of the Francis Crick Institute to renew her laboratory’s research licence to include gene editing of embryos. In its approval, the HFEA stated that no research using gene editing could take place without research ethics approval, and that it is illegal to transfer any embryo used in research to a woman for treatment.5 Around the world, laws and guidelines vary widely about whether germline, or hereditary, research is allowed. Some ban any research; some allow only lab research but not pregnancies; and, some have no policies.

Questions 1. Should a temporary or permanent global ban on human germline editing be introduced and, if so, on what basis? 2. Is there an ethical difference between using gene editing for the avoidance of severe inherited diseases or for ‘enhancement’ of human capabilities?

References 1. Ledford H. CRISPR, the disruptor. Nature. 2015;522(7554):20-4. 2. Tebas P et al. Gene editing of CCR5 in autologous CD4 T cells of persons infected with HIV. N Engl J Med. 2014;370(10):901-10. 3. Liang P et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6(5):363-72.

4. Lanphier E et al. Don’t edit the human germ line. Nature. 2015;519(7544):410-11. 5. Park A. UK approves first studies of new gene editing technique CRISPR on human embryos. [Internet] Available from: http://time.com/4200695/ crispr-new-gene-editing-on-human-embryos-approved/.

This is the eighth instalment of the RCSIsmj Ethics Challenge. The editorial staff would like to congratulate Deirdre Harford on her winning essay in the 2015/2016 Ethics Challenge. Please see page 6 for her submission. We invite students to submit an essay discussing the ethical questions raised in the scenario presented. Medical ethics is an essential aspect of the medical curriculum and we hope to encourage RCSI students to think critically about ethical situations that arise during their education and subsequent careers. All essays will be reviewed by a faculty panel of experts and the winning essay will be published in the 2017 print edition of the RCSIsmj. The deadline for submission of entries will be the same as the general submission deadline for the 2017 edition of the RCSIsmj. Please visit our website at www.rcsismj.com for specific dates. Please contact us at editorsmj@rcsi.ie with any questions or concerns.

Submission guidelines Please construct a lucid, structured and well-presented discourse for the issues raised by this scenario. Please ensure that you have addressed all the questions highlighted and discuss these ethical issues academically, making sure to reference when necessary. Your paper should not exceed 2,000 words. Your essay will be evaluated on three major criteria: 1. Ability to identify the ethical issues raised. 2. Fluency of your arguments. 3. Academic quality with regard to depth of research, appropriateness of references and quality of sources. Good luck! The winning entry will be presented with a prize at the launch of the next issue.

Volume 9: Number 1. 2016 | Page 5

RCSIsmjethics challenge ETHICS CHALLENGE WINNER 2015/2016

The use of untested drugs in the treatment of the Ebola virus

Deirdre Harford RCSI medical student

Introduction

Providing Ebola patients with an untested drug

The 2015/2016 RCSIsmj Ethics Challenge presents the dilemma surrounding Ebola treatments and their distribution.1 Mapp Biopharmaceuticals, an American pharmaceutical company, has developed a number of promising but untested vaccines for treatment of the virus.2 With rising incidence and high mortality rates, the WHO decided to back the use of ZMapp, an untested Ebola intervention, in humans.3 Faced with this multi-faceted outbreak, we find ourselves placing under the microscope our principles with regard to clinical trials, intervention availability and duty of care beliefs. Further ethical questions arose following news that American missionaries who became infected while providing care to Ebola patients4 received ZMapp treatment and subsequently recovered, having been selected over Africans to receive the treatment.1 This article aims to examine the ethical grounds for providing patients with an untested drug for diseases such as Ebola, and the distribution, prioritisation and criteria for deciding the recipients of said treatment.

“Never mind that they haven’t been tested for safety. Believe me, I’d run for the freezer and ask for forgiveness instead of permission.”5 Erica Ollmann Saphire, Scripps Research Institute, San Diego.

Page 6 | Volume 9: Number 1. 2016

In the face of a crisis of this scale, parameters of right and wrong became less well defined and the magnitude of the disaster forced healthcare professionals to re-evaluate previously held values and principles. Traditionally, medical practice hangs on the four ethical principles from the work of Beauchamp and Childress, who believed that it is “legitimate and rewarding” to apply general ethical principles to medicine.6 This framework sets out the following: Beneficence: providing benefits and balancing them with risks High mortality rates, as high as 70%, fuelled the WHO’s decision to offer untested drugs,3 as conventional care failed to produce acceptable clinical outcomes.7,8

RCSIsmjethics challenge As with all communicable diseases, containment is of the utmost importance, and therefore co-operation with health authorities, for instance regarding sanitation laws such as burial practices,9-11 is a top priority. Decisions about experimental treatments may damage the trust placed in a system and thereby jeopardise such protocols,10 should the experimental treatments prove to be harmful or of no benefit. However, some argue that on a public level, distribution of an experimental drug through a “transparent and equitable process” may rebuild and fortify the trust placed in health systems.12 It is also true that in return for any form of compliance or trust on the patient’s side, they expect the provision of respectable standards of care.13 Writing for the Journal of Medical Ethics, Angus Dawson described the use of ZMmapp as clearly following “directly from a physician’s general duty to do what is best for their patients, which is already explicitly endorsed by the Helsinki Declaration”.14,15 Respect for autonomy: respecting the capacity of autonomous persons to make decisions Ethical medicine recognises that a patient’s ability to think and act independently is what facilitates all other morals in life, and is therefore prioritised.16 It is questionable how informed a generally disadvantaged population – particularly with regard to education – can be about Ebola treatments. Indeed, one of the most contentious issues surrounding the Ebola outbreak is its geographical location. Many of the organisations tackling the outbreak believe that bringing an untested drug into a population that is already distrustful of the teams providing help is unfeasible.5 In their report, the WHO recommended that the limited supply of ZMapp should generate as much data as possible, with a moral obligation being placed on the collection and free distribution of this data.17 In other words, as close as is possible to a clinical trial should be conducted given the circumstances. To fulfil these criteria while respecting autonomy, clear explanations of these trials and informed consent from patients is vital.17 This outbreak has highlighted the need for trust, and for public understanding of treatment evaluation, and the necessity of conducting ethical research and subsequent interventions under crisis conditions.18 Non-maleficence: avoiding causation of harm Our duty of primum non nocere is in jeopardy when we experiment with untested drugs on patients,19 which is bad practice under usual circumstances. This potential harm not only threatens the patient, but also wider society.18 The consequences of unprecedented harm from use of an untested drug could jeopardise both the outbreak response (as the trust of patients and the public is lost) and efforts to develop future treatments.18 However, the lack of a definitive treatment equates to a limited incentive to present for medical help,20 which causes harm to patients who may nevertheless benefit from supportive care.

Many of the organisations tackling the outbreak believe that bringing an untested drug into a population that is already distrustful of the teams providing help is unfeasible. Justice: fairly distributing risks and benefits In the midst of an outbreak such as Ebola, there is still an obligation to ensure that all societies benefit equally. The development of stable, functional health systems offering a respectable level of care ensures that all communities obtain fair benefits from research during this epidemic, regardless of where this research is carried out.21 Offering an untested drug, under as close to clinical trial conditions as possible, challenges this principle. In order for clinical research to be ethical, it requires equipoise – a state of genuine uncertainty regarding comparative therapeutic merits. However, if it becomes known that one treatment is of superior therapeutic merit (with conventional care proving to be of little benefit), there is an ethical obligation to offer the superior treatment.22 ZMapp is considered a more acceptable treatment than whole-blood transfusions from convalescent survivors.20 While ZMapp has not as yet proven superior therapeutic merit, one would be acting ethically to offer ZMapp as soon as such a conclusion could be drawn. If an untested drug were solely used in the seriously ill, it might become more difficult to identify severe side effects associated with the drug.18 It has been argued that the experience in the first two people treated with ZMapp eliminated the possibility of a universally severe adverse response; however, as medics struggle to satisfy the principle of justice, one approach to investigating promising drugs for patients with Ebola would be to allow limited emergency use alongside studies in healthy volunteers to satisfy concerns about toxicity and adverse events. Under these circumstances, the provision of this untested drug is not unreasonable.18

Is it ethical to give an untested drug to healthcare professionals first? Perhaps the most controversial aspect of the current Ebola outbreak is the fact that the treatment, albeit untested, was first offered to white, western healthcare workers.1,23 A case in Germany in 2009 saw a researcher become exposed to Ebola following a needlestick injury.5 She remained asymptomatic after receiving immediate medical attention, with the vesicular stomatitis virus (VSV) vaccine rushed to Hamburg for her treatment. Whether the vaccine worked cannot be determined,5 as it is impossible to know whether she would have become infected otherwise. Such a response would not have been feasible in a developing country, demonstrating the inequitable risk distribution among healthcare workers and the general Ebola-affected population. Volume 9: Number 1. 2016 | Page 7

RCSIsmjethics challenge Reciprocity and consequentialism The ZMapp debate draws upon many complex arguments as to why we treat first responders first. It is often argued that as health professionals place themselves in harm’s way to care for patients, and could help more once recovered, we have a duty of care to them.21,24,25 The present Ebola outbreak is occurring in three of the world’s poorest countries, with not only the lowest per capita gross national incomes, but also extremely low physician ratios: fewer than 0.1 physician per 10,000 persons.26 Therefore, many draw on the principles of reciprocity (receiving help from others, having provided help for others) and consequentialism (the consequences of actions provide the basis for their judgement) to justify the prioritisation of healthcare workers.21 In contrast, some believe that good medical ethics needs to focus on public health and societal perspectives, instead of allowing individualistic values to dominate the Ebola discussion.14 However, it is widely accepted that healthcare workers are financially comfortable and well connected within the medical field.21 Their prioritisation may be seen as a source of tension as we preferentially treat the privileged. This is an especially contentious issue when one considers those who provide care without being health professionals.21

Populations who are terrified by Ebola, and who lack trust in healthcare workers and public authorities following civil wars, cannot be assumed to have the capacity to provide informed consent. Informed consent Despite this, to repeat what was done in Germany in 2009 for hundreds of people at a time in African countries is virtually impossible,27 not least due to issues of informed consent.5 Populations who are terrified by Ebola, and who lack trust in healthcare workers and public authorities following civil wars, cannot be assumed to have the capacity to provide informed consent.7 Therefore, it could be considered unethical to offer an untested treatment to these people. When recipients are healthcare workers, whose ability to understand risks is presumably high, the decision to prioritise them seems more ethically correct.10 There is still an influential school of thought which holds that the drug should be given on a first-come, first-served basis.12 According to this approach, prioritising access to experimental drugs in certain populations (healthcare workers) or countries (Western Hemisphere) promotes inequitable access to resources and is therefore unacceptable. In prioritising certain groups, we arguably negate the principles of distributive and social justice, which we previously achieved. This is of particular concern in places where human rights violations frequently occur, such as those countries affected by Ebola.12 Page 8 | Volume 9: Number 1. 2016

What ethical criteria should be used to decide which healthcare professionals receive the drug? If one accepts that the limited, untested treatment should be offered to healthcare workers exclusively, another aspect of the Ebola ethics dilemma unfolds. The WHO report sets out criteria regarding which healthcare professionals should receive the limited ZMapp supplies. Such guidelines include transparency about all aspects of care – informed consent, freedom of choice, confidentiality, respect for the person, preservation of dignity and involvement of the community.17 Nearly all of these guidelines focus on individualistic considerations.14 Indeed, one could consider the focus on autonomy of the patient inappropriate for those victims of Ebola who have limited capacity to provide consent.14 Arguably, one should prioritise those who can debate the risks and benefits of treatment and provide the most informed consent. The criteria provided also failed to address the ethical objectives of promoting patient benefits and protecting patients from harm.14 Perhaps those who are most likely to make a recovery should receive the drug.

Ethical Ebola research If the use of ZMapp is limited to healthcare workers, expansion of its use without additional testing would be irresponsible.21 Moreover, it would be careless to use the small amount of experimental interventions possible without any collection of systematic data about its drug profile.21 Given this social backdrop, it is ethical for the treatment to be provided to those from whom we can generate the most data efficiently and under the safest experimental conditions. When untested drugs such as ZMapp are used in this Ebola emergency, it is important that research ethics are upheld to avoid exploitation of affected individuals and communities. The eight ethical principles for research as outlined by Emanuel et al. must be met to facilitate supply of the drug:21 ■ informed consent; ■ collaborative partnership; ■ social value; ■ scientific validity; ■ fair selection of study population; ■ favourable risk–benefit ratio; ■ independent review; and, ■ respect for recruited participants and study communities.

Any discussion regarding possible treatment programmes highlights that the identification of target groups may require improved viral transmission surveillance systems and a better understanding of Ebola transmission.28

RCSIsmjethics challenge Conclusion Despite there being compelling arguments for the immediate and widespread use of ZMapp in times of global crises, closer inspection of the situation indicates that this would be not only unfeasible but unethical. Any global epidemic with a 70% mortality rate7 poses momentous problems, but these were exacerbated further by the geographical and cultural setting of this virus. It would be reasonable to conclude that, given the

circumstances of this illness, an untested drug may be ethically employed for compassionate use in conjunction with other trials.18 As soon as a proven treatment (such as ZMapp if proven efficacious), becomes available, global expansion of the treatment group is morally imperative. Regardless, the controversy surrounding the prioritisation of white healthcare workers and accessing Ebola interventions continues.

References 1. RCSIsmj Editors. Ethics Challenge 2015/2016. Royal College of Surgeons in Ireland Student Medical Journal. 2015;8(1):5. 2. McCarthy M. US signs contract with ZMapp maker to accelerate development of the Ebola drug. BMJ. 2014;349:g5488. 3. Kupferschmidt K. Using experimental drugs and vaccines against Ebola is ethical, WHO panel says. [Internet] Available from: http://news.sciencemag.org/africa/2014/08/using-experimentaldrugs-an d-vaccines-against-Ebola-ethical-who-panel-says. 4. Lyon GM, Mehta AK, Varkey JB, Brantly K, Plyler L, McElroy AK et al. Clinical care of two patients with Ebola virus disease in the United States. N Engl J Med. 2014;371(25):2402-9. 5. Enserink M. Infectious diseases. Ebola drugs still stuck in lab. Science. 2014;345(6195):364-5. 6. Beauchamp TL. Methods and principles in biomedical ethics. J Med Ethics. 2003;29(5):269-74. 7. Adebamowo C, Bah-Sow O, Binka F, Bruzzone R, Caplan A, Delfraissy JF et al. Randomised controlled trials for Ebola: practical and ethical issues. Lancet. 2014;384(9952):1423-4. 8. Gao J, Yin L. Drug development for controlling Ebola epidemic – a race against time. Drug Discov Ther. 2014;8(5):229-31. 9. Dixon MG, Schafer IJ, Centers for Disease Control and Prevention (CDC). Ebola viral disease outbreak – West Africa, 2014. MMWR Morb Mortal Wkly Rep. 2014;63(25):548-51. 10. Kass N. Ebola, ethics, and public health: what next? Ann Intern Med. 2014;161(10):744-5. 11. Hewlett BS, Amola RP. Cultural contexts of Ebola in northern Uganda. Emerg Infect Dis. 2003;9(10):1242-8. 12. Folayan M, Brown B, Yakubu A, Peterson K, Haire B. Compassionate use of experimental drugs in the Ebola outbreak. Lancet. 2014;384(9957):1843-4. 13. Haire BG, Folayan MO. Ebola: what it teaches us about medical ethics. A response to Angus Dawson. J Med Ethics. 2016;42(1):59-60. 14. Dawson AJ. Ebola: what it tells us about medical ethics. J Med Ethics. 2015;41(1):107-10. 15. World Medical Association. World Medical Association Declaration of Helsinki. Ethical principles for medical research involving human subjects. Bull World Health Organ. 2001;79(4):373-4. 16. Beauchamp TL, Childress JF. Principles of Biomedical Ethics. Oxford University Press, 2001.

17. World Health Organisation. Ethical considerations for use of unregistered interventions for Ebola virus disease (EVD). Summary of the panel discussion. [Internet] Available from: http://www.who.int/mediacentre/news/statements/2014/eb ola-ethical-review-summary/en/. 18. Goodman JL. Studying “secret serums” – toward safe, effective Ebola treatments. N Engl J Med. 2014;371(12):1086-9. 19. Omonzejele PF. Ethical challenges posed by the Ebola virus epidemic in West Africa. J Bioeth Inq. 2014;11(4):417-20. 20. Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB et al. Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature. 2014;514(7520):47-53. 21. Rid A, Emanuel EJ. Ethical considerations of experimental interventions in the Ebola outbreak. Lancet. 2014;384(9957):1896-9. 22. Freedman B. Equipoise and the ethics of clinical research. N Engl J Med. 1987;317(3):141-5. 23. Langreth R, Chen C, Nash J, Lauerman J. Ebola drug made from tobacco plant saves US aid workers. [Internet] 2014. Available from: http://www.bloomberg.com/news/articles/2014-08-05/ebola -drug-made-from-tobacco-plant-saves-u-s-aid-workers. 24. Weintraub K. Experimental Ebola therapies raise ethical questions. [Internet] Available from: http://www.usatoday.com/story/news/nation/2014/08/07/e bola-serum-et hical-issues/13731363/. 25. Yakubu A, Folayan MO, Sani-Gwarzo N, Nguku P, Peterson K, Brown B. The Ebola outbreak in Western Africa: ethical obligations for care. J Med Ethics. 2014:medethics-2014-102434 [Epub ahead ofprint]. 26. Fischer WA 2nd, Hynes NA, Perl TM. Protecting health care workers from Ebola: personal protective equipment is critical but is not enough. Ann Intern Med. 2014;161(10):753-4. 27. Shah SK, Wendler D, Danis M. Examining the ethics of clinical use of unproven interventions outside of clinical trials during the Ebola epidemic. Am J Bioeth. 2015;15(4):11-6. 28. Lee BY, Moss WJ, Privor-Dumm L, Constenla DO, Knoll MD, O’Brien KL. Is the world ready for an Ebola vaccine? Lancet. 2015;385(9964):203-4.

Volume 9: Number 1. 2016 | Page 9

RCSIsmjcase report A rare case of post-gastric bypass hypoglycaemia

Abstract A 46-year-old woman with a history of Roux-en-Y gastric bypass (RYGB) surgery in 2010 was referred to the hepatobiliary oncology clinic in the University of Colorado Hospital in May 2013 with frequent episodes of post-prandial hypoglycaemia with neurogenic and neuroglycopenic symptoms. Findings in her biochemical profile, a 72-hour fast, and a mixed meal test were all negative. Subsequent CT abdomen and endoscopic ultrasound did not identify pancreatic lesions. Interventional radiology (IR) hepatic venous sampling with calcium gluconate localised excess insulin production to the tail of the pancreas. Medical management with acarbose and octreotide was commenced, but due to progressive symptoms and life-threatening episodes of hypoglycaemia, the pancreas was surgically resected. Pathology failed to show neoplastic tissue; histology demonstrated mild hyperplasia and hypertrophy, although within normal limits. A diagnosis of nesidioblastosis – a rare disease that causes pancreatic hyperfunction in the absence of an insulinoma and with evidence of hyperplasia – was made. It is a leading cause of hyperinsulinaemic hypoglycaemia in childhood, but causes <5% of cases in adults. Although the exact pathogenesis is not understood, nesidioblastosis is increasingly recognised as a late complication of bariatric surgery, where it is termed “post-gastric bypass hypoglycaemia” to distinguish from other entities associated with nesidioblastosis.

Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:10-12.

Tayyaub Mansoor RCSI medical student

Page 10 | Volume 9: Number 1. 2016

Introduction

benign and 90% are solitary.2 Diagnostic

Patients experiencing episodes of hypoglycaemia

investigations include a 24-hour fast, 72-hour fast,

may experience a broad range of symptoms. These

and assay for insulin antibodies. C-peptide,

can be either neurogenic or neuroglycopenic (Table

proinsulin, and insulin levels can be measured to

1). The presence of hypoglycaemic symptoms, low

rule out factitious hypoglycaemia. Imaging includes

measured glucose levels, and relief of symptoms

CT abdomen and endoscopic ultrasound, with a

with glucose administration – Whipple’s triad –

combined sensitivity of >90%.3 An octreotide scan

suggests true hypoglycaemia and is a diagnostic

may show somatostatin receptor-positive tumours

hallmark for insulin-secreting tumours (insulinomas).

and interventional radiology (IR) hepatic venous

Differential diagnoses for true hypoglycaemia are

sampling with calcium gluconate localises regions of

categorised as endogenous or exogenous in origin

pancreatic hyperfunction. Surgical resection of the

(Table 2). The most common cause in non-diabetic

affected pancreas is the gold standard, with a cure

and otherwise healthy adults is an insulinoma, a rare

rate of 97.5%.4 Surgical options include enucleation,

tumour with an incidence of four cases per million

distal resection, total pancreatic resection and

person-years.1 Approximately 90% of these are

duodenopancreatectomy (Whipple’s procedure).

RCSIsmjcase report Case report

Outcome

A 46-year-old Caucasian woman with a history of Roux-en-Y gastric

In August 2015 the patient had her spleen and two-thirds of her

bypass (RYGB) surgery in 2010 was referred to the hepatobiliary oncology

pancreas removed. Pathological examination of pancreatic tissue ruled

clinic in the University of Colorado Hospital in May 2013 with frequent

out neoplasm and all sampled lymph nodes were negative. Hyperplasia

episodes of post-prandial hypoglycaemia accompanied by neurogenic

and hypertrophy in the pancreatic tissue were present but within normal

and neuroglycopenic symptoms. She reported sweating, tremors,

limits. She was discharged on day six postoperatively after an uneventful

palpitations, weakness, and dizziness, which came on approximately two

recovery and reported no further episodes of hypoglycaemia, with all

hours after consuming simple sugars. The episodes had increased in

measured glucose levels above 4.4mmol/l.

frequency, requiring several emergency department visits. She denied pain, changes in appetite, or weight loss, but reported eating more

Discussion

frequently to prevent episodes from occurring. Her past medical history

Nesidioblastosis is a rare disorder first described by George Laidlaw in

was significant for Graves’ disease, systemic lupus erythematosus,

19385 as neoformation of Langerhans islets in the pancreatic ductal

seizures, and asthma. Physical examination revealed no abnormalities.

epithelium. Initially observed in neonates and now recognised as the

Blood investigations including insulin, proinsulin, C-peptide, and

primary cause of hyperinsulinaemic hypoglycaemia in childhood,6 it is

sulfonylurea were all within normal limits, ruling out exogenous causes of

rare in adults and accounts for <5% of cases.7 RYGB surgery was first

hypoglycaemia. She was negative for insulin antibodies. Both 24- and

associated with adult onset nesidioblastosis in 2005; fewer than 100

72-hour fasts were conducted with negative results. Imaging with CT

cases of post-gastric bypass nesidioblastosis have been identified as of

with an α-glucosidase inhibitor (acarbose 25mg) and frequent

November 2014.8 Nesidioblastosis should be included as a differential

abdomen was unremarkable. The patient was managed conservatively

diagnosis in hyperinsulinaemic hypoglycaemia, with a negative 72-hour

low-carbohydrate meals, but intolerance of acarbose necessitated

fast and unremarkable findings on imaging.

replacement with a somatostatin analogue (octreotide 100mcg three

IR hepatic venous sampling with calcium stimulation test is a useful

times daily). She responded well initially, but by March 2014 her

investigation when other imaging modalities fail to localise a pancreatic

octreotide dose was increased to 200mcg three times daily and she was

lesion. The technique involves placing a catheter in the right hepatic

still experiencing weekly episodes of hypoglycaemia. She reported a

vein, and performing a pancreatic angiography via the femoral artery.

blood glucose of 1.44mmol/l with her latest episode, and had fallen on

Calcium gluconate is then injected into the selectively catheterised

several occasions due to weakness or loss of consciousness. An octreotide

gastroduodenal, proximal splenic, and superior mesenteric arteries.

scan failed to localise somatostatin receptor-positive tumour cells, but IR

Venous samples are collected at 0, 30, 60, and 120 seconds for each site.

hepatic venous sampling with calcium gluconate showed over a six-fold

Five minutes are allowed between each injection. A greater than

rise in insulin levels localised to the pancreatic tail. A CT abdomen and

two-fold rise in insulin levels within 30-120 seconds is recorded as a

endoscopic ultrasound in April and May 2015, respectively, were both

positive result in the distribution of the relevant artery.9 This technique

unremarkable. Hepatic venous sampling was repeated and confirmed

can thus indicate pancreatic hyperfunction and suggest either an

previous findings. It was then decided that due to the very low reported

insulinoma or (less commonly) nesidioblastosis, as well as guiding the

insulin levels with each episode, and the increasing risk of fall-related

surgical approach for resection.10

injury, the benefits of surgery outweighed the risks. The patient was

Nesidioblastosis is diagnosed based on the absence of an insulinoma and

scheduled for a distal pancreatectomy and splenectomy.

the presence of islet cell hyperplasia on histological examination. It is

Table 1: Symptoms of hypoglycaemia.

Table 2: Causes of hypoglycaemia in non-diabetic patients.

Neurogenic features

Neuroglycopenic features

• • • •

• • • • •

Sweating Palpitations Tremors Anxiety

Dizziness Double vision Blurry vision Weakness Coma

Endogenous

• Pancreatic β-cell tumour • Post-gastric bypass dumping syndrome • Noninsulinoma pancreatogenous hypoglycaemia (adult nesidioblastosis) • Post-gastric bypass hypoglycaemia (adult nesidioblastosis) • Autoimmune insulin syndrome

Exogenous • Factitious hypoglycaemia • Sulfonylurea induced

Volume 9: Number 1. 2016 | Page 11

RCSIsmjcase report important to note that the diagnostic criteria for hyperplasia are not

Conclusion

universally agreed upon; Rindi et al. define hyperplasia in adults as an

Nesidioblastosis is a rare cause of hyperinsulinaemic hypoglycaemia in

expansion of the endocrine cell mass to more than 2% of total pancreas

adults and can occur as a late complication of RYGB surgery. Diagnosis

mass. Due to the impracticalities of conducting detailed pancreatic

must be suspected when 72-hour fast is negative and imaging fails to

morphometry of a sample, the diagnosis may often be subjective.

identify insulinoma, and is established when pathological assessment

However, most would regard an increase in islet numbers as evidence of

confirms absence of insulinoma and presence of pancreatic hyperplasia.

hyperplasia. Four major criteria have been proposed to diagnose

A multidisciplinary approach becomes necessary when the diagnosis is

nesidioblastosis:

unclear and investigations suggest a rare pathology; as in this case, involvement of endocrinologists, general surgeons, interventional

1. Exclusion of insulinoma by macroscopic, microscopic and immunohistochemical examinations.

radiologists and pathologists can ensure that an adequate management plan is put in place to bring about the best possible patient outcomes.

2. Multiple β-cells with enlarged, hyperchromatic nuclei and abundant clear cytoplasm (β-cell hyperplasia and hypertrophy).

Typically, management is dietary and medical, but surgery may be considered in refractory cases such as this one. Where surgery is

3. Islets with normal spatial distribution of various cell types.

deemed necessary, IR hepatic venous sampling may localise the site of

4. No proliferative activity of endocrine cells.3

pancreatic hyperfunction to determine the extent of surgical resection. As our case demonstrates, the subjective and impractical nature of

Utilisation of this criterion may help to improve diagnostic

pathological assessment can show hyperplasia and hypertrophy to be

consistency. The recommended management of post-gastric bypass

within normal limits, thus making definitive diagnosis of nesidioblastosis

surgery hypoglycaemia is with frequent, low-carbohydrate diet or

a technical difficulty. Implementation of established diagnostic criteria

medical management (α-glucosidase inhibitors, diazoxide,

can help to resolve this issue and improve inter-observer consistency.

octreotide). If these fail, reversal of gastric bypass can be performed.

Further research and long-term studies are needed to understand the

Often symptoms persist; in an attempt to preserve pancreatic

pathogenesis of post-gastric bypass hypoglycaemia and the therapeutic

function, a partial pancreatectomy may be performed, but

outcome, as this has implications for the future of gastric bypass surgery

symptoms often return and necessitate further surgery.

as an option for weight loss.

References 1. Service FJ, McMahon MM, O’Brien PC et al. Functioning

7. Raffel A, Krausch M, Anlauf M et al. Diffuse nesidioblastosis as a

insulinomas – incidence, recurrence, and long-term survival of

cause of hyperinsulinemic hypoglycemia in adults: a diagnostic

patients: a 60-year study. Mayo Clin Proc. 1991;66(7):711-19.

and therapeutic challenge. Surgery. 2007;141(2):179-84.

2. Finlayson E, Clark OH. Surgical treatment of insulinomas. Surg Clin N Am. 2004;84:775-85. 3. Garcia-Santos EP, Manzanares-Campillo Mdel C, Padilla-Valverde D et al. Nesidioblastosis. A case of hyperplasia of the islets of Langerhans in the adult. Pancreatology. 2013;13(5):544-8. 4. Rothmund M, Angelini L, Brunt LM et al. Surgery for benign insulinomas: an international review. World J Surg. 1990;14(3): 393-8. 5. Laidlaw GF. Nesidioblastoma, the islet tumor of the pancreas. Am J Pathol. 1938;14(2):125-134.5. 6. De Lonlay-Debeney P, Pogggi-Travert F, Fournet JC, Sempoux C

8. Mala T. Postprandial hyperinsulinemic hypoglycemia after gastric bypass surgical treatment. Surg Obes Relat Dis. 2014;10(6):1220-5. 9. Brandle M, Pfammatter T, Spinas GA, Lehmann R, Schmid C. Assessment of selective arterial calcium stimulation and hepatic venous sampling to localise insulin-secreting tumours. Clin Endocrinol (Oxf). 2001;55(3):357-62. 10. Thompson GB, Service FJ, Andrews JC et al. Noninsulinoma pancreatogenous hypoglycaemia syndrome: an update in 10 surgically treated patients. Surgery. 2000;128:937-45. 11. Rindi G, Solcia E. Endocrine hyperplasia and dysplasia in the

et al. Clinical features of 52 neonates with hyperinsulinism. N

pathogenesis of gastrointestinal and pancreatic endocrine

Engl J Med. 1999;340:1169-75.

tumors. Gastroenterol Clin North Am. 2007;36(4):851-65.

Page 12 | Volume 9: Number 1. 2016

RCSIsmjcase report Kicking up a cytokine storm: an unusual presentation of Castleman’s disease Abstract Castleman’s disease (CD) is a rare lymphoproliferative disorder that can be separated into localised disease and multicentric Castleman’s disease (MCD). Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8) is the causal agent for Kaposi’s sarcoma (KS) and MCD in human immunodeficiency virus (HIV)-infected patients. This virus encodes a homologue of interleukin 6 (vIL-6), which may mediate some systemic features of MCD. A 58-year-old man presented to the infectious disease department with a three-day history of dyspnoea, fever, and cough. He had a history of HIV and had been on antiretroviral treatment for the previous year. Despite compliance, his CD4 count had dropped and he was found to have widespread lymphadenopathy and pancytopaenia on admission. Biopsy showed the presence of KS and it was decided to treat him for an ‘MCD-like’ syndrome based on his clinical presentation. The patient responded well to treatment with rituximab, an agent used for MCD, and his haematological profile improved. This case lends support to the theory that some patients with HIV and HHV-8 co-infection, but without MCD, can develop severe systemic inflammatory symptoms associated with elevated levels of HHV-8 vIL-6, IL-6 and HHV-8 viral loads. It additionally illustrates the challenges faced in the diagnosis of this unusual form of MCD in patients with HIV. Most importantly, this case highlights the importance of a thorough history and examination in eliciting the clues to diagnosis in the face of these challenges. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:13-17.

Introduction Castleman’s disease (CD), or giant lymph node

diagnosis of MCD requires the clinical features of

hyperplasia, is a rare disorder first described by

active disease described above plus pathologic

Castleman et al. in 1956. CD is separated into

Rachel MacCann RCSI medical student

confirmation on biopsy.

localised unicentric disease, with solitary

In HIV-infected patients, MCD is usually caused by

hyperplastic mediastinal lymph nodes, or

Kaposi’s sarcoma-associated herpesvirus (KSHV),

multicentric disease (MCD). Histologically, CD is

also called human herpesvirus-8 (HHV-8). This virus

divided into the hyalinised vascular form and a

encodes a homologue of interleukin 6 (vIL-6),

plasma cell variant, the former being more

which may mediate the systemic features of MCD.

common in localised disease, and the latter more

Symptomatic patients with HHV-8-positive MCD

common in MCD. Mixed forms of CD have also

have HHV-8 viral loads that are exponentially

been documented.2

greater than asymptomatic HHV-8-positive patients

MCD is characterised by polylymphadenopathy

(Table 1). In accordance with this, the increased

and inflammatory manifestations including fevers,

viral load correlates with increased serum levels of

malaise, wasting, hypoalbuminaemia,

IL-6.3 This virus predisposes patients to much

cytopaenias, and hyponatraemia. These

higher risk of other malignancies, including

symptoms are a result of inflammatory cytokine

Kaposi’s sarcoma (KS) (13% increased risk)2 and

overproduction, especially IL-6 (Figure 1).2 The

primary effusion lymphoma. Volume 9: Number 1. 2016 | Page 13

RCSIsmjcase report Table 1: Definition of a HIV MCD attack.4 Fever At least three of the following symptoms:

Castleman’s lymph node

Peripheral lymphadenopathy Enlarged spleen Oedema

Multicentric Castleman’s disease (MCD)

Unicentric Castleman’s disease (UC)

Pleural effusion Ascites Cough Nasal obstruction Xerostomia

HHV-8 +

HHV-8 -

Rash Central neurologic symptoms Jaundice Autoimmune haemolytic anaemia Increased serum C-reactive protein level >20mg/L in the absence of any other aetiology

IL-6 production

HIV = human immunodeficiency virus; MCD = multicentric Castleman’s disease. FIGURE 1: Castleman’s disease variants.

There is evidence that MCD has become more common since the 5

previously, and he was being treated with antiretroviral medications

advent of combination antiretroviral therapy, affirming the theory

– specifically, oral combined tenefovir and emtricitabine (Truvada®;

that immune-overactivation rather than immunosuppression leads to

Gilead Sciences, Foster City, CA, USA), and darunavir. However, his

MCD. Like MCD that is unrelated to HHV-8, the clinical presentation

CD4 count had decreased over the previous year from 800 to 285

of HHV-8-associated MCD is dominated by systemic inflammatory

cells/mm3, despite compliance with his medications. Other medical

symptoms and polylymphadenopathy. It is diagnosed upon lymph

history included a parietal skull fracture three years previously

node biopsy and has a fluctuating course, which, if untreated,

following a fall, hypothyroidism, for which he took 100mcg

proves fatal. This report discusses the presentation of a new variant

levothyroxine once daily, and depression, for which he took 37.5mg

of HHV-8-associated MCD and the difficulties faced in diagnosis and

venlafaxine once daily. His father passed away from lung cancer at

management.

the age of 83 and his mother passed away from a cerebral sarcoma aged 50. He was a non-smoker and non-drinker, who lived alone

The case

and worked as an optometrist.

A 58-year-old Caucasian gentleman presented to St George’s

On examination, he appeared pale and dyspnoeic. Auscultation of

Hospital in London with a three-day history of dyspnoea, fever, and

the lungs elicited increased vocal fremitus and crackles of the right

cough. This was on a background history of community-acquired

lower zone. A full blood count revealed low neutrophil and platelet

pneumonia five weeks previously, for which he had been successfully

counts, and C-reactive protein (CRP) was elevated. X-ray findings

treated at the same hospital.

were consistent with right lower lobe pneumonia. He was

Past medical history was significant for HIV, diagnosed 13 months

commenced on an amoxicillin and doxycycline antibiotic regimen

Page 14 | Volume 9: Number 1. 2016

RCSIsmjcase report

FIGURE 2: Cervical lymph node biopsy from patient with a CD31 positive stain showing: a) lymph node follicle with KS x20 magnification; b) KS with HHV-8 x20 magnification; c) lymph node follicle with KS x200 magnification; and, d) KS cell with HHV-8 x200 magnification. Typical histologic findings in KS include: proliferation of spindle cells; prominent, slitlike vascular spaces; and, extravasated red blood cells. KS = Kaposiâ&#x20AC;&#x2122;s sarcoma.

with 30mg prednisolone. Upon completion of his treatment course,

regimen to raltegravir 400mg twice daily in an effort to improve his

his chest symptoms resolved but his platelets remained remarkably low

CD4 count.

and CRP remained elevated. He became progressively fatigued and his

Two weeks after his admission, the patient developed a palpable light

blood profile failed to improve despite medical treatment, prompting

brown lesion on his right forearm measuring 6cm by 7cm in diameter.

a re-evaluation of his initial diagnosis.

Following a cervical lymph node biopsy, a histological diagnosis of

Further questioning uncovered a four-month history of fatigue, night

HHV-8-positive KS was made (Figure 2). A plan was made to

sweats, and weight loss. Repeat bloods revealed worsening

commence chemotherapy treatment once his platelet levels could be

pancytopaenia in addition to persistently elevated CRP, lactate

raised to a level above 50 x 109/L with his ITP-specific therapy.

dehydrogenase (LDH) and hyponatraemia. CT showed widespread

However, following a five-day treatment course, his platelet levels

lymphadenopathy and splenomegaly. Based on these findings, and as

failed to respond. As a result, he was initiated on a weekly romiplostim

a result of immunosuppression because of his low CD4 count, a

regimen with continuation of prednisolone.

diagnosis of immune thrombocytopaenia (ITP) was made. He was

This also failed to improve his condition, so a discussion between the

commenced on ITP-specific therapy, which consisted of platelet

departments of haematology, infectious diseases, and oncology was

transfusion, intravenous immunoglobulin (IVIG) and glucocorticoids

held. This patientâ&#x20AC;&#x2122;s clinical and haematological presentation fit the

(prednisolone 30mg once daily) in an effort to raise his platelet count.

diagnosis of MCD, yet the tissues obtained for histological diagnosis

His antiretroviral medication was switched from a darunavir-based

were only positive for HHV-8 and not for MCD (Figure 3). It was Volume 9: Number 1. 2016 | Page 15

RCSIsmjcase report

FIGURE 3: Lymph node biopsy demonstrating the histological appearance of MCD: a) haematoxylin and eosin-stained section of lymph node (100× magnification) showing the concentric layering of lymphocytes in the mantle zone of the lymphoid follicle – ‘onion-ring’ appearance; and, b) HHV-8 immunohistochemical stain showing mantle zone concentricity and distinct HHV-8 positive nuclear staining of lymphoid cells in the mantle zone (100× magnification). MCD = multicentric Castleman’s disease.7 Table 2: Working case definition of KSHV (HHV-8) inflammatory cytokine syndrome.5 1. Clinical manifestations a. Symptoms Fever Fatigue Oedema Cachexia Respiratory symptoms (including cough, dyspnoea, airway hyperreactivity) Gastrointestinal disturbance (including nausea, anorexia, abdominal discomfort, altered bowel habit) Arthralgia and myalgia Altered mental state Neuropathy with or without pain

b. Laboratory abnormalities Anaemia Thrombocytopaenia Hypoalbuminaemia Hyponatraemia c. Radiologic abnormalities Lymphadenopathy Splenomegaly Hepatomegaly Body cavity effusions

2. Evidence of systemic inflammation Elevated C-reactive protein (≥3g/dL) 3. Evidence of KSHV lytic activity Elevated KSHV viral load in peripheral blood mononuclear cells (≥100 copies/106 cells) 4. No evidence of KSHV-associated Castleman’s disease Exclusion of MCD requires pathologic assessment of lymph node, bone marrow, or spleen The working case definition of KICS requires the presence of at least two clinical manifestations drawn from at least two categories (1a, b, and c), together with each of the criteria in 2, 3, and 4. Clinical manifestations for the working definition are drawn from the initial case series and from findings commonly seen in KSHV–MCD (HHV-8–MCD). hypothesised that the patient’s symptoms of lymphadenopathy and

called ‘KSHV inflammatory cytokine syndrome’ (KICS) (Table 2).6 Due to

inflammation might not be caused by HHV-8–MCD, but might instead

its relatively new classification, the treatment approach for KICS is still

result from HHV-8 lytic activation and consequent cytokine production.

largely theoretical and based on MCD treatment. Our patient was

The patient was found to have a substantial elevation of vIL-6 and hIL-6,

started on a trial of rituximab 375mg/m2 once weekly for four weeks.

and so he was proposed to have a rare and newly described syndrome

His first dose was well tolerated and his platelets increased from 22 x

Page 16 | Volume 9: Number 1. 2016

RCSIsmjcase report 109/L prior to treatment to 69 x 109/L following treatment. His

observational studies, and usually involves a combination of

haemogloblin levels and white cell count also improved, and CRP began

immunotherapy, chemotherapy and antiviral agents. Treatment

to show a downward trend. For the first time since admission, the

selection depends upon whether the patient is HIV/HHV-8 positive,

patient showed encouraging clinical improvement and was discharged

and on the clinical aggressiveness of the disease. Concurrent

home, with the plan to return for his remaining three rituximab

combination antiretroviral therapy (HAART) is generally used in

treatments. At the most recent follow-up he had symptomatically

HIV-infected patients. Prompt therapy must be instituted to avoid

improved and was tolerating rituximab.

potentially fatal complications from organ failure and infections.6 Rituximab, a humanised monoclonal antibody against the B-cell

Discussion

antigen CD20, has been shown to be effective in MCD treatment.10

The differential diagnosis of fever and adenopathy in HIV-infected

Two prospective phase II studies have shown a significant reduction in

patients, even with other laboratory abnormalities, is broad. As a

symptoms and decreased HHV-8 viral load.10,4 Other case reports have

result, HHV-8–MCD can be difficult to diagnose and is often missed.

used a successful combination of rituximab and liposomal doxorubicin

This is an unusual case of a HIV-infected patient who had

to kill KS spindle cells. It is on the basis of these studies and previous

lymphadenopathy, severe inflammatory symptoms, KS and

case reports that this therapy was commenced with this patient.

pancytopaenia, but in whom a histological diagnosis of MCD could

Furthermore, the patient’s positive response to his rituximab treatment

not be made. Recently, another HHV-8-associated condition, KICS, has

strengthens the theory of a KICS diagnosis for our patient.

been described. Its clinical manifestations resemble those of HHV8–MCD but, as seen in this case, the histological changes of

Conclusion

HHV-8–MCD are absent. Patients with KICS exhibit elevated HHV-8

CD and its associations are broad and complex in their presentation

viral loads and elevation of vIL-6, a homologue of human interleukin-6

and diagnosis. KICS demonstrates that the clinical manifestations of

and IL-10 comparable to those seen in HHV-8–MCD.8 The pathological

HHV-8 infection may vary and sometimes overlap. Future work to

evolution of this syndrome and its relationship with HHV-8–MCD

establish the incidence of this syndrome and its ideal treatment, and

remains to be elucidated. No standardised therapy exists for MCD,

to clarify how it differs from MCD or KS, is crucial. Additionally, this

and only one RCT has been conducted for MCD treatment.

case reminds us to consider an IL-6-related inflammatory syndrome in

Management thus far has been guided by case reports or

critically ill patients with HIV and KSHV co-infection.2

References 1. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer. 1956;9(4):822-30. 2. Waterston A, Bower M. Fifty years of multicentric Castleman’s disease. Acta Oncol. 2004;43(8):698-704. 3. Oksenhendler E, Carcelain G, Aoki Y, Boulanger E, Maillard A, Clauvel JP et al. High levels of human herpesvirus 8 viral load, human interleukin-6, interleukin-10, and C reactive protein correlate with exacerbation of multicentric castleman disease in HIV-infected patients. Blood. 2000;96(6):2069-73. 4. Gérard L, Bérézne A, Galicier L et al. Prospective study of rituximab in chemotherapy-dependent human immunodeficiency virus associated multicentric Castleman’s disease: ANRS 117 CastlemaB Trial. J Clin Oncol. 2007;25(22):3350-6. 5. Powles T, Stebbing J, Bazeos A, Hatzimichael E, Mandalia S, Nelson M et al. The role of immune suppression and HHV-8 in the increasing incidence of HIV-associated multicentric Castleman’s disease. Ann Oncol. 2009;20(4):775-9.

6. Polizzotto MN, Uldrick TS, Hu D, Yarchoan R. Clinical manifestations of Kaposi sarcoma herpesvirus lytic activation: multicentric Castleman disease (KSHV–MCD) and the KSHV inflammatory cytokine syndrome. Front Microbiol. 2012;3(73). 7. Patel M, Philip V, Lakha A, Pather S, Waja MF, Singh L et al. Multicentric Castleman’s disease. In: Metodiev K (ed.). Immunopathology and Immunomodulation. ISBN: 978-953-51-2210-4. InTech. DOI: 10.5772/61709. 2015. 8. Uldrick TS, Wang V, O’Mahony D, Aleman K, Wyvill KM, Marshall V et al. An interleukin-6-related systemic inflammatory syndrome in patients co-infected with Kaposi’s sarcoma-associated herpesvirus and HIV but without multicentric Castleman disease. Clin Infect Dis. 2010;51(3):350-8. 9. van Rhee F et al. Siltuximab for multicentric Castleman’s disease: a randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2014;15(9):966-74. 10. Bower M, Powles T, Williams S, Davis TN, Atkins M, Montoto S et al. Brief communication: rituximab in HIV-associated multicentric Castleman disease. Ann Intern Med. 2007;147(12):836-9.

Volume 9: Number 1. 2016 | Page 17

RCSIsmjcase report Toxic shock syndrome complicated by necrotising fasciitis: back to basics Abstract Necrotising soft tissue infections (NSTIs) are uncommon but potentially fatal, and both their recognition and management represent significant challenges for clinicians. A 68-year-old male presented to the emergency department complaining of pain in his left lower limb following abrasion injuries sustained from a fall off a wooden ladder the previous evening. His injuries extended from the left anterior tibia up along the medial aspect of the left knee and thigh, and showed erythema, induration, and vesiculation. The patient had a history of hypertension and hypercholesterolaemia. On examination, he was hypotensive, tachycardic, and hypothermic. He rapidly deteriorated and developed acute kidney injury secondary to septic hypovolaemia, requiring haemodynamic support, long-term intravenous antibiotics, several surgical debridements, dialysis, and skin grafts, but he subsequently made a full recovery. The clinical, laboratory, and radiological findings in NSTIs can vary significantly, and definitive diagnosis is made by surgical exploration. Pain out of proportion to clinical findings, rapid clinical deterioration, and signs of systemic involvement are important clues for the clinician. This case demonstrates how rapid diagnosis and multidisciplinary management (in which surgery is the cornerstone) can lead to the most favourable outcome for patients. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:18-22.

Background Necrotising soft tissue infections (NSTIs) encompass

anti-inflammatory drug (NSAID) use has been

a relatively broad spectrum of potentially

described, but remains controversial.1 Virtually all

life-threatening infections, including necrotising

untreated cases are fatal, and mortality with

forms of cellulitis, fasciitis, and myositis. NSTIs can be

treatment approaches 35%.2

classified according to the depth of tissue Sarvenaz Esmaeilzadeh1

We describe a 68-year-old male who self-presented

describes type I polymicrobial infections (especially

to the emergency department with abrasions and

anaerobes), type II monomicrobial infections (most

commonly group A β-haemolytic streptococci such

pain in his left leg along the anterior tibia, medial

as S. pyogenes and, increasingly, Staphylococcus

a wooden ladder the previous evening. Following

aureus), and type III infections (gram-negative

the injury, the patient self-administered povidone

aquatic organisms).1 NSTIs are uncommon, with

iodine ointment, cetrimide 0.5% (w/w) cream,

recent reports estimating up to 1,500 cases in the

chlorhexidine gluconate 0.1% (w/w), and

Fidelma Fitzpatrick 1

RCSI medical student

Department of Surgery,

Beaumont Hospital, Dublin Department of Plastic Surgery, Beaumont Hospital, Dublin 4

Case

organism. The most commonly used classification

Colm Power

involvement, severity of infection, and causative

Barry O’Sullivan3

Department of Microbiology, Beaumont Hospital, Dublin

Page 18 | Volume 9: Number 1. 2016

1,2

United States annually.

Predisposing factors include

knee and medial thigh, from a three-foot fall from

mentholatum to the wound. He complained that

diabetes and other chronic diseases, traumatic

he had been awakened from sleep with severe

injuries (with or without skin injury), and intravenous

pain and swelling in the leg, and that he “felt

(IV) drug use. An association with non-steroidal

unwell”.

RCSIsmjcase report Table 1: Relevant laboratory results. Test

Result

Flag

Reference interval

Sodium

123mmol/L

133-146mmol/L

Lactate, serum

6.4mmol/L

0-1.8mmol/L

Urea, serum

14.2mmol/L

2.5-8.5mmol/L

Creatinine, serum

188µmol/L

64-104µmol/L

WCC

20.1x109/L

4.0-11.0x109/L

CRP

378mg/L

0-5mg/L

WCC: White cell count; CRP: C-reactive protein. The patient had a high BMI, but past medical history was significant

resuscitation. Blood, urine, and vesicular fluid samples were sent to

only for alcohol use (approximately 50 units of alcohol weekly) and

the laboratory for culture. Piperacillin-tazobactam, vancomycin, and

ongoing hypertension and hypercholesterolaemia. On examination,

gentamicin were commenced, and the patient was transferred to

the patient was profoundly hypotensive (66/43mmHg), tachycardic

the intensive therapy unit (ITU), where he was intubated and

(95bpm), and hypothermic (34.6ºC). He appeared pale and

mechanically ventilated. A CT scan showed evidence of infection but

clammy, but was oriented to person, place, and time with a GCS of

no direct evidence of necrotising fasciitis (Figure 1). With this

15/15. Examination of the left lower limb revealed leg weakness,

diagnosis unconfirmed, antibiotic treatment was escalated to a

well-demarcated pretibial erythema with warmth and tenderness

combination of clindamycin, piperacillin-tazobactam, linezolid, and

distally, and a hemi-circumferential area of yellow discolouration,

β-haemolytic streptococci (GAS), Panton-Valentin leukocidin-positive

overlying vesiculation, and induration on the medial thigh. This region was exceptionally tender. Clinically, necrotising fasciitis was

ciprofloxacin to provide broad-spectrum cover for group A

methicillin-resistant Staphylococcus aureus, gram-negative bacilli, and

suspected and initial management involved IV fluid resuscitation,

anaerobes. Due to ongoing hypotension and the associated AKI, the

analgesics, and clindamycin. Laboratory results (Table 1) indicated a

patient was started on inotropes and placed on continuous

non-oliguric acute kidney injury (AKI) secondary to hypoperfusion

veno-venous haemodialysis (CVVH). He received prophylaxis for

caused by septic shock and a likely hypovolaemic hyponatraemia.

venous thromboembolism with unfractionated heparin, and was

The patient remained hypotensive despite ongoing fluid

taken to theatre for a decompressive fasciotomy; no evidence of

FIGURE 1: CT femur. Marked oedema and stranding within the subcutaneous tissues of the left lower extremity, with fluid tracking along the intermuscular planes of the medial and posterior compartments. No dominant focal fluid collection to suggest a discrete abscess. No air within the soft tissues.

FIGURE 2: CT femur. Views of the legs demonstrate left thigh medial fasciotomy. No evidence of subcutaneous emphysema or collection visualised within the scan range (to mid calf). There is a vac dressing in situ. Volume 9: Number 1. 2016 | Page 19

RCSIsmjcase report

FIGURE 3: Lateral (top) and medial (bottom) views of the patient’s left leg following debridement, prior to skin grafting.

FIGURE 4: Anterior view of the patient’s left leg following surgical skin grafting.

necrotising fasciitis was found intraoperatively. However, theatre

was given high-dose IV immunoglobulin (IVIG) with

samples grew GAS and vesicular fluid cultured Staphylococcus

pre-administration of antihistamines, hydrocortisone, and

aureus. A diagnosis of toxic shock syndrome (TSS) was made on

anti-inflammatories. CT imaging of the abdomen and left leg

the basis of his clinical picture and microbiology results.

remained unremarkable (Figure 2).

In the following days, the patient’s blood pressure and renal

By day seven, increasing urine output indicated improving renal

function proved too unstable to reduce CVVH. He developed

function, and the patient was able to maintain blood pressure

profuse diarrhoea (Clostridium difficile negative), and wound

without inotropic support. However, he developed bilateral

appearance continued to worsen. Questions arose concerning the

pleural effusions with significant peripheral oedema, likely from

patient’s immunological status, due to the extent and severity of

fluid loading, and evidence of cholestasis (elevated alkaline

the infection. HbA1c levels proved normal, and HIV tests were

phosphatase (ALP) and bilirubin), likely secondary to antibiotic

negative. Given the lack of a history of recurrent soft tissue or

treatment; no liver or biliary abnormalities were noted on

respiratory tract infections, normal immunoglobulin levels and

ultrasound. As a result, linezolid and piperacillin-tazobactam were

serum protein electrophoresis results, hypogammaglobulinaemia

discontinued, daptomycin was commenced and the patient

was outruled. However, a positive GAS culture, without an

continued on clindamycin.

associated rise in the antistreptolysin O titre (ASOT), indicated a

The patient continued to improve, and was successfully

possible functional humoral defect. In the context of a worrying

extubated on day nine. However, blood cultures grew Klebsiella

clinical picture and suspected GAS-induced sepsis, the patient

pneumoniae, while Candida spp. was cultured from the tip of a

Page 20 | Volume 9: Number 1. 2016

RCSIsmjcase report Table 2: Common features of necrotising fasciitis. Symptoms3,7

Clinical findings3,7

Laboratory studies2

Radiological imaging10

Surgical exploration2,7

Extreme pain, disproportional to clinical findings

Rapid progression of clinical manifestations

Evidence of sepsis (elevated lactate, WCC, CRP, altered electrolytes, abnormal renal or liver profiles)

Early changes are similar to those in cellulitis: soft tissue thickening, increased opacity

Easy blunt dissection of the subcutaneous tissues from deep fascia ('finger test')

Rapid progression and spread of lesions, erythema, and tenderness

Tenderness and oedema past the apparent area of erythema

WCC >15.4*109/L and serum sodium <135mmol/L

Subcutaneous emphysema, may track along fascial plains

Gray, swollen tissue/fascia

Systemic symptoms of infection/toxicity: fever, fatigue

Supralesional vesiculation, bullous formation

LRINEC score >8 suggests high risk of NSTI

Fluid or air collections in subfascial planes

Lack of bleeding, thrombosis of vessels

Indurated, hard, wooden feeling of subcutaneous tissue; inability to feel underlying muscle groups

Dermal thickening

Thin exudate, lack of excessive pus

Signs of sepsis: tachycardia, hypotension, hypothermia or fever, end organ dysfunction

Inflammatory fat stranding

Abbreviations: WCC – white cell count; CRP – C-reactive protein; LRINEC score – laboratory risk indicator for necrotising fasciitis score (variables include WCC, haemoglobin, sodium, glucose, serum creatinine and C-reactive protein); NSTI – necrotising soft tissue infection. right jugular line. Aztreonam and caspofungin were added to the

Discussion

antimicrobial regimen.

This patient presents a classic example of TSS complicated by

Over the following ten days the patient deteriorated, became

necrotising fasciitis. The microbial aetiology – GAS with synergistic

pyrexic, required re-intubation and a further dose of IVIG. His

Staphylococcus aureus – and the previously healthy patient’s history

wounds began to show evidence of necrotic tissue. Surgical

of a minor injury with skin breach were consistent with that of most

exploration confirmed the presence of necrotic change of the

type II NSTIs described in the literature.3

subcutaneous tissues and fascia, and a diagnosis of necrotising

While most infections evolve over a period of two or three days,

fasciitis was made. The patient underwent a total of four

GAS has been shown to be particularly aggressive;3 in this case, the

debridements over the next few days before it could be

patient was in septic shock less than 12 hours following the initial

confirmed that no involved tissue remained (Figure 3). While at

injury. Many factors, including advanced age and comorbidities,

times agitated, the patient began to show significant clinical

have been shown to adversely affect patient outcome, but delayed

improvement, and was systemically stable and suitable for

surgical intervention is the most important factor leading to

surgical skin grafting by day 26 of hospital stay; extensive skin

increased mortality.4,5 However, neither surgery nor antimicrobial

grafts were required along his upper medial thigh (Figure 4). The

therapy alone are sufficient in patient management.6 It has been

patient was transferred out of the ITU on day 27 and recovered

well documented that early and complete surgical debridement,

on the ward, completing three weeks of physiotherapy before

appropriate antimicrobial therapy, and physiological support and

being discharged home.

monitoring provide the best chance for patient recovery.2,7 Novel Volume 9: Number 1. 2016 | Page 21

RCSIsmjcase report but controversial therapies include IVIG8 and hyperbaric oxygen.2

during surgical exploration remains the most important feature of

IVIG was used in this patient based on evidence that suggests its

an NSTI, and is the only way to make a definitive diagnosis.7 Thus,

usefulness in GAS-induced sepsis. Importantly, this case shows

maintaining a high index of clinical suspicion is crucial, and in

excellent patient management by the multidisciplinary clinicians

suspected cases, surgical intervention should not be delayed while

involved and demonstrates the benefit of early senior clinical input.

awaiting laboratory, microbiological, or radiological studies. Some of

Emergency physicians recognised sepsis, suspected necrotising

the important surgical findings and supporting clinical, laboratory

fasciitis, provided appropriate resuscitation, and referred to ITU

and radiological evidence are summarised in Table 2.

when septic shock developed. From the outset, the patient received input from emergency, surgery, microbiology, critical care, renal,

Conclusion

radiology and immunology experts, demonstrating a co-ordinated

While uncommon, NSTIs can affect healthy individuals as well as

multidisciplinary approach to patient management. Early diagnosis,

at-risk groups, and are rapidly fatal if not promptly diagnosed and

while of paramount importance, can be challenging even for

treated. Appropriate patient management requires multidisciplinary

experienced physicians. NSTIs can resemble simple cellulitis in the

care, and core principles are early surgical debridement,

early stages, and overlying skin changes may not necessarily reflect

broad-spectrum antibiotic therapy, and organ and haemodynamic

the ongoing extensive subcutaneous disease process.4 Clinical

support. These interventions crucially depend on high clinical

presentation may vary depending on various factors, including time

suspicion and early diagnosis.

of presentation within the natural history of infection, and microbial aetiology.3 Scoring systems to aid in diagnosis are typically more

Acknowledgements

useful for ruling out an NSTI, or discriminating between necrotising

I would like to express my gratitude and appreciation to the

and non-necrotising forms, than for confirming it.2 Additionally,

patient for his help and co-operation throughout the

radiological signs may be absent or non-specific; for example, gas in the fascial planes (while highly specific) is not a sensitive finding.

The direct visualisation of the subcutaneous tissues and fascial planes

development of this case study. Many thanks also to Dr Mark Sheehan and Dr Mohammad Alakkad for helping to procure and interpret patient images.

References 1. Hakkarainen TW, Kopari NM, Pham TN, Evans HL. Necrotising soft tissue infections: review and current concepts in treatment,

7. Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL et al. Practice guidelines for the diagnosis and

systems of care, and outcomes. Curr Probl Surg.

management of skin and soft tissue infections: 2014 update by

2014;51(8):344-62.

the Infectious Diseases Society of America. Clinical Infect Dis.

2. Anaya DA, Dellinger EP. Necrotising soft-tissue infection: diagnosis and management. Clin Infect Dis. 2007;44(5):705-10. 3. Tintinalli JE, Kelen GD, Stapczynski JS. Emergency Medicine: A Comprehensive Study Guide (6th ed.). McGraw-Hill, 2004. 4. Wong CH, Chang HC, Pasupathy S, Khin LW, Tan JL, Low CO. Necrotising fasciitis: clinical presentation, microbiology, and

2014;59(2):e10-52. 8. Alejandria MM, Lansang MA, Dans LF, Mantaring JB 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013;9:Cd001090. 9. Norrby-Teglund A, Ihendyane N, Darenberg J. Intravenous immunoglobulin adjunctive therapy in sepsis, with special

determinants of mortality. J Bone Joint Surg Am.

emphasis on severe invasive group A streptococcal infections.

2003;85-a(8):1454-60.

Scand J Infect Dis. 2003;35(9):683-9.

5. Bellapianta JM, Ljungquist K, Tobin E, Uhl R. Necrotising fasciitis. J Am Acad Orthop Surg. 2009;17(3):174-82. 6. Hsiao GH, Chang CH, Hsiao CW, Fanchiang JH, Jee SH. Necrotising soft tissue infections. Surgical or conservative treatment? Dermatol Surg. 1998;24(2):243-7; discussion 247-8.

Page 22 | Volume 9: Number 1. 2016

10. Chaudhry AA, Baker KS, Gould ES, Gupta R. Necrotising fasciitis and its mimics: what radiologists need to know. AJR Am J Roentgenol. 2015;204(1):128-39.

RCSIsmjcase report A missed coarctation

Abstract Coarctation of the aorta (CoA) is a very dangerous congenital heart defect, with many patients presenting in the neonatal period with heart failure. This defect is especially serious since many cases are missed at birth due to inaccurate examination or lack of screening. Recommended pulse oximetry and blood pressure screening is currently not a mandatory screen in the HSE guidelines for newborn checks, but provides a much-needed support to clinical skills in detecting a CoA defect. This is the case describing a nine-day-old boy whose cardiac condition was misdiagnosed, leading to preventable and potentially fatal consequences. His defect was missed at both a newborn assessment and his presentation to Cavan General Hospital. He presented to Cavan General Hospital with upper extremity cyanosis and discolouration, pale trunk and legs, and tachypnoea. After clinical assessment, the impression was septicaemia on underlying congenital heart disease (CHD), and he was then transferred to Our Lady’s Children’s Hospital Crumlin (OLCHC). Upon examination and screening, he was determined to have CoA, which was successfully repaired surgically with end-to-end anastomosis with patent ductus arteriosus (PDA) ligation. This case highlights the importance of complete paediatric examinations and the necessity for pulse oximetry and blood pressure screening for CoA to prevent future complications. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:23-6.

Introduction Coarctation of the aorta (CoA) is a common 1

Corey Nixon RCSI medical student

defects, CoA was the most common at 64/104

condition, accounting for 5-8% of all congenital

(62%).4

heart conditions,2 and can be one of the most

The pathogenesis of CoA is currently unknown,

fatal congenital heart defects depending on its

but it is known to be associated with aortic

classification. The danger of CoA is further

valvular defects and, most commonly, Turner’s

emphasised by its subtlety, as it can easily be

syndrome, among many other syndromes. The

missed; a Swedish study showed that of 104

main pathology underlying this condition is the

missed diagnoses of duct-dependent cardiac

narrowing of the aorta either proximal to or at Volume 9: Number 1. 2016 | Page 23

RCSIsmjcase report Table 1: Comparison of pre-ductal and post-ductal CoA. Comparative qualities

Pre-ductal/ductal CoA

Post-ductal CoA

Age

Neonatal presentation

Adolescent/adult presentation

Symptoms/signs

Cyanosis when DA closes Dyspnoea, tachypnoea Loss of consciousness Absent femoral pulses Plethora of upper extremity Upper extremity hypertension Decreased lower extremity perfusion Cardiogenic shock

Cyanosis during exercise/stress Dyspnoea, tachypnoea Loss of consciousness Rib notching and pulsations Upper extremity hypertension Possible cardiogenic shock

Investigations

Pulse oximetry of four limbs Blood pressure of four limbs VBG – metabolic acidosis CXR – cardiomegaly ECG – arrhythmia ECHO – RVH

Pulse oximetry of four limbs Blood pressure of four limbs ABG – metabolic acidosis CXR – cardiomegaly ECG – arrhythmia and RVH/LVH ECHO – RVH and LVH CT or MRI angiography

Management

Alprostadil/Prostin Dobutamine CPAP and intubation (if needed) Diuretics – if fluid overloaded NPO prep. for surgery Anti-hypertensive medication

Dobutamine High flow oxygen Diuretics – if fluid overloaded NPO prep. for surgery Anti-hypertensive medication

Abbreviations: CoA – coarctation of the aorta; DA – ductus arteriosus; VBG – venous blood gas; ABG – arterial blood gas; CXR – chest x-ray; ECG – electrocardiogram; ECHO – echocardiogram; RVH – right ventricular hypertrophy; LVH – left ventricular hypertrophy; CPAP – continuous positive airway pressure; NPO – nil per os. This presentation is associated with a mortality rate of approximately 13.6%.1 Post-ductal CoA patients typically have the classic sign of rib notching and pulsations due to intercostal collateral circulation. Non-duct-dependent children may never experience symptoms until adulthood due to collateral circulation through intercostal arteries, but eventually experience cardiac decompensation.3 Management of a duct-dependent coarctation requires immediate administration of prostaglandin E1 to maintain the ductus arteriosus. The ductus arteriosus is the primary means of perfusion to the lower extremities, especially in very narrow coarctations.3 If prostaglandin E1 is not FIGURE 1: Comparison between pre-ductal (left) and post-ductal (right) coarctation of the aorta. Image courtesy of Catherine Tennant, RCSI medical student.

administered, death is nearly certain from cardiogenic shock. Dobutamine must also be given to maintain cardiac output in heart failure. Management of post-ductal coarctation presentation is

the junction with the ductus arteriosus (pre-ductal/ductal) or distal

dependent on the severity of narrowing and symptoms. Surgery is

to the ductus arteriosus (post-ductal), as shown in Figure 1.

always required for pre-ductal CoA, while patients with post-ductal

Pre-ductal and ductal coarctations are duct dependent and have a

CoA should have surgery prior to decompensation to increase life

worse prognosis due to ductus arteriosus closure at about seven

expectancy.5 The common types of surgical intervention in

days postnatally, leading to cardiac decompensation.3 Postnatally

pre-ductal and post-ductal CoA repair include stent placement,

diagnosed pre-ductal CoA typically presents at approximately seven

end-to-end anastomosis, and catheter balloon aortoplasty with

days postnatally with cardiogenic shock or signs of heart failure,

concurrent patent ductus arteriosus (PDA) ligation.5 A comparison of

typically central cyanosis, breathlessness, and systemic oedema.2

both classifications based on presentation age, signs and

Page 24 | Volume 9: Number 1. 2016

RCSIsmjcase report management can be seen in Table 1. Failure to operate on CoA in

He received morphine for pain relief and eventually required

both pre- and post-ductal cases has been shown to result in 75%

nasogastric (NG) tube feed and ventilated intubation at FiO2 30%

mortality by the age of 46 years, with an average life expectancy of

due to CPAP intolerance. After hours of no improvement, he was

35 years. These statistics emphasise the need for early detection and

urgently transferred to Our Lady’s Children’s Hospital Crumlin

intervention. The purpose of this article is to present a rare case of

(OLCHC) for tertiary care. This diagnosis of pre-ductal coarctation

missed CoA, and emphasise the importance of complete

of the aorta was due to his classical findings of breathlessness and

examinations, maintaining suspicion of CoA, and screening, both at

cyanosis. A successful urgent end-to-end anastomosis repair of the

neonatal check-ups and upon presentation to hospital.

coarctation and PDA ligation was performed. Postoperative echocardiogram revealed left and right ventricular hypertrophy and

The case

postoperative gradient of 19mmHg, much decreased from its

A nine-day-old baby boy presented to Cavan General Hospital in

previous coarced state. He was also initiated on morphine for pain

Cavan, Ireland, with a one-hour history of blue/purple facial and

relief, paracetamol to continue closure of the PDA, furosemide with

upper extremity colour and pallor of the trunk and lower

spironolactone to decrease fluid overload, and clonidine for

extremities associated with fast, deep breathing. On the previous

hypertension. He began to improve with no cyanotic episodes on

night, he had been normally active and feeding, with his last feed

close observation, and was then discharged with daily medication

at 6.00pm, but the parents noted fatigue and irritability with

to combat further ventricular hypertrophy and prevent heart failure.

feeding. At about 4.00am, he was noted to have a purplish blue face and upper chest, with pale trunk and legs. He was tired,

Discussion

floppy, cold, sweating, and taking fast, deep breaths. He was

While this case’s end results were good, with no immediately

immediately brought by ambulance to Cavan General Hospital and

noticeable neurological or pulmonary damage, this missed

admitted to the neonatal ICU. He spent one day there, initiated on

diagnosis is a failure from the physician’s point of view. Palpating

antibiotics and intubated due to continuous positive airway

femoral pulses is a necessary part of the paediatric exam and may

pressure (CPAP) intolerance. He had multiple cyanotic episodes

appear to be relatively simple, but children may be irritated by

lasting 15-20 minutes every three hours while at Cavan General

finger pressure into the sensitive inguinal area, making it difficult to

Hospital. He was noted to have passed bowel motions and to have

appreciate. Due to either lack of clinical experience or

urinated at normal frequency and colour with no pain. He had no

circumstances, many physicians have missed congenital heart

past medical history of any illness or medication use. Birth weight

abnormalities, specifically CoA. One study showed that 21/22

was 3.78kg at 40+2 gestation without complications pre- or

infants presenting and diagnosed with CoA had weak or absent

postnatally.

femoral pulses.1 However, femoral pulse palpation should not be

Initial examination only revealed cyanotic features in the upper

the only screening tool for CoA, as a PDA can possibly provide

extremity, pale and cold lower extremities, with weak peripheral

enough blood volume from the right ventricle to create a palpable

pulses and a continuous systolic murmur. There was noted

pulse.6 While a normal femoral pulse may appear to be a good sign

increased work of breathing but no wheeze, consolidation, or

of perfusion, it also masks the hidden danger of a coarctation. One

crepitations in both lung fields. Temperature was recorded at

study showed that 22/83 misdiagnosed infants were readmitted

38.2ºC. Full blood count revealed WBC of 14.2 x 109/L (ref.

with circulatory failure and 3/83 died from CoA.7 If CoA does not

4.0-11.0), which is slightly raised, but not entirely suggestive of

present in earlier life, adults may go untreated for hypertension,

severe infection. Arterial blood gases revealed combined metabolic

resulting in stroke or cardiac failure, with most patients dying

and respiratory acidosis with severe deoxygenation: pH 7.22;

before the age of 46 years.5 This emphasises the importance of

PaCO2 6.3kPa; PaO2 4.2kPa; and, HCO3 19.2mEq/L. Chest x-ray

diagnosing CoA at birth and not waiting for hospital admission

revealed cardiomegaly.

with cardiogenic shock. Simply put, doctors are fallible and can

Initial impression led to a diagnosis of sepsis compounded by

miss diagnoses. This does not mean that the physicians involved in

underlying decompensated congenital heart disease, with triple

the missed diagnoses are necessarily poor or lazy; other

antibiotics implemented but with no relief. He also received

investigations supporting clinical skills may be necessary to

prostaglandin E1 and dobutamine to maintain perfusion and

diagnose CoA. It is also difficult to assess the sensitivity of palpating

cardiac output, but remained cyanotic with low oxygen saturations.

femoral pulses for CoA versus lack of experience, given the Volume 9: Number 1. 2016 | Page 25

RCSIsmjcase report expertise required for confidence at this examination. A secondary

Wilson and Jungner Screening Criteria from the evidence listed

assessment for CoA is to use pulse oximetry and measure blood

above.10 Other investigations to diagnose CoA have been explored,

pressure on all four limbs to find CoA, and this has been a

but with little success.

recommended evidence-based screening method in previous

Antenatal echocardiogram screening for CoA has been shown to

studies.5,6 A noticeably diminished blood oxygen saturation of the

have modest results in improving outcome, but is not sensitive

lower versus upper limbs should trigger a diagnostic

enough to stand alone as a diagnostic tool.1

echocardiography or CT scan.5 Pulse oximetry screening (POS) and

A major limitation to antenatal echocardiogram screening is also

four-limb blood pressure measurements are easy to perform,

the heavy expense on the healthcare system. Pulse oximetry and

non-invasive, and require little economic input due to the use of

blood pressure screening, in addition to femoral pulse palpation,

previously stocked equipment for which little training is required.

require a commitment of a great deal of time on already

Neither femoral pulse palpation nor POS are sensitive enough to

time-pressured physicians, but should be used like the standardised

rule out CoA, but together this combination provides the best

heel-prick test to recognise this potentially fatal condition.

screening tool for CoA in the newborn. The largest expense and greatest barrier to using both POS and femoral pulse palpation is

Conclusion

extra time spent by the physician or nurse to perform these

This is a lesson in the importance of paediatric physical

screening procedures. A POS and blood pressure screen algorithm

examinations and investigations, both at the first neonatal check

is provided by the Health Service Executive, but is not a mandatory

and at subsequent checks. This case also shows the necessity of

part of newborn testing.8 Currently, the only required newborn

detecting CoA as early as possible, and the importance of pulse

screens are bloodspot and hearing test,9 but CoA screening should

oximetry and blood pressure screening in early life. While CoA

be done to prevent fatal complications in the young infant as it is

patient signs may be missed by multiple physicians, this does not

both non-invasive and potentially life saving. Pulse oximetry and

excuse the use of simple, non-invasive screening in addition to

blood pressure screening of newborns appears to satisfy each of the

femoral pulse palpation to identify CoA in the newborn stage.

References 1. Franklin O, Burch M, Manning N, Sleeman K, Gould S, Archer N.

6. Mellander M. Diagnosis and management of life-threatening

Prenatal diagnosis of coarctation of the aorta improves survival

cardiac malformations in the newborn. Semin Fetal Neonatal

and reduces morbidity. Heart. 2002;87(1):67-9.

Med. 2013;18(5):302-10.

2. Peres A, Martins JD, Parames F, Gil R, Matias C, Franco J et al.

7. Lannering K, Bartos M, Mellander M. Late diagnosis of

Isolated aortic coarctation: experience in 100 consecutive

coarctation despite prenatal ultrasound and postnatal pulse

patients. Rev Port Cardiol. 2010;29(1):23-35.

oximetry. Pediatrics. 2015;136(2):e406-12.

3. Lissauer TC, Clayden G. Illustrated Textbook of Paediatrics (4th ed.). Mosby Elsevier, 2012. 4. Mellander M, Sunnegardh J. Failure to diagnose critical heart

8. Royal College of Physicians of Ireland FoP. Pulse Oximetry Testing for Newborn CHD: Clinical Care Pathway: Health Service Executive, 2012 [updated 2014 September; cited 2015 Oct 19].

malformations in newborns before discharge â&#x20AC;&#x201C; an increasing

Available from:

problem? Acta Paediatr. 2006;95:407-13.

http://www.hse.ie/eng/about/Who/clinical/natclinprog/paediatric

5. Warnes CA, Williams RG, Bashore TM, Child JS, Connolly HM, Dearani JA et al. ACC/AHA 2008 Guidelines for the Management

sandneonatology/resources/PulseOximetryTesting.pdf. 9. Health Service Executive. Newborn Screening: Health Service

of Adults with Congenital Heart Disease: a report of the American

Executive, 2013 [cited 2015 October 19]. Available from:

College of Cardiology/American Heart Association Task Force on

http://www.hse.ie/eng/health/child/newbornscreening/.

Practice Guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Circulation. 2008;118(23):e714-833.

Page 26 | Volume 9: Number 1. 2016

10. Wilson JMG, Jungner G. Principles and Practice of Screening for Disease. WHO: Public Health Papers, 1968;34.

RCSIsmjoriginal article Exploring the views of healthcare professionals on increasing smoking cessation advice for patients Abstract Background: Smoking cessation advice provided by healthcare professionals can be effective in increasing smoking cessation among patients. Any successful intervention will require staff knowledge of local barriers to implementation. However, the views of Irish healthcare professionals on increasing the provision of smoking cessation advice and the associated barriers remain unexplored. Aims: To explore the views of Irish healthcare professionals on barriers to increasing smoking cessation advice for patients in a large Irish university teaching hospital. Method: Semi-structured interviews were conducted separately with 16 healthcare professionals in a large Irish university teaching hospital. Results: The main barriers identified were patient and staff attitudes, time and service constraints, information not readily available, and issues and opinions on a smoke-free campus policy in a hospital setting. Conclusion: Our results revealed several barriers, expressed by Irish healthcare professionals, to providing smoking cessation advice to patients. This supports the need to implement a multi-component intervention in a hospital setting to improve the rate of provision of smoking cessation advice in patients by healthcare professionals.

Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:27-32.

Introduction

Shu Ying Ho,1 Noel McElvaney,2 Myles Balfem,3 Frank Doyle4 1

RCSI medical student

Respiratory Research Division,

Department of Medicine, RCSI; Education and Research Centre, Beaumont Hospital, Dublin, Ireland 3

Department of Epidemiology and Public Health Medicine, RCSI 4

Division of Population Health Sciences (Psychology), RCSI

Smoking is the single most important preventable cause of illness, chronic disability, and death in Ireland.1,2 According to the Health Survey Ireland 2015, 23% of the Irish population are smokers.2 Smokers lose an average of 10-15 years from their life expectancy;1 according to the HSE website on smoking cessation, “one in every two smokers will die of tobacco-related disease”.3,4 Every year, there are over 5,000 deaths due to tobacco in Ireland.2 To combat this problem, healthcare professionals (HCPs) are encouraged to provide cessation advice to patients who are smokers. Based on a Cochrane review in 2008, brief cessation advice provided by doctors increases the possibility of smokers being successful in quitting.5 The Health Survey Ireland 2015 reported that a “majority (63%) of smokers are trying to, planning to or considering quitting”.2 However, there is a low prevalence of provision of

cessation advice by HCPs, in Ireland and more widely. An Irish study (2012) found that 61% of hospitalised patients were asked about smoking status, and only 44% of current smokers received advice from HCPs.6 This was also recently explored in another Irish study (2014) carried out in two large Irish university teaching hospitals, which reported that 62% of inpatients did not receive smoking cessation advice, despite 55% being interested in quitting when asked.7 In a German study, only 39% of patients who smoked recalled being counselled to quit,8 while only 10.5% of general practitioners in Montreal and 22.6% of university hospital physicians in Turkey offered smoking cessation advice.9,10 Use of the Ottawa Model for Smoking Cessation (OMSC) has been proposed to accomplish a systematic approach to the delivery of cessation advice by HCPs to patients Volume 9: Number 1. 2016 | Page 27

RCSIsmjoriginal article in an Irish hospital setting. A study evaluating the OMSC showed that 69% of smokers receiving the OMSC intervention achieved six-month continuous abstinence, suggesting that it is a successful cessation

■ Do you smoke? ■ Do you routinely record patients’ smoking status?

model.11 A cross-sectional study in Japan reported HCPs lacking knowledge and training, and patients’ unwillingness to quit, as 12

potential barriers to smoking cessation care. In the UK, a qualitative study showed that patients were more likely to consider cessation when referred to a separate specialist smoking cessation centre, and

■ Do you routinely provide patients who are smokers with smoking cessation advice? ■ Do you follow up on all these patients that you provide with smoking cessation advice?

this service was favoured by HCPs because they felt that they lacked the time and expertise to intervene during daily practice.13 The views of HCPs on increasing the provision of smoking cessation advice in Ireland are not well elucidated. This study aims to explore the views of HCPs on current barriers to the provision of cessation advice to

■ On average, how many years of life would you estimate for smokers to lose in comparison to non-smokers? ■ Do you refer patients to a community smoking cessation programme or any other that is similar?

patients, and their recommendations on how to increase such advice, in a large university teaching hospital.

Methods Participants and setting

■ Are you familiar with the 5As model, 5Rs model or the Ottawa model? ■ If the 5As model were implemented in this hospital, do you think it would be effective?

Venue-based and snowball sampling methods were employed, whereby 16 HCPs were recruited from Beaumont Hospital. Once a HCP was interviewed, they then recommended two to three others who might consider participating in the project. Each HCP was contacted in turn, and the researcher (SYH) met those who agreed to

■ If the 5Rs model were implemented in this hospital, do you think it would be effective? ■ What do you think about the Ottawa model, if it were to be implemented in this hospital?

participate, and conducted the interviews within the allocated timeframe. Participants were selected and interviewed if they fulfilled the criteria: a healthcare professional working in an environment

■ Do you think practice-based supports such as stickers on a patient’s chart, or posters or emails, would increase the rate of delivery of smoking cessation advice to patients?

where they would have daily contact with patients. Interview appointments were arranged from July 4-11, 2012. HCPs were categorised as doctors, surgeons, nurses and allied HCPs to ensure anonymity.

■ Do you think brief smoking cessation advice from a healthcare professional is effective in increasing quit rates? ■ How long do you think brief smoking cessation advice should take?

Procedure Ethical approval was given by the Beaumont Hospital Ethics (Medical Research) Committee. Each participant was given a leaflet about the study and its purpose, and a consent form to sign prior to the interview. A set list of open-ended questions was used to maintain consistency (Figure 1). All participants were interviewed by the same interviewer. Each session lasted 15-30 minutes, and was recorded with the respondent’s permission. Participants were questioned on their smoking status, whether they routinely provide cessation

■ Present results suggest that 10-15 minutes is the optimal length for provision of smoking cessation advice. How realistic do you think this is? What do you think of this? ■ Do you have any other recommendations for improving the rate of recording patients’ smoking status and providing smoking cessation advice? ■ What do you think about this hospital as a smoke-free campus? Would that help patients?

advice, barriers to delivering such advice to patients, and recommendations.

Analysis Digital recordings were analysed and fully transcribed. A thematic Page 28 | Volume 9: Number 1. 2016

■ In this hospital, what systematic barriers do you and your staff experience in terms of recording patients’ smoking status and providing smoking cessation advice? FIGURE 1: List of interview questions.

RCSIsmjoriginal article Total HCPs approached (n=26)

HCPs that declined (n=10) Busy (n=8) Did not respond to emails (n=2)

Total HCPs who participated (n=16)

Doctors (n=6) Surgeons (n=2) Nurses (n=5) Allied HCPs (n=3)

FIGURE 2: Flow chart illustrating recruitment of HCPs. analysis was done to identify the main themes (barriers and

time spent for provision of cessation advice was less than five minutes.

recommendations) relating to smoking cessation from interview

“We would contact the smoking cessation officer, but we don’t offer

transcripts. Significant key words, phrases and quotes from

advice for patients who come in.” (Interview 3 – nurse)

transcripts were identified and marked with ‘descriptive tags’ or codes by a researcher (SYH). Coded transcripts were then reviewed

“We would [provide cessation advice] in young breast cancer patients

by another researcher (MB) to ensure the reliability of the first

who are getting better and will live a long life, but if it’s somebody who

author’s (SYH) codings and to see if any further themes could be

is quite sick and palliative, it’s not really considered important to do

detected in the transcripts. Once both researchers (SYH, MB) agreed

that.” (Interview 10 – allied healthcare professional)

on the codings, all codes that were thematically similar were grouped together and labelled as a category, which became the

“I am not sure whether everyone does anything other than record [smoking

organising themes of our analysis.

status] as part of the history that they take.” (Interview 6 – doctor)

Results

There was also lack of routine documentation of patients’ smoking

HCP recruitment and participation

history by staff. According to one nurse, patients’ smoking history

Of the 26 HCPs approached, 16 agreed to participate. Of the 10

was not “written in black and white” and there was no “specific

that declined to participate, eight stated that they were busy and

column for it”.

two did not respond to the emails. The HCPs who participated were

“Sometimes it’s pack years, sometimes it’s ‘ex-smoker gave up 15 years

doctors (n=6), surgeons (n=2), nurses (n=5) and allied HCPs (n=3),

ago’, but not the amount. Maybe [it would be documented more] if

none of whom currently smoked. One nurse had stopped smoking

there was a routine hospital policy on how you document and to always

11 years previously (Figure 2).

document it.” (Interview 10 – allied HCP)

Current practice

Barriers to delivering smoking cessation advice

Most HCPs (75%; 12/16) routinely recorded patients’ smoking

All HCPs interviewed viewed the provision of smoking cessation

status on admission, 18.75% (3/16) did not do this routinely, and

advice as effective in increasing quit rates among patients. However,

6.25% (1/16) did not record patients’ smoking status at all. The

several barriers were reported when providing patients with such

18.75% (3/16) of participants recorded smoking status when

advice.

reminded to do so (i.e., on admission note or social history), or when it was relevant to the patient’s medical condition (i.e., if the

1. Patient and staff attitudes

patient had a respiratory condition).

Participants said that it can be difficult to encourage patients to quit

Only 43.75% (7/16) of the interviewed participants provided

smoking when they have no intentions of quitting at all.

smoking cessation advice to patients routinely, 37.5% (6/16) did not

“When you start talking to a patient about smoking, you can see them

routinely provide it, and 18.75% (3/16) did not provide it at all. The

shut off. Most patients when asked, they smile and, it’s like, ‘I suppose Volume 9: Number 1. 2016 | Page 29

RCSIsmjoriginal article you are going to give me a lecture now’…” (Interview 6 – doctor)

One nurse voiced the opinion that there should be immediate

It was also voiced that patients come to the hospital for specific

access to a cessation officer at all times.

medical problems and not smoking cessation, making it difficult for

“You can’t send people over and say ‘we will have them talk to you

HCPs to initiate.

tomorrow’.” (Interview 3 – nurse)

“The patient didn’t come to quit smoking, they came for [a different] problem, so it won’t have an impact.” (Interview 1 – surgeon)

One surgeon suggested that a smoking cessation clinic should be

One noted that there was no routine management for smoking

surgeon). With the heavy workload and the time constraints every

cessation.

HCP has, having a smoking cessation clinic where patients could be

“It was maybe done once or twice during a patient’s stay. I haven’t

followed up consistently and seen primarily for cessation would be a

seen it done any more.” (Interview 13 – doctor)

great improvement. Facilities such as community smoking cessation

With regard to staff attitudes, participants felt that there was a

pharmacotherapy for cessation are unavailable, affecting the quit

available in the hospital for patients willing to quit (Interview 1 –

programmes, support groups and follow-up services for patients on

“huge lack of awareness”, as most doctors “don’t know the actual

rates among patients.

process of referring someone for smoking cessation”. Furthermore,

“I think it’s important when a patient avails of a service, they should be

most HCPs do not think that this is their primary goal, and believe

followed up within six months.” (Interview 16 – allied HCP)

that they are not the “primary people” to give cessation advice. Both of these factors contributed greatly to the lack of provision of

“There are no community cessation programmes and facilities

cessation advice to patients.

available.” (Interview 15 – doctor)

“They are not coming to me actually to see that [smoking cessation], they are coming to me to diagnose a tumour, or treat their COPD with

Staff shortages in the hospital contributed to inconsistent provision

whatever medication. That is what I’m supposed to do as a doctor.”

of cessation advice. One nurse suggested that having a cessation

(Interview 15 – doctor)

nurse assigned to wards to follow up on patients would improve the

The lack of knowledge among junior staff also contributed to a lack

“I think if someone was assigned specifically, a nurse to go around and

of provision of smoking cessation advice. This resulted in HCPs not

check what patients are smokers and sit down [with them], maybe that

providing cessation advice routinely or intensively in the hospital.

will help.” (Interview 5 – nurse)

rate of delivering cessation advice.

Another doctor suggested that staff should be educated on “actual smoking-related illnesses and the latest figures on how smoking

3. Information not readily available

impacts on patients” in addition to cessation advice.

One practical barrier expressed by participants was a lack of

“I think [smoking cessation advice] needs to come from all members of

availability of information on smoking cessation. Without

the teams, because I think just one advising them to stop smoking is

information leaflets and posters readily available throughout the

not helpful.” (Interview 11 – allied HCP)

hospital, HCPs can only provide cessation advice verbally.

2. Time and service constraints

there were leaflets on the wards, it might help inpatients as well.”

Most respondents viewed time as a major factor in providing brief

(Interview 8 – doctor)

“There aren’t any information leaflets and things like that. So maybe if

cessation advice to patients. “We just lack time to talk to patients.” (Interview 14 – doctor)

“When you are in A&E admitting patients, you always ask about

“You have to do so much work. There is no time to spend per patient to

they make it to the wards, it’s forgotten, and you deal with their acute

give cessation advice.” (Interview 1 – surgeon)

problems.” (Interview 8 – doctor)

Having a part-time smoking cessation officer (three days per week)

4. Smoke-free campus

smoking history and it’s at the forefront of your mind ... By the time

was among the barriers faced by HCPs, as referrals made were “not

During the study period, the hospital had just implemented a

always consistent” (Interview 15 – doctor).

smoke-free campus policy and experienced several issues. Patients

Page 30 | Volume 9: Number 1. 2016

RCSIsmjoriginal article smoking in a hospital affects not only their health, but also subjects

However, Duffy et al. reported that only 17% of inpatient veteran

non-smoking parties to passive smoking, so with the hospital being

smokers received advice, despite more than two-thirds being

designated a smoke-free campus, there would have to be an increase

motivated to quit.15 In Ireland, Bartels et al. reported that 40% of

in the rate of provision of cessation advice and encouraging patients

smokers would like to receive cessation advice.6 A further barrier

to quit smoking. Hospital staff would also theoretically be motivated

identified was the lack of a facility to follow up patients who had

and encouraged to quit smoking, as there is a “restriction they have

received smoking cessation advice from HCPs. It has been

to respect” (Interview 1 – surgeon). However, the idea of the

demonstrated previously that cessation rates were higher in groups

smoke-free campus was not supported by all. One doctor said it “is

receiving extended counselling (22% versus 20% in the control

not fair for the palliative patients”, despite helping other patients with

group) and follow-up (28% versus 24% in the control group)

smoking cessation, and suggested that exceptions should be made

compared with those receiving brief advice.21 Training residents and

for these patients (Interview 9 – doctor).

labelling medical records with reminders has more than doubled the percentage (from 9% to 23%) of patients receiving advice.22

Discussion

Intervention, including a follow-up call, showed a rise in the

This is the first qualitative study to explore the views of HCPs in

six-month continuous abstinence rate (29.4% vs. 18.3%).11 Rigotti et

Ireland on the barriers to increasing smoking cessation advice for

al. confirmed that intensive intervention with follow-up support

patients. The main barriers identified from our study were time and

increased cessation rates.23 Multi-component interventions that

service constraints, patient and staff attitudes, information not readily

increase provision of cessation advice have demonstrated some

available, and issues with the smoke-free campus policy. Time

success. Freund et al. implemented a multi-strategic approach, which

constraint was viewed as the major barrier to the provision of

involved seven broad intervention strategy areas, and this was

smoking cessation advice to patients by HCPs. In an Irish study, 74%

effective in increasing hospital smoking care delivery and provision of

of nurses had no time to provide cessation advice to patients.14 In

nicotine replacement therapy.24 A further multi-strategic intervention

another study, smoking cessation counselling was perceived as too

trial showed that improving the routine provision of cessation care

time-consuming by physicians.8 According to Duffy et al., having

practices in a hospital setting is achievable.25 This confirms the need

trained nurses to deliver cessation care to patients is ideal, as nurses

for multi-component intervention to increase the efficiency of

are well informed on patients’ medical conditions, nursing time is

provision of cessation advice in a hospital setting.

more cost-effective compared to physician time, and nurses have

This study has several limitations. Results were based on interview

access to and immediate rapport with patients. Future research

sessions with HCPs, leading to recollections and biases of individuals

should investigate the suitability of nurses to deliver cessation care.

affecting the data’s accuracy. The sample size was 16 HCPs from a

Another barrier perceived was that HCPs underestimate the relevance

single large university teaching hospital, suggesting that the sample

of cessation advice to the patients and do not regard it as their

may not be representative of the entire HCP population. However,

primary goal and priority. This was reflected in other research: 76.3%

the HCPs interviewed are involved with patients directly in their

of physical therapists asked patients’ smoking status but only 21.6%

clinical practice and would be the ones providing cessation advice

reported assisting patients to quit smoking (due to lack of training).16

directly.

Despite HCPs being aware of the importance of smoking cessation, there is a lack of knowledge as regards counselling patients. Desalu et

Conclusion

al. found that 67% of physicians were aware of smoking cessation but

This study investigated the views of HCPs on increasing smoking

only 30.3% had knowledge on cessation counselling and 66.3% had

cessation advice for patients. We identified several barriers expressed

poor knowledge of interventions.17 An Irish study reported that 65%

by HCPs to providing cessation advice to patients. With the

of nurses lacked training in delivering cessation advice.14 Smoking

knowledge of these barriers, we are able to understand and overcome

patients who received cessation advice from two or more types of

them, and to personalise and improve the provision of smoking

HCP had an almost three-fold increase in quit attempts and readiness

cessation advice to patients, thus increasing smoking cessation rates.

to quit in the next six months.

Overall, this supports the need to implement a multi-component,

With regard to patient attitudes, patient resistance or unwillingness to

hospital-based intervention, or specialist cessation care, to promote

quit smoking was also among the barriers. Dentists and general

and increase the rate of provision of smoking cessation advice to

practitioners in the UK reported patient resistance as a barrier.19,20

patients by HCPs. Volume 9: Number 1. 2016 | Page 31

RCSIsmjoriginal article References 1. Department of Health. [Internet]. 2012 [cited 2012 Jul 17]. Available from:

service delivered in a United Kingdom hospital: a qualitative study.

http://www.dohc.ie/issues/smoking_ban/smokekey.html.

Tob Induc Dis. 2014;12(1):2.

2. Department of Health. Health Ireland Survey 2015. Ireland: Stationery Office, 2015. 3. Health Service Executive. Quit. [Internet]. 2010 [cited 2012 Jul 25]. Available from: http://www.quit.ie/en/1_in_every_2_smokers. 4. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ. 2004;328(7455):1519. 5. Stead LF, Bergson G, Lancaster T. Physician advice for smoking cessation. Cochrane Database Syst Rev. 2008;(2):CD000165. 6. Bartels C, Abuhaliga AR, McGee H, Morgan K, McElvaney NG,

14. O’Donovan G. Smoking prevalence among qualified nurses in the Republic of Ireland and their role in smoking cessation. Int Nurs Rev. 2009;56(2):230-6. 15. Duffy SA, Reeves P, Hermann C, Karvonen C, Smith P. In-hospital smoking cessation programs: what do VA patients and staff want and need? App Nurs Res. 2008;21(4):199-206. 16. Johnson NW, Lowe JC, Warnakulasuriya KA. Tobacco cessation activities of UK dentists in primary care: signs of improvement. Br Dent J. 2006;200(2):85-9. 17. Desalu OO, Adekoya AO, Elegbede AO, Dosunmu A, Kolawole TF, Nwogu KC. Knowledge of and practices related to smoking

Doyle F. A survey of the prevalence of smoking and smoking

cessation among physicians in Nigeria. J Bras Pneumo.

cessation advice received by inpatients in a large teaching

2009;35(12):1198-203.

hospital in Ireland. Ir J Med Sci. 2012;181(3):445-9. 7.

healthcare professionals’ views on a specialist smoking cessation

Ohakim A, Mellon L, Jafar B, O’Byrne C, McElvaney NG, Cormican L et al. Smoking, attitudes to smoking and provision of smoking cessation advice in two teaching hospitals in Ireland: do smoke-free policies matter? Health Psychol Behav Med. 2014;3(1):142-53.

8. Raupach T, Merker J, Hasenfuss G, Andreas S, Pipe A. Knowledge gaps about smoking cessation in hospitalized patients and their doctors. Eur J Cardiovas Prev Rehabil. 2011;18(2):334-41. 9. O’Loughlin J, Makni H, Tremblay M, Lacroix C, Gervais A, Déry V

18. An LC, Foldes SS, Alesci NL, Bluhm JH, Bland PC, Davern ME et al. The impact of smoking-cessation intervention by multiple health professionals. Am J Prev Med. 2008;34(1):54-60. 19. Bodner ME, Rhodes RE, Miller WC, Dean E. Smoking cessation and counselling: practices of Canadian physical therapists. Am J Prev Med. 2012;43(1):67-71. 20. Stacey F, Heasman PA, Heasman L, Hepburn S, McCracken GI, Preshaw PM. Smoking cessation as a dental intervention – views of the profession. Br Dent J. 2006;201(2):109-13. 21. Hjalmarson A, Boethius G. The effectiveness of brief advice and

et al. Smoking cessation counseling practices of general

extended smoking cessation counselling programs when

practitioners in Montreal. Prev Med. 2001;33(6):627-38.

implemented routinely in hospitals. Prev Med. 2007;45(2-3):202-7.

10. Gunes G, Karaoglu L, Genc MF, Pehlivan E, Egri M. University

22. Garnier CV, Meyer M, Leuppi J, Battegay E, Zeller A. Smoking

hospital physicians’ attitudes and practices for smoking cessation

cessation counselling: impact of chart stickers and resident training.

counseling in Malatya, Turkey. Patient Educ Couns.

Swiss Med Wkly. 2010;140(11-12):175-80.

2005;56(2):147-53. 11. Reid RD, Mullen K, Slovinec D’Angelo ME, Aitken DA, Papadakis S, Haley PM et al. Smoking cessation for hospitalized smokers: an evaluation of the “Ottawa Model”. Nicotine Tob Res. 2011;12(1):11-8. 12. Saito A, Nishina M, Murai K, Mizuno A, Ueshima F, Makiishi T et al. Health professionals’ perceptions of and potential barriers to smoking cessation care: a survey study at a dental school hospital in Japan. BMC Res Notes. 2010;3:329. 13. Bains M, Britton J, Marsh J, Jayes L, Murray LR. Patients’ and

Page 32 | Volume 9: Number 1. 2016

23. Rigotti NA, Clair C, Munafo MR, Stead LF. Interventions for smoking cessation in hospitalised patients. Cochrane Database Syst Rev. 2012;5:CD001837. 24. Freund M, Campbell E, Paul C et al. Increasing smoking cessation care provision in hospital: a meta-analysis of intervention effect. Nicotine Tob Res. 2009;11(6):650-62. 25. Freund M, Campbell E, Paul C et al. Increasing hospital-wide delivery of smoking cessation care for nicotine-dependent in-patients: a multi-strategic intervention trial. Addiction. 2009;104(5):839-49.

RCSIsmjoriginal article An investigation of responsiveness to PI3K inhibition in breast cancer cells expressing high levels of androgen receptor Abstract Introduction: Approximately 75% of breast cancers express androgen receptor (AR). There is conflicting evidence regarding the role of androgen signalling and breast cancer survival; a number of studies suggest a protective function but, more recently, AR has been shown to drive oestrogen receptor (ER) gene expression in ER-negative apocrine (AR positive, triple negative) breast cancer. This concept is echoed by a number of studies that have focused on the oncogenic potential of the AR. In this study, we evaluated responsiveness to PI3K inhibition in a series of breast cancer cell lines expressing varying levels of AR. Methods: IC50 values for the pan-class I PI3K inhibitor BEZ235 were established in a range of breast cancer cells in vitro. BEZ235 inhibits phosphorylation of Akt and also blocks the mTOR pathway. MTS assays were optimised and suitable drug concentrations were then evaluated. Endocrine-sensitive (MCF7) and -resistant (LetR, ZR75.1) cell lines were assessed. Results: MCF7 cells had an IC50 of 0.01031M, ZR75.1 cells had an IC50 of 0.001064M, and LetR cells had an IC50 of 0.001826M. Conclusion: Low-AR expression MCF7 cells were found to be much less sensitive to PI3K inhibition than the high-AR cell lines. AR could be used to identify endocrine-resistant patients who would benefit from second-line PI3K inhibitor therapy. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:33-8.

Introduction An estimated 246,660 new cases of invasive

phosphatase and tensin homologue (PTEN)

breast cancer are expected to be diagnosed in

mutations in Cowden syndrome and p53

2016 in the United States alone. While the exact

mutations in Li Fraumeni syndrome â&#x20AC;&#x201C; have also

aetiology is unclear, certain risk factors have been

been implicated.5,6 More recent studies have led

identified, with the majority related to prolonged

to the discovery of various subtypes of breast

oestrogen exposure. Risk factors include genetics,

cancer, and have elucidated the roles of different

family history, increasing age, early menarche,

hormones and oncogenic mutations.

late menopause, and high levels of sex steroid

Subtypes

hormones (e.g., for women on the oral

1 2

contraceptive pill or on hormone replacement

Four well-defined subtypes, based on cell

Oludare Alabi1

therapy).2 Pertaining to genetics, those with

receptor expression, have been identified:

Marie McIlroy2

BRCA 1 and 2 mutations are at a greatly

basal-like; human epidermal growth factor

increased risk, with some opting for prophylactic

receptor 2 (HER2) enriched; luminal A; and,

mastectomies and/or bilateral salpingo-

luminal B. Luminal A breast cancers are ER and

RCSI medical student

RCSI Department of Surgery

3,4

oophorectomies in order to reduce their risk.

progesterone receptor (PR) positive and HER2

Other rare genetic mutations â&#x20AC;&#x201C; such as

negative. Luminal B tumour cells are hormone Volume 9: Number 1. 2016 | Page 33

RCSIsmjoriginal article

FIGURE 1: Diagram showing the mechanism of action for BEZ235, adapted from Davis (2014).22 receptor (ER and PR) and HER2 positive. The HER2-enriched subtype

invasive and non-invasive carcinomas vary depending on

is hormone receptor (ER and PR) negative with HER2 amplification.

menopausal status. Studies suggest that premenopausal patients

Basal-like tumour cells are hormone receptor (ER and PR) and HER2

receive tamoxifen as first-line therapy, ovarian ablation as a suitable

negative, and are so-called â&#x20AC;&#x2DC;triple negativeâ&#x20AC;&#x2122; tumours. Subtype is a

second-line therapy, and an AI as a third-line therapy.11 However, for

prognostic factor; luminal A tumours account for about 72.7% of

postmenopausal women there is more variability in treatment

breast tumours in the United States and have a better prognosis

methods. Five years of treatment with tamoxifen has until recently

than luminal B (4.6%), triple negative (12.2%) and HER2-enriched

been seen as first-line therapy, followed by AIs as second-line

tumours (12%), with the latter three being more clinically

therapy, and a switch to another AI as third-line therapy.12,13 The use

aggressive.8 These subtypes are also useful in patient management

of AIs for five years instead of tamoxifen is also commonly accepted,

and treatment choice.

especially in patients with high recurrence risks.9 There has been

Breast cancer management

as first-line therapy in postmenopausal women, with tamoxifen

Treatment is determined by stage of disease, size of tumour, tumour

usually favoured in practice.9 However, the Arimidex, Tamoxifen,

prolonged debate over whether tamoxifen or an AI should be used

subtype, and patient age. Surgery remains the mainstay of breast

Alone or in Combination (ATAC) trial showed that AIs compare

cancer treatment, with radiotherapy, chemotherapy and endocrine

favourably to tamoxifen in disease-free survival, withdrawals and

therapy used as adjuvants. Endocrine therapy is highly dependent

side effects associated with tamoxifenâ&#x20AC;&#x2122;s partial agonist activity on the

on the molecular profile of the tumour.9 ER-positive tumours can be

ER (including vaginal discharge, thromboembolic disorders, and

successfully treated with complete oestrogen antagonists such as

endometrial cancer),13 suggesting that AIs should be seen as a

fulvestrant, selective oestrogen receptor modifiers (SERMs) such as

first-line treatment.

tamoxifen, or therapies that prevent the synthesis of oestrogen, e.g., aromatase inhibitors (AIs) such as anastrozole.10 The stage of breast

Role of androgen receptors

cancer is essential in determining optimal treatment. Non-invasive

There is now an increased recognition of the role of androgen

breast cancers are usually treated with breast-conserving surgery

receptors (ARs) in breast cancer, with about 60-70% AR positivity.14

(BCS) and prophylactic radiation; invasive carcinoma, on the other

The effects of ARs seem to vary based on the subtype in question.

hand, may require mastectomy, almost always requires a sentinel

ARs suggest good prognoses in ER-positive breast cancers, where

lymph node biopsy, and requires axillary clearance if there is nodal

they help to balance oestradiol-induced cell proliferation.7,15

involvement.9 Adjuvant endocrine treatment methods for both

However, in certain classes of ER-negative cancers, AR expression has

Page 34 | Volume 9: Number 1. 2016

RCSIsmjoriginal article Aims 1. Define the IC50 of BEZ235 for each of the following breast cancer cell lines: • MCF7 – endocrine sensitive; • ZR75.1 – endocrine sensitive; and, • LetR – endocrine resistant. The endocrine-sensitive cells are highly responsive to treatment by AI and tamoxifen, while the endocrine-resistant cell line is unresponsive despite being ER positive. 2. Evaluate if AR is wild-type or mutated in cells with varying sensitivity to BEZ235.

FIGURE 2: Western blot showing higher levels of AR in the letrozole-resistant (LetR) compared with the parental endocrine-sensitive MCF7aro cells.

Materials and methods

been linked to poor prognosis along with increased proliferation,

Previous work has shown that LetR cells express higher levels of AR

particularly in the molecular apocrine subtype, which is ER negative

than the sensitive MCF7 and MCF7aro cells (MCF7 cells

but AR positive.

Therefore, AR has become a possible target in the

treatment of breast cancer.

Cell models

overexpressing the enzyme aromatase) (Figure 2). The control line used was ZR75.1 cells, which have a luminal A profile like MCF7, but exhibit much higher levels of AR.20

PI3 kinase link with androgen receptors Because increased AR levels in certain cancers are a sign of poor

Cell culture

prognosis, current studies focus on factors that could cause

All cell culture work was carried out in a sterile fume hood with

abnormalities in normal AR functioning. Of interest, a recent study

laminar airflow. All methods were performed using aseptic

reported a link between kinase domain PI3K mutations and

technique. Cells were maintained in an incubator at 37°C with a

increased AR levels.16 The PI3K pathway has also been linked with

humid 5% (v/v) CO2 atmosphere.

survival of letrozole-resistant (LetR) cell lines;17 in addition, an association has been established between the PI3K and other

Routine passaging of cells in vitro

growth factor pathways with ligand-independent activation of the

Cells were grown in T-75cm2 filtered tissue culture flasks (Sarstedt;

AR. Relapses after successful inhibition of the AR have been

Germany) and passaged when approximately 80% confluent.

attributed to this.

By this logic, an inhibition of the PI3 kinase

Maintenance work was carried out by removing the old media and

pathway could be used as treatment for AR-positive tumours that do

washing cells with 5ml phosphate buffered saline (PBS; Oxoid Limited;

not respond well to conventional endocrine treatment.

Basingstoke, Hampshire, England). 2ml of 0.05% trypsin (v/v) 0.02%

BEZ235 mechanism of action

growing surface, for incubation for five minutes at 37°C. Trypsin was

EDTA (v/v) solution (Sigma Aldrich) was used to detach cells from

BEZ235 is a pan-class PI3K inhibitor, which has been shown to

neutralised with 5ml of phenol red-free Minimum Essential Medium

inhibit the PI3K/Akt/Mammalian target of rapamycin kinase

(PRFMEM; Gibco LifeSciences) and the cell suspension was transferred

pathway. It works by binding to the adenosine triphosphate (ATP)

from the flask to a 15ml tube for centrifugation at 1,000rpm for three

cleft of these enzymes, competitively preventing binding of ATP. The

minutes at room temperature. The pellet was then re-suspended in the

PI3K pathway has been implicated in various cancers, and therefore

appropriate volume of suitable media and sub-cultured at a lower

its inhibition by BEZ235 is a possible treatment option for various

confluency into a T-75 flask.

cancers.19 The mechanism of action can be seen in Figure 1.

Endocrine treatment of cells Hypothesis

MCF7 cells express ER and PR, are negative for HER2 amplification,

Breast cancer cells that express high levels of AR will exhibit greater

and were obtained from the American Type Culture Collection

sensitivity to the pan-class I PI3K BEZ235 (provided by Novartis).

(ATCC). These were maintained in minimum essential media (Sigma Aldrich; Germany), supplemented with 10% (w/v) foetal calf serum Volume 9: Number 1. 2016 | Page 35

RCSIsmjoriginal article Table 1: Key to Figures 3, 4, and 5.

(FCS) (Sigma Aldrich) and 2mmol/l L-glutamine (Sigma Aldrich),

Concentration

Log concentration

1µm

0.000

0.1µm

-1.000

along with 1% (w/v) Penicillin Streptomycin (Pen/Strep). LetR cells were created by long-term treatment (>3 months) of MCF7aro cells with letrozole (Novartis; Basel, Switzerland). Cells

0.01µm

-2.000

were cultured in PRFMEM containing 10% (w/v) charcoal dextran

0.001µm

-3.000

stripped-FCS, androstenedione (10-9M; Sigma Aldrich), letrozole

0.0001µm

-4.000

(10-6M) and G418 (200g/ml). ZR75.1 cells were maintained in RPMI 1640 media (Sigma Aldrich) and supplemented with 10% (w/v) FCS, 1mmol/l L-glutamine

IC50 MCF-7 Bez

(Sigma Aldrich) and 1% (w/v) Pen/Strep.

Normalised cell growth

150 IC50

0.01031

100

Cell counting The cell pellet was re-suspended after centrifuging in 10ml of media. 15µl of this suspension was transferred to a 1.5ml Eppendorf

tube along with 15µl of trypan blue (Sigma Aldrich). 10µl of this mixture was then pipetted onto a haemocytometer (Marienfeld

0 -4

-3

-2

-1

Superior; Germany). Cells were counted manually under the

microscope in each of the four 4x4 grids on the haemocytometer

Log concentration

and averaged. The appropriate volume of cell suspension was

FIGURE 3: Graph showing IC50 for MCF-7.

calculated and seeded into a suitable culture plate for its purpose.

Cell proliferation assay

IC50 ZR75.1 Bez

Cells were cultured, trypsinised, counted and seeded at a defined

Normalised cell growth

150 IC50

~ 0.001064

100

concentration. 50µl of the cell suspension was placed in each well at 3x103 cells per well. Cells were plated into a 96-well plate (Greiner Bio-One; Germany). Dimethyl sulfoxide (DMSO) was used as the vehicle control.

0 -4

Method development for IC50 -3

-2 -1 Log concentration

The IC50 is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug/inhibitor

FIGURE 4: Graph showing IC50 for ZR75.1.

compound is needed to inhibit a given biological process by half, in this case cell viability.

Normalised cell growth

IC50 LetR Bez 150

Optimisation IC50

0.001826

100

Cell concentration per well, drug concentration and treatment duration were optimised over a series of preliminary phases. Stage 1: During the exploratory stage of the research the optimal

cell concentration for treatment was determined. Cells were initially seeded at 1×103 and treated with BEZ235 and DMSO (control

0 -4

-3

-2

-1

Log concentration FIGURE 5: Graph showing IC50 for LetR. Page 36 | Volume 9: Number 1. 2016

treatment) at varying concentrations for 24 hours. Stage 2: This was the drug concentration optimisation stage. Following an evaluation of the results, the cells were seeded at 3×103 cells per well and treated for 24 hours using the same

RCSIsmjoriginal article Discussion

Table 2: Summary of BEZ235 IC50 for each cell line. AR expression

We compared the responsiveness to treatment with BEZ235 in

BEZ235 IC50 (molar)

ZR75.1 and LetR vs MCF7 cell lines. High levels of AR expression MCF7

LOW

equated to greater sensitivity to PI3K/mTOR pathway disruption

0.01031

by BEZ235. This effect was seen when comparing IC50s for the cell lines with higher AR levels (ZR75.1 and LetR) with the IC50

ZR75.1

HIGH

for MCF7 cells, which express low levels of AR. The fact that

0.001064

ZR75.1 cells and MCF7 cells primarily differ in their expression of the AR further reinforces this point. LetR

HIGH

0.001826

Most work on adjuvant treatment of breast cancer currently focuses on the role of ER, PR, and HER2, as these are the most

concentrations as in Stage 1. Insolubility of BEZ235 at high

commonly expressed hormone receptors in breast tumours.

concentrations led to an adjustment of drug concentrations. Stage 3: Final changes were made and cells were seeded at 3×10

However, the role of the AR should not be understated, as it is 3

becoming increasingly evident that the AR plays a role in the

cells. The duration of the treatment was also adjusted to 48 hours to

development, progression and prognosis of breast cancer. The

allow enough cell growth that would display adequate differences

results from this experiment indicate that there are interplays

between the drug and control treatments.

downstream in the signalling cascade, which could affect treatment response. This study shows the role of the AR in the

DNA isolation

PI3K pathway, which could be just one of many; however, we

DNA extraction was carried out with a DNeasy Kit (Qiagen). Pellets

can ascertain that exploration of the AR in breast cancer could

were harvested from six-well plates on which cells had been

lead to a whole new realm of therapeutic options for patients.

cultured. Pellets were stored in Eppendorf containers in a freezer at

Assessment of AR expression could indicate which patients

-81°C until DNA isolation was ready to be carried out. Cells were

would benefit from PI3K inhibitors; this accentuates the need to

re-suspended in 200µl of PBS and 20µl of proteinase K was added.

develop a wider range of endocrine therapies and explore

200µl of Buffer AL was added, the mixture was homogenised by

factors that can be used to optimise treatment for individual

vortexing and incubated for 10 minutes at 56°C. 200µl of ethanol

patients.

was added to the mixture, followed by further vortexing. The mixture was transferred to a spin column and placed in a 2ml

Conclusion

collection tube. It was centrifuged at 8,000rpm for one minute, with

Clinical studies are currently being carried out in order to

the flow-through subsequently discarded. This step was repeated

determine the tolerability of BEZ235 and its efficacy as an

after the addition of Buffer AW1. Buffer AW2 was added to the spin

anti-tumour drug.21 However, there has not been much research

column and centrifuged for three minutes at 14,000rpm.

done investigating the relationship and interplay between AR

The flow-through was discarded once again and the spin column

levels and the PI3K/mTOR pathway.

was transferred to a 1.5ml microcentrifuge tube. DNA was eluted by

More research must be carried out in order to discover factors

adding 200µl Buffer AE to the centre of the spin column. The DNA

that could help to select the best therapies for individuals based

was incubated at room temperature for one minute and centrifuged

on their tumour’s receptor profile, particularly with regard to AR

again at 8,000rpm. This step was repeated once again to optimise

expression.

the yield.

Acknowledgements Results

Thanks to Dr Marie McIlroy, to my supervisor Laura Creevey,

IC50 curves were graphed using the software GraphPad Prism 5.

and to all in the Department of Surgery lab. This project was

LetR and ZR75.1 cells (IC50: 0.001826 and 0.001064, respectively),

funded by the RCSI Undergraduate Research Summer School

which have high levels of AR, were more responsive to BEZ235 than

Student Fund, RCSI Alumni, The Charitable Infirmary Charitable

the MCF7 cell line (IC50: 0.0103) (Table 1; Figure 3; Figure 4;

Trust, and the Association of Physicians of Great Britain &

Figure 5; Table 2).

Ireland. Volume 9: Number 1. 2016 | Page 37

RCSIsmjoriginal article References 1. American Cancer Society. Breast Cancer Facts & Figures 2013-2014. [Internet] 2014. Available from: http://www.cancer.org/acs/groups/content/@research/docume nts/document/acspc-042725.pdf. 2. McPherson K, Steel CM, Dixon JM. ABC of breast diseases.

12. Barrios C, Forbes JF, Jonat W, Conte P, Gradishar W, Buzdar A et al. The sequential use of endocrine treatment for advanced breast cancer: where are we? Ann Oncol. 2012;23(6):1378-86. 13. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in

Breast cancer-epidemiology, risk factors, and genetics. BMJ.

Combination) trial after completion of 5 years’ adjuvant

2000;321(7261):624-8.

treatment for breast cancer. Lancet. 2005;365(9453):60-2.

3. King MC, Marks JH, Mandell JB; New York Breast Cancer Study

14. Ni M, Chen Y, Lim E, Wimberly H, Bailey Shannon T, Imai Y et al.

Group. Breast and ovarian cancer risks due to inherited

Targeting androgen receptor in estrogen receptor-negative breast

mutations in BRCA1 and BRCA2. Science.

cancer. Cancer Cell. 2011;20(1):119-31.

2003;302(5645):643-6. 4. Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL, van’t Veer L,

15. Hu R, Dawood S, Holmes MD, Collins LC, Schnitt SJ, Cole K et al. Androgen receptor expression and breast cancer

Garber JE et al. Bilateral prophylactic mastectomy reduces

survival in postmenopausal women. Clin Cancer Res.

breast cancer risk in BRCA1 and BRCA2 mutation carriers: The

2011;17(7):1867-74.

PROSE Study Group. J Clin Oncol. 2004;22(6):1055-62. 5. Masciari S, Dillon DA, Rath M, Robson M, Weitzel JN, Balmana J et al. Breast cancer phenotype in women with TP53 germline mutations: a Li-Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012;133(3):1125-30. 6. Schrager CA, Schneider D, Gruener AC, Tsou HC, Peacocke M.

16. Gonzalez-Angulo AM, Stemke-Hale K, Palla SL, Carey M, Agarwal R, Meric-Berstam F et al. Androgen receptor levels and association with PIK3CA mutations and prognosis in breast cancer. Clin Cancer Res. 2009;15(7):2472-8. 17. Cavazzoni A, Bonelli MA, Fumarola C, La Monica S, Airoud K, Bertoni R et al. Overcoming acquired resistance to letrozole by

Clinical and pathological features of breast disease in

targeting the PI3K/AKT/mTOR pathway in breast cancer cell

Cowden’s syndrome: an underrecognized syndrome with an

clones. Cancer Lett. 2012;323(1):77-87.

increased risk of breast cancer. Hum Pathol. 1998;29(1):47-53. 7. Fioretti FM, Sita-Lumsden A, Bevan CL, Brooke GN. Revising the role of the androgen receptor in breast cancer. J Mol Endocrinol. 2014;52(3):R257-65. 8. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LAG

18. Manin M, Baron S, Goossens K, Beaudoin C, Jean C, Veyssiere G et al. Androgen receptor expression is regulated by the phosphoinositide 3-kinase/Akt pathway in normal and tumoral epithelial cells. Biochem J. 2002;366(Pt 3):729-36. 19. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C et

et al. US incidence of breast cancer subtypes defined by joint

al. Identification and characterization of NVP-BEZ235, a new

hormone receptor and HER2 status. J Natl Cancer Inst.

orally available dual phosphatidylinositol 3-kinase/mammalian

2014;106(5). pii: dju055. doi: 10.1093/jnci/dju055.

target of rapamycin inhibitor with potent in vivo antitumor

9. Kataja V, Castiglione M, Group Obot EGW. Primary breast cancer: ESMO Clinical Recommendations for diagnosis,

activity. Mol Cancer Ther. 2008;7(7):1851-63. 20. Magklara A, Brown TJ, Diamandis EP. Characterization of

treatment and follow-up. Ann Oncol. 2009;20(Suppl.

androgen receptor and nuclear receptor co-regulator expression

4):10-4.

in human breast cancer cell lines exhibiting differential regulation

10. Ciruelos E, Pascual T, Arroyo Vozmediano ML, Blanco M, Manso L, Parrilla L et al. The therapeutic role of fulvestrant in the management of patients with hormone receptor-positive breast cancer. Breast. 2014;23(3):201-8. 11. Carlson RW, Henderson IC. Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or

of kallikreins 2 and 3. Int J Cancer. 2002;100(5):507-14. 21. Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I. Targeting the translation machinery in cancer. Nat Rev Drug Discov. 2015;14(4):261-78. 22. Davis J. BEZ235-dual PI3K/mTOR inhibitor. [Internet] 2012 [cited 2014 July 24]. Available from:

anastrozole. Breast Cancer Res Treat. 2003;80(Suppl.

http://www.selleckchem.com/blog/BEZ235-dual-PI3K-mTOR-inhi

1):S19-26;discussion S7-8.

bitor.html.

Page 38 | Volume 9: Number 1. 2016

RCSIsmjreview Epidemiological evaluation of rotavirus burden and potential impact of vaccination in Uganda

Abstract Rotavirus is an RNA virus that causes diarrhoeal disease and represents a significant cause of hospitalisation and death in children under five worldwide. The disease burden is particularly high in developing countries, including those in sub-Saharan Africa, where the population is young, sanitation is often poor and access to healthcare limited. Vaccination against the virus has been available since 2006, but population vaccination schedules have not yet been introduced worldwide. Vaccination programmes, including those in several sub-Saharan countries, have been successful in significantly relieving the burden of disease. Uganda, which has one of the highest rotavirus-associated death rates in the world, is scheduled to introduce the vaccine into its national schedule during 2016. As such, it seems an appropriate time to assess the current epidemiological status of rotavirus infection in Uganda, and to discuss important factors that must be considered in the implementation of the vaccine. These factors include cost-effectiveness and a dosing schedule for maximal efficacy, while minimising potential dangerous side effects like intussusception. If implemented properly and effectively, the rotavirus vaccine stands to save millions of lives in Uganda and around the world.

Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:39-43.

Introduction

Alison Cameron-Vendrig Katie Dunleavy

Rotavirus is the leading cause of diarrhoeal illness

significantly decreased rates of infection. In

in children under five, killing over 450,000

Uganda, where 49% of the population is under

children annually.1,2 Infection with the virus

15 years of age, rotavirus is a significant cause of

occurs in all parts of the world; however, the

childhood mortality and poses a substantial

burden of disease and death is greatest in Asia

healthcare burden.7 Newly developed and

and Africa.

3,4

In these regions, the threat of

licensed rotavirus vaccines have proven

rotavirus is most substantial because of the lack

successful in developing countries, and have the

of supportive care, such as rehydration and

potential to help abate Ugandan childhood

Samuel Skulsky

electrolyte therapy, often due to poor healthcare

mortality.1,2,6,8 This paper will review the

Caroline Treacy

infrastructure and lack of funding.1,5,6 It is

epidemiology of rotavirus infection in Uganda

thought that the virus is transmitted via the

and explore the potential benefits of the

hands of contaminated individuals, as countries

introduction of a national vaccination

with improved sanitation systems exhibit

programme.

Justin Greco Zhubene Mesbah

RCSI medical students

Volume 9: Number 1. 2016 | Page 39

RCSIsmjreview Rotavirus

Uganda has an estimated annual incidence of 10,944 non-severe

Rotavirus is a double-stranded RNA virus whose serotypes are

and 576 severe cases of rotavirus per 100,000 people aged one to

determined by the proteins VP7 (G protein) and VP4 (P protein).

59.13 A study conducted at the Mulago National Referral Hospital in

These antigens are located on the outer capsid of the virus and elicit

Kampala showed that rotavirus accounted for 32.8% of cases of

an antibody-mediated response, which facilitates partial humoral

acute diarrhoea in children, most of whom were between three and

immune protection.1,9 A Cochrane review by Soares-Weiser et al.

23 months old.14 Another 2010 study by Nakawesi et al. at the same

reported the presence of approximately 15 G and 26 P antigen

hospital found that rotavirus accounted for almost half of the cases

types in human rotavirus strains, theoretically producing 390

of acute diarrhoeal hospitalisations in children.15 This figure is

(15Gx26P) combinations of various viral subtypes.2 This large

consistent with WHO global networks for surveillance of rotavirus

genetic diversity results from point mutations creating new G or P

data, and the actual figure is likely somewhere between 30 and

antigens, reassortment of related strains causing antigenic shift, and

50%.15

crossing of animal strains with the capability to infect humans. Only five strains have been associated with the majority of human infections: G1P[8]; G2P[4]; G3P[8]; G4P[8]; and G9P[8].

1,2,9,10

Increased prevalence of rotavirus in Uganda Nakawesi et al. also observed that breastfeeding children were 2.5 times more likely to contract rotavirus than those who did not.

Course of infection

This is in contrast to previously published data, which suggested

Rotavirus is transmitted through the faecal-oral route, frequently due

that breastfeeding confers some protection against contracting the

to inadequate hygiene, especially when preparing food. Following

virus.16,17 Nakawesi et al. explained the contrasting result of their

ingestion, the virus enters the villi of the epithelial cells lining the

study by hypothesising that the majority of infants included in

small intestine and replicates. The virus inhibits absorption of vital

their study were not exclusively breastfed, and therefore did not

nutrients, including glucose and sodium, which subsequently causes

consume enough breastmilk to confer immunity.15 However, in a

luminal water retention and diarrhoea. Although humoral immunity

2011 matched case-control study performed at the same hospital,

increases with repeated infection, it fails to achieve complete

breastfeeding failed to show protection against rotavirus

protection, thus allowing re-infection at any age. The average

infection.18

incubation period for rotavirus is 48 hours, with fever and vomiting

The authors also found that dehydration in children resulted in a

developing thereafter. Watery diarrhoea typically begins 24-48 hours

two-fold risk of contracting rotavirus. This finding corroborates

after initial symptoms present, with up to 20 bowel movements per

previous literature and speaks to the higher disease burden in

day. The illness typically lasts for three to eight days, with primary

low-income countries, where there is more limited access to clean

complications of dehydration, electrolyte imbalances and metabolic

water for rehydration therapy.15 Studies conducted in sub-Saharan

acidosis,5 which can be exacerbated in areas lacking access to basic

Africa (excluding Uganda) have also found that nutritional status,

medical care. Enzyme-linked immunoassay (EIA) and latex

disease during the dry season, and age under two years are linked

agglutination remain the laboratory diagnostic tools of choice for

to the prevalence of rotavirus. Interestingly, no association between

identification of rotavirus viral antigens in stool samples.1,5 Most

rotavirus and HIV has been found, and children infected with HIV

deaths caused by rotavirus are seen in young children in developing

have been shown to mount a similar seroresponse to rotavirus

countries in Asia and Africa; Angola and Uganda have the highest

infection as those not infected with HIV, and to clear the virus

mortality rates in the world at 1.9% and 2.3%, respectively.3

effectively.15,19-21

Uganda and rotavirus

burden. A study of the microbial risks to human health in the water

Sanitation is also an important factor contributing to disease

Uganda is a landlocked country located in East Africa with a

in the Bwaise III slum in Kampala estimated that 20% of infections

population of approximately 35 million.11 The life expectancy at

were due to rotavirus contamination, mainly from exposure to open

birth in Uganda is 57 and its under-five mortality rate is ranked

surface water drainage channels.22 This study also found that the

thirtieth in the world at 74 deaths per thousand.11 In 2013, 8,383

total disease burden from water-borne pathogens was 680

deaths were reported in children under four from diarrhoeal disease,

disability-adjusted life years (DALYs) per 1,000 persons per year. This

which is the sixth leading cause of death in children under five in

is several orders of magnitude higher than the WHO reference level

Uganda and accounts for 8% of deaths in this age group.7,12

of tolerable risk.22

Page 40 | Volume 9: Number 1. 2016

RCSIsmjreview Rotavirus vaccine

sub-Saharan African countries.29 The cost-effectiveness of a new

Medically, rotavirus gastroenteritis has no cure, although

health intervention is an important factor requiring consideration

supportive therapy is frequently employed and typically includes

by decision-makers prior to its introduction.13 Reports on the

fluid replacement and electrolyte replenishment.1 Two rotavirus

cost-effectiveness of introducing the rotavirus vaccine in Uganda

vaccines have been approved and are used worldwide: RV1

estimate that approximately four million cases of rotavirus and 1,6,23

70,236 rotavirus-related deaths from 2016 through to 2035 would

RV1 is a monovalent, attenuated rotavirus vaccine of the common

be avoided,30 with an estimated cost per DALY averted of $34 USD

G1P strain. RV5 is a pentavalent vaccine derived from five naturally

in Uganda.13 Vaccines could potentially prevent 4.4 million

occurring bovine strains, which have undergone genomic

DALYs.30 Administered orally, these vaccines are 85-98% effective

reassortment to introduce features of the human rotavirus strains.

in preventing severe rotavirus disease in infants and young

Four of the strains express G1, G2, G3 and G4 human rotavirus

children.31 RotaTeq (RV5) is given in three doses at ages two

(Rotarix速) by GlaxoSmithKline and RV5 (RotaTeq速) by Merck.

surface proteins. The fifth strain expresses the P(8) surface proteins

months, four months, and six months, while Rotarix (RV1) is given

from human rotavirus strains.2,6 The vaccines were initially tested in

in two doses at ages two months and four months. The timing of

developed countries, but recent concerns have arisen about the

the vaccines tends to differ between middle to upper-income

effectiveness of the vaccines within countries in Africa and Asia,

countries and lower-income countries, since access to healthcare has

which have the highest incidence of disease.24,25 Strain diversity in

greater barriers in low-income countries, making the Rotarix

Africa is much more heterogeneic than Asia; predominant strains

two-dose vaccine more appealing, with a higher chance of complete

include G1, G9, G2, P[8], P[6], and P[4] P proteins.26 Although

dosing. This is primarily due to existing vaccination schedules, and

some variation exists between vaccine strains and circulating

the logistics of delivering and storing multiple vaccines. In many

strains, evidence suggests that rotavirus vaccines provide both

low-income countries, poor health service access precludes some

heterotypic and homotypic protection. However, the vaccine is less

children from timely vaccination. The WHO rotavirus position urges

effective in developing countries.

2,10,25

Currently, 79 countries have

implemented rotavirus vaccination programmes. Financial aid from

countries to consider providing rotavirus vaccination to these children, even if it would be later than recommended.32 In

the Global Alliance for Vaccines and Immunization (GAVI) has

low-income countries with a high burden of rotavirus disease, the

enabled the implementation of rotavirus vaccine programmes in

protection provided by the licensed vaccines is lower (39% for

many low-income African countries. However, countries such as

RotaTeq and 49% for Rotarix) than that reported in high-income

Uganda, which has one of the highest burdens of disease, have

countries (about 85% for RotaTeq and 82% for Rotarix).8

only recently planned a national rotavirus vaccination

A birth dose strategy for rotavirus vaccination may have the

programme.

3,6,27

potential to address these challenges.33 Rotavirus infection occurs at a younger age in low-income countries and early infection is

Vaccination strategies

often associated with more severe disease.34,35 Administration of

Several evidence- and population-based strategies can be

the first dose of the vaccine at six weeks of age leaves a gap in

employed to attenuate the disease burden of rotavirus in Uganda.

protection. A birth dose would bridge this gap, and potentially

Introduction of a national rotavirus vaccination schedule offers the

enhance coverage and timeliness of vaccine completion,

opportunity to reduce rotavirus-related disease. Of the ten

particularly in countries with immunisation-related challenges.36

countries comprising East Africa, eight have already incorporated

Additionally, intestinal barriers to vaccine efficacy, such as

the rotavirus vaccine into their national immunisation

interference from breastmilk antibodies or environmental

programmes. Uganda has yet to implement the vaccine, although

enteropathy, may be limited if the vaccine is administered at birth

according to the WHO Ugandan National Planning Cycles,

when breast milk intake is still low and intestinal microbiota has

introduction of the vaccine is planned for April 2016.28 Uganda has

not yet been established.33,37,38,39 Intussusception is considered rare

shown a preference towards the monovalent RV1 Rotarix vaccine,

in the first two months of life, so it is thought that administration

as have a majority of developing countries, due to longer shelf life

of a birth dose could also improve the safety profile of rotavirus

and a shorter dosing schedule.29 The WHO recommends that

vaccines.33 Neonatal and infant vaccination with the RV3-BB

rotavirus vaccines should be included in all national immunisation

rotavirus vaccine was found to be well tolerated and

programmes, particularly in South Asian, Southeast Asian, and

immunogenic.33 Volume 9: Number 1. 2016 | Page 41

RCSIsmjreview Conclusion The burden of disease of rotavirus in Uganda presents a significant

vaccine in Uganda is a cost-effective solution to significantly reduce

strain on the healthcare system and continues to pose a threat to its

the burden of the virus. With the aid of the GAVI initiative, which

young population. In sub-Saharan African countries, such as Malawi,

provides rotavirus vaccines at reduced cost, the Ugandan Ministry of

Ghana, and Kenya, a vaccine schedule has been successfully

Health will be adding Rotarix to its national vaccination calendar in

implemented, and has prevented over 60% of severe disease in

2016.16,17 With the implementation of this prevention strategy,

children in their first year of life.40 The introduction of the rotavirus

Uganda’s children stand to benefit for years to come.

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double-blind, placebo-controlled trial. Lancet Infect Dis.

23. Jiang V, Jiang B, Tate J, Parashar UD, Patel MM. Performance of rotavirus vaccines in developed and developing countries. Hum Vaccin. 2010;6(7):532-42. 24. Madhi SA, Cunliffe NA, Steele D, Witte D, Kirsten M, Louw C et al. Effect of human rotavirus vaccine on severe diarrhea in African infants. N Engl J Med. 2010;362(4):289-98. 25. Groome MJ, Page N, Cortese MM, Moyes J, Zar HJ, Kapongo CN et al. Effectiveness of monovalent human rotavirus vaccine

2015;15(12):1389-97. 34. Tiku VR, Sharma S, Verma A, Kumar P, Raghavendhar S, Aneja S et al. Rotavirus diversity among diarrheal children in Delhi, India during 2007-2012. Vaccine. 2014;32(Suppl. 1):A62-7. 35. Mathew A, Rao PSS, Sowmyanarayanan TV, Kang G. Severity of rotavirus gastroenteritis in an Indian population: report from a 3 year surveillance study. Vaccine. 2014;32(Suppl.1):A45-8. 36. World Health Organization. Weekly epidemiological record

against admission to hospital for acute rotavirus diarrhoea in

2011:pp. 432-3. [Internet] Available from:

South African children: a case-control study. Lancet Infect Dis.

http://www.who.int/wer/2011/wer8639.pdf?ua=1.

2014;14(11):1096-104. 26. Seheri M, Nemarude L, Peenze I, Netshifhefhe L, Nyaga MM, Ngobeni HG et al. Update of rotavirus strains circulating in Africa from 2007 through 2011. Pediatr Infect Dis. 2014;33(Suppl.1):S76-84. 27. Mwenda JM, Ntoto KM, Abebe A, Enweronu-Laryea C, Amina I,

37. Chan J, Nirwati H, Triasih R, Bogdanovic-Sakran N, Soenarto Y, Hakimi M et al. Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries? Vaccine. 2011;29(6):1242-7. 38. Groome MJ, Moon S-S, Velasquez D, Jones S, Koen A, van Niekerk N et al. Effect of breastfeeding on immunogenicity of

Mchomvu J et al. Burden and epidemiology of rotavirus diarrhea

oral live-attenuated human rotavirus vaccine: a randomized trial

in selected African countries: preliminary results from the African

in HIV-uninfected infants in Soweto, South Africa. Bull World

Rotavirus Surveillance Network. J Infect Dis. 2010;202(Suppl.1):S5-11. 28. Ruth AJ. Uganda National Expanded Program on Immunization

Health Organ. 2014;92(4):238-45. 39. Kosek M, Guerrant RL, Kang G, Bhutta Z, Yori PP, Gratz J et al. Assessment of environmental enteropathy in the MAL-ED cohort

Multi Year Plan 2012-2016. [Internet] [Accessed 2015 October

study: theoretical and analytic framework. Clinical Infect Dis.

28] Available from:

2014;59(Suppl.4):S239-47.

http://www.nationalplanningcycles.org/sites/default/files/plannin g_cycle_repository/uganda/uganda_epi_cmyp_2012-2016.pdf. 29. World Health Organisation. Rotavirus. [Internet] [Accessed 2015

40. Gavi, the Vaccine Alliance. Rotavirus vaccine support. [Internet] [Accessed 2015 November 18] Available from: http://www.gavi.org/support/nvs/rotavirus/.

November 8] Available from: http://www.who.int/immunization/diseases/rotavirus/en/.

Volume 9: Number 1. 2016 | Page 43

RCSIsmjreview The history, mystery, and management of fibromyalgia

Abstract Fibromyalgia is a chronic condition characterised by widespread musculoskeletal pain and somatic symptoms of fatigue, depression and sleep disturbance. For years, patients presenting with longstanding regional pain were given a label of â&#x20AC;&#x2DC;chronic painâ&#x20AC;&#x2122;. To date, the exact pathophysiological mechanism underlying the development of fibromyalgia has not been fully elucidated, although many theories have been put forth in the literature. The most prominent theory describes an underlying central neuropathophysiology characterised by altered pain processing. The use of novel functional imaging studies has provided us with potentially the most objective evidence to date of the mechanism of central sensitisation, which remains the most widely accepted theory to date. However, the most recent literature describes widespread small nerve fibre pathology, consistent with significant reports of peripheral neuropathic symptoms in patients with fibromyalgia. Other theories under investigation include roles for immune system abnormalities such as elevated levels of cytokines and hypoactivity of the hypothalamuspituitary-adrenal (HPA) axis. There is also much debate regarding the role of vitamin D deficiency, with some studies suggesting a correlation between low levels of vitamin D and patient-reported Ghaleb Halaseh RCSI medical student

pain scores. This review will discuss some of the prominent theories about fibromyalgia and the current recommendations for management of the disease. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:44-50.

Page 44 | Volume 9: Number 1. 2016

RCSIsmjreview Background

sensitisation, imbalances in systemic levels of pro-inflammatory

Fibromyalgia is a chronic condition characterised by widespread

and anti-inflammatory cytokines, and disturbances in the HPA

musculoskeletal pain with multiple soft tissue tender points

axis are becoming more evident.4,5,10,11 Together with the two

symmetrically distributed across the body. Allodynia,

characteristic symptoms of allodynia and diffuse hyperalgesia,

hyperalgesia, fatigue, sleep disturbances, and neurocognitive

these theories are in line with the notion of an underlying

impairment are also features of the condition, which affects

central nervous system pathology in pain processing.13

2-3% of the population, predominantly middle-aged females.1,2 For years, patients presenting with longstanding regional pain for which a definite cause could not be identified, and for which inflammatory and biochemical markers were negative, were simply given a label of ‘chronic pain’, or diagnoses ranging from temporomandibular joint syndrome, to irritable bowel syndrome, to simply chronic back pain.3

Data from these studies are adding to an already impressive volume of evidence that points towards an underlying enhancement of pain processing in fibromyalgia.

A more coherent picture is now being drawn, with recent studies suggesting that syndromes characterised by chronic regional pain are not separate entities, but different

Central nervous system

manifestations of a sole central neuropathophysiology. This

Studies have shown that patients with fibromyalgia have a lower

shifts the historical blame from a local pathologic process,

pain threshold, with greater pain scores in response to heat,

corresponding to the region of pain, to the central nervous

cold, electrical and pressure stimuli. Furthermore, these patients

system.3 Other prominent theories describe a potential link

do not exhibit the typical exercise-induced analgesic

between hypoactivity of the hypothalamus-pituitary-adrenal

response.15,16 However, these studies are often scrutinised for

(HPA) axis and fibromyalgia.4,5 The roles of the immune system

the lack of an objective pain scale, often resorting to

and vitamin D levels have also been extensively explored.6-11

patient-reported pain as a data reference.17,18

In 1990, The American College of Rheumatology (ACR) released

With the use of functional magnetic resonance imaging (fMRI)

a set of diagnostic criteria for fibromyalgia. These included both

and positron emission tomography, regions of the brain central

a history of widespread pain – which is defined as pain above

to pain processing, such as the insula and the anterior cingulate

and below the waist, on both sides and in the axial skeleton – as

cortex, have been identified.19,20 In one study, fMRI

well as at least 11 out of 18 identified tender points.

demonstrated a decreased activation of the rostral anterior

However, this ignored major manifestations of fibromyalgia such

cingulate cortex (rACC) in patients with fibromyalgia as

as psychiatric and sleep disturbances. In 2010, these criteria

compared to controls. The rACC region is made up of a high

were revised to include such manifestations, causing the ratio of

density of opioid receptors, and is a vital descending inhibitory

women to men affected to fall from 10:1 to 2:1, which is in line

system.19 This dysfunction is in line with other reports regarding

with many other chronic pain disorders.

In 2011 the criteria

the inefficacy of opioids as a treatment in fibromyalgia.21,22 In

were further revised, eliminating physician assessment scores

another study using fMRI, patients with fibromyalgia produced a

entirely.

cerebral response to the application of a mild stimulus

This most recent set of diagnostic guidelines includes the

equivalent to that of the control group’s response to a stimulus

widespread pain index (WPI) scored from 0-19, indicating the

of twice the magnitude.23 In one study of 10 patients with

number of areas of self-reported pain over the previous week,

chronic regional pain syndrome, also characterised by altered

along with a symptom severity score involving self-reported

pain processing, Freund et al. demonstrated enhanced cerebral

fatigue, waking unrefreshed, cognitive disturbance, headaches,

response with the use of functional imaging.24 Data from these

abdominal cramps and depression.

studies are adding to an already impressive volume of evidence that points towards an underlying enhancement of pain

Pathophysiology theories

processing in fibromyalgia.

The exact aetiology of fibromyalgia is currently unknown, but

The use of structural imaging has also allowed for the

underlying pathophysiological mechanisms of central

demonstration of morphological changes in the brain: one study Volume 9: Number 1. 2016 | Page 45

RCSIsmjreview reported significant grey matter volume loss in patients with fibromyalgia.

However, depression is a common psychiatric

comorbidity in fibromyalgia, and is also associated with a higher

aetiology, multiple studies have reported imbalances of cytokine levels in fibromyalgia.11,40-43 Cytokines, some of the immune system’s chemical messengers, can be divided into pro- and

rate of grey matter volume loss. When depression was

anti-inflammatory, with IL-1, IL-6 and IL-8 being some of the

controlled for in other fibromyalgia studies, this association lost

more prominent pro-inflammatory biomessengers.11

its significance.26,27

Several studies have reported increased levels of

Neurotransmitter levels have also been shown to be significantly

pro-inflammatory cytokines in fibromyalgia.11,42,44 In studies of

altered in fibromyalgia, with an increase in those associated with

patients receiving IL-2/LAK (lymphokine activated killer) cell

pain transmission (such as glutamate, nerve growth factor,

therapy and IFN-alpha for renal cell carcinoma45 and chronic

substance P, and the action of serotonin on the 5HT-2a/3a

hepatitis,46 respectively, classical symptoms of fibromyalgia such

receptors). This is accompanied by a decrease in

as diffuse pain and sleep disturbance developed. However, up to

pain-attenuating neurotransmitters such as norepinephrine,

one-quarter of patients on interferon therapy will develop

gamma-aminobutyric acid (GABA), and serotonin acting on the

depressive symptoms, which include diffuse pain and sleep

5HT-1a/1b receptors.

13,28-30

disturbance. No correction for depression was made, and thus

One system that appears to be working paradoxically in

further research into this relationship is needed.47 Furthermore,

fibromyalgia is the endogenous opioid system, which is

the literature has reported elevated levels of IL-8 in patients with

normally responsible for inhibiting pain. There appears to be an

fibromyalgia.48 While IL-8 has been shown to be implicated in

increase in endogenous opioid activity, with concomitant

the enhancement of anterior cingulate cortex processing in

decrease in μ-opioid receptor availability.

13,31

This is in line with

animals with chronic inflammatory pain, it did not display a

promising results produced by clinical trials on the use of

significant association with clinical pain in fibromyalgia.49 Acute

naltrexone, an opioid antagonist, as a treatment modality in

stress has been shown to be associated with higher IL-8 levels,

fibromyalgia.

32,33

which may account for the observed relationship.50 The number

The pathophysiology of fibromyalgia is complex, however, and

of studies on anti-inflammatory cytokines pales in comparison,

there is minimal but consistently growing evidence that

with conflicting results reported. One study reports a positive

peripheral nervous system abnormalities may also play a role.

association between IL-4 gene polymorphism and fibromyalgia, while others found none.51,52 Another study reported low levels

Peripheral nervous system

of Th2 cytokines such as IL-4, IL-5 and IL-13.40,41 A search of the

Peripheral neuropathic symptoms described as ‘pins and

literature produced no evidence to support a role of IL-10, the

needles’, and ‘hot’ and ‘tingling’ sensations are prevalent in

body’s major inflammatory cytokine, in fibromyalgia. Until a

fibromyalgia, with studies reporting 76-95% of patients using

decade ago, the dichotomy of Th1/Th2 cell balance dominated

those terms as symptom descriptors.10,34,35 This is in keeping

the immunology realm. However, Th17, a recently discovered

with other diseases with proven peripheral neuropathic

subtype of T helper cells, has demonstrated a role in the

pathology, such as diabetes mellitus, in which 66% of patients

development of autoimmune pathologies such as multiple

have a sensory neuropathy.

sclerosis and psoriasis.53 The major cytokine secreted by the

Epidermal nerve fibre density has been shown to be a reliable

Th17 cell, IL-17, has also been shown to be elevated in

indicator for the presence of small nerve fibre pathology, with

fibromyalgia.44 Furthermore, one study by Kim et al.

one study reporting a diagnostic efficiency of 88%.37 Several

demonstrated a role for IL-17 in mediating pain hypersensitivity.

studies have demonstrated the presence of this pathology by

However, further research is needed into the exact role of this

obtaining skin biopsies from patients with fibromyalgia.

cytokine in fibromyalgia.54

However, these studies have not controlled for the potential

It is known that cytokines can sensitise nociceptors and

deconditioning and lack of physical activity in this cohort, which

potentially modulate the HPA axis, but it is unclear how this

may confound these findings.

38,39

would lead to central sensitisation.40,55 Rodriguez-Pinto et al. have proposed the use of cytokine and chemokine levels as

Immune system dysregulation

possible biomarkers of fibromyalgia, with implications for

Despite cementing its status as a disease of non-inflammatory

fostering future treatments.40

Page 46 | Volume 9: Number 1. 2016

RCSIsmjreview The role of vitamin D

consensus among clinicians on the initial approach to

Vitamin D deficiency has been implicated as a potential

fibromyalgia includes pharmacological monotherapy in addition

component in the pathogenesis of a host of conditions, ranging

to non-pharmacological treatments such as patient education,

from multiple sclerosis and inflammatory bowel disease to

cognitive behavioural therapy and exercise.

Parkinson’s disease and depression.56-58 In exploring the

Non-pharmacological therapy has been reported to have effects

relationship between vitamin D deficiency and fibromyalgia, the

of larger magnitude than its pharmacological counterpart.13,64,66

literature suffers from conflicting reports regarding both the

Historical editorials held that informing patients of their

strength of association and the implications of vitamin D

fibromyalgia diagnosis would lead to a rise in patient access to

supplementation as a potential treatment modality.

6-9,56-61

healthcare services, placing further stress on the system.67

Vitamin D has well known anti-inflammatory properties, and low

However, recent studies show that a diagnosis is often followed

level states have been postulated to increase levels of

by a sharp decline in access to healthcare, fewer referrals, fewer

inflammatory cytokines, resulting in increased central

drug prescriptions, and less diagnostic testing.68,69

sensitisation to mechanical pain. The central nervous system

A diagnosis often provides a source of relief to patients who

mechanisms of attenuating or suppressing pain are theorised to

have been suffering from an ‘invisible disorder’ that is widely

become dysfunctional if vitamin D levels are low.8,60,61

misunderstood by both the public and clinicians.13 Highlighting

In one study, 69.3% of patients who met the 1990 ACR criteria for fibromyalgia were found to have low levels of vitamin D.

These results were similar to those obtained by von Kanel et al.,

this knowledge gap, Jay et al. reported receiving a patient referred by a primary physician for “fibromyalgia of the right shoulder”.70

which found that 71% of chronic pain patients were vitamin D deficient.8 While one randomised controlled trial found no

Secondary fibromyalgia

significant difference in vitamin D levels between patients with

Patients with fibromyalgia can be categorised clinically into two

fibromyalgia and controls, the expected rise of vitamin D levels

groups – one in which no biological evidence of inflammation

in the summer was absent in those with fibromyalgia.6

can be found, and another in which a concomitant

Armstrong et al. reported a significant association in

inflammatory condition such as rheumatoid or osteoarthritis

fibromyalgia patients between low vitamin D levels and anxiety

exists. The latter is also known as ‘secondary fibromyalgia’.13,71,72

or depression. Both these findings can potentially be explained

In the latter subset of patients, it has been proven that pain

by a lack of sun exposure, prevalent in patients with

eventually centralises and becomes unresponsive to peripherally

fibromyalgia due to the impact of disease on patient activity.56

directed treatment modalities, such as NSAIDs and opioids, and

Evidence has also shown that by supplementing vitamin D,

more responsive to centrally acting treatments. It has been

symptoms of pain in fibromyalgia were reduced.9 Another study

proposed that this centralisation of the pain appears to be

suggested a role for low levels of vitamin D in augmenting

driven by continuing peripheral nociceptive input.3,13,66

central sensitivity to physically evoked pain, which actively

As such, identifying individuals at risk of developing this

involves centres of the brain that are distinct from those

centralised pain state and intensively treating them at the time

involved in spontaneous pain.

of these acute pain episodes could be essential to ‘preventing’ the development of fibromyalgia. By shifting the research

Managing fibromyalgia

landscape from the management of symptoms of fibromyalgia

The literature on fibromyalgia management is currently

to prevention, our ability to combat fibromyalgia may

dominated by trials of complementary and alternative therapies,

potentially improve.13

underlining the limitations of modern medicine in treating fibromyalgia.62,63

Conclusion

Management of fibromyalgia must be carried out in a primary

Numerous studies to date have attempted to outline the

care setting, unless clinically indicated otherwise. Patients whose

mechanisms underlying fibromyalgia. The use of novel diagnostic

diagnoses are in question or who are refractory to initial therapy

imaging such as fMRI and positron emission tomography has

warrant a referral to the relevant departments, such as

provided potentially the best objective evidence to date of the

rheumatology, for further investigation.64,65 The general

mechanisms of central sensitisation in fibromyalgia.19,23 However, Volume 9: Number 1. 2016 | Page 47

RCSIsmjreview the role of numerous other factors, such as vitamin D deficiency

inflammatory mediators. However, much research is needed into

and inflammatory biomarker elevation, have yet to be fully

the extent of its role in the pathogenesis of fibromyalgia and, to

appreciated, with conflicting results in the literature.6,9-11

date, central sensitisation remains the most widely accepted

The most recent evidence suggests that small fibre neuropathy

theory.39,73-75

potentially plays a role in the pathogenesis of fibromyalgia. It has

Further studies would allow for a more holistic understanding of

been postulated that pain-inhibiting nerve fibres are selectively

fibromyalgia, which is essential to adequately manage this

destroyed, rendering the remaining fibres more sensitive to

chronic, and oftentimes debilitating, condition.

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rheumatologists. Clin Rheumatol. 2012;31(8):1177-81.

51. Su SY, Chen JJ, Lai CC et al. The association between fibromyalgia and polymorphism of monoamine oxidase A and interleukin-4. Clin Rheumatol. 2007;26(1):12-6. 52. Yigit S, Inanir A, Tekcan A et al. Association between fibromyalgia syndrome and polymorphism of the IL-4 gene in a Turkish population. Gene. 2013;527(1):62-4. 53. Waite JC, Skokos D. Th17 response and inflammatory autoimmune diseases. Int J Inflam. 2012;2012:819467. 54. Kim CF, Moalem-Taylor G. Interleukin-17 contributes to neuroinflammation and neuropathic pain following peripheral nerve injury in mice. J Pain. 2011;12(3):370-83. 55. Staud R. Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome. Arthritis Res Ther. 2006;8(3):208. 56. Armstrong DJ, Meenagh GK, Bickle I et al. Vitamin D deficiency is associated with anxiety and depression in fibromyalgia. Clin Rheumatol. 2007;26(4):551-4. 57. Cantorna MT, Mahon BD. Mounting evidence for vitamin D as an environmental factor affecting autoimmune disease prevalence. Exp Biol Med (Maywood). 2004;229(11):1136-42. 58. Knekt P, Kilkkinen A, Rissanen H et al. Serum vitamin D and the risk of Parkinson's disease. Arch Neurol. 2010;67(7):808-11. 59. Daniel D, Pirotta M. Fibromyalgia – should we be testing and treating for vitamin D deficiency? Aust Fam Physician. 2011;40(9):712-6. 60. Hsiao MY HC, Chang KV, Han D, Wang TG. Is serum hypovitaminosis D associated with chronic widespread pain

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66. Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311(15):1547-55. 67. Hadler NM. "Fibromyalgia" and the medicalization of misery. J Rheumatol. 2003;30(8):1668-70. 68. Annemans L, Wessely S, Spaepen E et al. Health economic consequences related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum. 2008;58(3):895-902. 69. Hughes G, Martinez C, Myon E et al. The impact of a diagnosis of fibromyalgia on health care resource use by primary care patients in the UK: an observational study based on clinical practice. Arthritis Rheum. 2006;54(1):177-83. 70. Jay GW, Barkin RL. Fibromyalgia. Dis Mon. 2015;61(3):66-111. 71. Lauche R, Cramer H, Hauser W et al. A systematic review and meta-analysis of qigong for the fibromyalgia syndrome. Evid Based Complement Alternat Med. 2013;2013:635182. 72. Lee YC, Lu B, Boire G et al. Incidence and predictors of secondary fibromyalgia in an early arthritis cohort. Ann Rheum Dis. 2013;72(6):949-54. 73. Caro XJ, Winter EF. The role and importance of small fiber neuropathy in fibromyalgia pain. Curr Pain Headache Rep. 2015;19(12):55. 74. Clauw DJ. What is the meaning of "small fiber neuropathy" in fibromyalgia? Pain. 2015;156(11):2115-6. 75. Uceyler N. Small fiber pathology – a culprit for many painful disorders? Pain. 2016;157(Suppl. 1):S60-6.

RCSIsmjreview The road to the gold standard: whole genome sequencing in the clinic

Abstract Costs and time involved in generating whole genome sequences with next-generation technology are continually dropping, and in this regard are nearing feasibility in clinical settings. The most significant obstacles to clinical application now derive from the massive amounts of data generated by each genome sequenced. Storage, analysis and interpretation pose technical and knowledge-based challenges to researchers, who must also confront ethical, legal and social issues raised by mass (electronic) storage and sharing of inherently identifiable data. Medical genomics as a field is still new. There is a dearth of established standards for the return of results to clinicians and patients, and few evidence-based guidelines pertaining to most of the variants identified by whole genome sequencing (WGS). However, the ability to comprehensively identify all genomic variants holds thrilling opportunities for personalised medicine. Platforms to integrate patients’ clinical information with their genomic data are being developed and tested with promising results. The statistical power to associate genotypes with phenotypes and clinical outcomes continues to rise; initiatives like the UK’s 100,000 Genomes Project are paving the way for clinical adaptation. Currently, narrower targets than the whole Jenna Geers RCSI medical student

genome are more feasible in the clinic, but there is a reasonable expectation that it will eventually become the ‘gold standard’ in personalised medicine. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:51-6. Volume 9: Number 1. 2016 | Page 51

RCSIsmjreview Background

Laboratory Improvement Amendments programme – to ensure

Next-generation sequencing (NGS) technologies can now

the quality and reliability of sequencing and analysis. The

sequence the entire human genome in less than three days and,

ultimate goal is to ensure downstream accuracy, identify

according to industry claims, at a total cost of $1,000 USD or

medically important variants, and maximise utility for clinicians

less.1,2 This “massively parallel sequencing” generates short

and patients.8,18

“reads” or nucleotide sequences from a DNA sample and aligns the reads against a standard reference genome in a

Challenges to evidence-based progress:

high-throughput process.2-4 Sequence variants are identified by

ethical, legal, social

comparing the sample and reference genomes, and stored in a

Data sharing and integration

variant call file (.vcf) containing the several million variants each

Challenges to the uptake and widespread implementation of

genome typically contains. Medical geneticists and clinicians then

WGS in clinical practice include formulating ethical policy for

compare the data with a genotype-phenotype database,

conducting research, creating decision frameworks for clinical

interpreting which are pathogenic and which are “actionable”

practice, and overcoming institutional and practical inertia to

(have an established intervention and an agreed-upon policy on

implement new technology.18 Issues of data sharing, the

whom to treat), and provide results to the patient.5 With the

electronic health record, and informed consent in a

ability to rapidly generate massive amounts of genomic data,

technologically advanced era of healthcare information

analysis of this data has now overtaken sequencing as the major

assimilation and storage are particularly relevant to the

challenge and time-consuming process.

formulation of ethical policy. Decision frameworks require the

Genome analysis encounters technical, legal, ethical, and

establishment of criteria for ‘actionability’ of variants for return to

interpretive obstacles.3,6-9 Since a complete, standardised, fully

clinicians, return to patients, and support in choosing

annotated and linked genotype-phenotype database does not

interventions,19 which in turn requires efficient and ethically

exist, the reality is that the protocol above represents the ideal

acceptable data sharing. Concerns about consent to long-term

model rather than the practical reality. It is statistically

(and possibly indefinite/irreversible) storage of genomic

challenging to assimilate enough evidence to determine

information have resulted in the limitation of accessibility of

pathogenic significance for variants, particularly rare or unique

genomic data collected in these projects to very specific uses and

ones. This makes practical interpretation of variants

groups of people.20 Widespread accessibility of genomic

challenging.6,10,11 Several methods are being utilised to raise

databases is difficult to arrange while respecting privacy and

statistical power but the problem persists, especially as there

confidentiality. Research on these ethical, legal, and social issues

often exists little to no information on phenotypic/clinical

has long been acknowledged as necessary and is funded

presentations associated with specific variants.12

alongside empirical research.21 Statistical analysis identifying relationships between genotype and

Training and education

disease alone is not adequate to create clinical guidance. Systems

To work with genomic technology, clinical laboratory staff must

biology and systems medicine aim to integrate data including

be computationally skilled and adequately trained in sample and

genomics, proteomics, and bioinformatics with clinical

data collection, preparation, analysis, and interpretation.

observations. This is crucial in order to understand disease

Pathologists play a crucial role in assessment of specimens;

aetiology, progression, and characteristics in the real world.11,20

recognising this, several major institutions have incorporated

Bioinformatics tools to integrate clinical, biological, and genomic

genomics training into pathology residencies, along with online

data are in development, and some of the early products show

resources and educational programmes to address the increasing

great promise for personalising treatment, particularly in

need for medical professionals competent in the growing field of

oncology,22 but their use will grow slowly as the evidence base

genomic medicine.

12,13

There are also academic reviews written

from research and drug development gradually expands. Current

specifically for clinicians on implanting current technology in

efforts like the electronic Medical Records and Genomics

practice,14-16 and organisations such as the College of Genomic

(eMERGE) network aim to integrate the electronic health record

Medicine aim to train and update practising clinicians in these

with compilations of biogenetic information in an ethically

areas.17 Laboratories are certified – for example, by the Clinical

competent manner, and to test frameworks for validating variants

Page 52 | Volume 9: Number 1. 2016

RCSIsmjreview the genome, previously considered ‘junk DNA’, begun to be

(including phenotypic associations) and returning findings to clinicians and research participants/patients.

19,23

The 100,000

understood and explored, thanks to the results of the international

Genomes Project is a nationwide effort by the National Health

collaborative Encyclopedia of DNA Elements (ENCODE) project.28,29

Service in the UK to obtain and integrate clinical information with

An estimated 15% of Mendelian disorders arise from mutations

whole genome sequences from patients with rare diseases and

outside the exome.7 These variants, which are detectable only

their families, and patients with cancer. The aim is to improve

through WGS or (limited) tests such as karyotyping, can have

understanding of disease aetiology, identify and diagnose disease

significant functional effects, but are less straightforward to

where it exists, and optimise patient management including

understand and interpret.4,9,25,30 Once the impact of these

treatment selection.24

non-exomic variants is better elucidated, WGS will be ideal in situations of clinical disease where WES, gene panels and other

Return of findings and evidence-based decisions

technologies have failed to provide diagnostic and interventional

WGS invariably identifies variants in patients’ genomes not

guidance. For this reason, WGS has already begun to be

related to the stated purpose of the test. These ‘incidental

implemented in specialist centres as a tool to help diagnose

findings’ can have a significant impact on patients’ well-being in

paediatric pathologies believed to have a genetic component, but

terms of future planning, healthcare decisions, and mental and

which have failed to be elucidated after other extensive laboratory

emotional health. The American College of Medical Genetics and

and genetic tests.18,27 This currently limited clinical use of WGS is

Genomics has released recommendations for return of incidental

largely overshadowed by its use in oncology.

findings from clinical WGS and whole exome sequencing (WES) testing, but these guidelines have been accused of ignoring the

Oncology

patient’s right to refuse the return of results. This ‘right not to

The affirmation that genome instability is a major contributor to

know’ presents a complex challenge to the establishment of

cancer development was a crucial result of early WGS

criteria and procedures for returning findings while providing the

implementation in the field of oncology.30 In research and clinical

full disclosure essential to patient autonomy. projects are examining this topic,

19,23

25-27

Several eMERGE

practice, genomes of tumour cells are sequenced and compared to non-cancerous cells from the same individual.22 This allows

and large-scale initiatives

including the Evaluation of Genomic Applications in Practice and

tracking of the genomic changes that occur between normal and

Prevention (EGAPP) produce evidence-based reviews on the

cancerous cells in an individual – ‘somatic variants’ – stored in

utilisation of genomic tests. These projects form part of a larger

databases such as the Catalogue of Somatic Mutations in Cancer

effort to prime NGS technologies for regular clinical

(COSMIC) or The Cancer Genome Atlas (TCGA). Somatic variants

implementation, as well as clinical decisions in utilising and

across individuals with tumours of varying types are compared to

returning results to patients.

reveal pathways leading to cancerous growth in specific types of

Physicians often rely on referral to or collaboration with medical

cancer, as well as commonalities between them.31 Variants found

geneticists in providing care based on genomic testing; however,

can be looked up in cancer databases to determine whether they

demand for these specialists may soon overwhelm availability.27 In

are ‘druggable’ targets, which have responded well to a certain

cases where evidence-based decision-making is not possible,

pharmacological treatment. This is the idea behind personalised

clinicians must use their best judgment (or institutional policy,

cancer care – find the best treatment option based on an

where it exists) to decide what course of action to take based on

individual’s profile of genomic, histological and other clinical

a patient’s genomic findings.

information to achieve the best outcomes (Figure 1).32

‘Early-adopter’ institutions will

continue to be essential in establishing, troubleshooting and

As tumours grow, subpopulations of cells diverge genetically, as

modelling use of genomic testing and utilisation in clinical

they acquire different mutations and continue to proliferate. This

settings. They act as examples to convince institutional

‘intratumoural heterogeneity’ is at least partially responsible for

stakeholders to fund genomic testing regimens – currently a major obstacle to establishment of genomic testing in the clinic.

the phenomenon of treatment resistance. Metastatic tumours can 18

also develop differentially – ‘intertumoural heterogeneity’ – with similar implications for treatment.33 The use of WGS and other

Current practice and opportunities

NGS technologies to comprehensively identify tumour

Only in the past five years has the role of the non-exomic region of

heterogeneity, and to identify treatment options based upon Volume 9: Number 1. 2016 | Page 53

RCSIsmjreview

Tumour biopsy

Tumour DNA sample for WGS

Comprehensive somatic mutation databases

Genome analysis

Patient’s clinical status

Macro- and microscopic tumour images

Bioinformatics integration software

Prognosis

Intervention options

Clinical trials and evidence-based reviews

Intervention

Death

Remission

Treatment resistance

FIGURE 1: A model for personalised cancer treatment using WGS data. Adapted and expanded from Simon and Roychowdhury (2013).40

heterogeneity and temporal development of somatic mutations, is

recruiting cancer patients for treatment trials based on shared

currently being assessed in several different trials for clinical

genetic aberrations rather than site of origin – are underway.38

feasibility.

34,35

Histological assessment can provide a great deal of

In addition to identification of appropriate treatment, early

practical information about a biopsy, and indeed is the standard

detection of, and response to, cancer in an individual is crucial

by which neoplasticity is determined, but it is subjective, and on

for a good prognosis.33 Recent investigation of circulating

its own cannot capture the vast heterogeneity of the cancer

cell-free tumour DNA (ctDNA) as a cancer biomarker, and

genome.

sequencing of it to characterise tumours genetically, has yielded

The genetic characterisation of an individual’s cancer is therefore

cautiously optimistic results as a relatively non-invasive diagnostic

crucial for personalised diagnostic, prognostic and treatment

and monitoring tool for cancer progression and treatment

purposes.36 A recent study found that in 43% of tumours

response. It can also be used to monitor cancers to assess

examined, mutation similarities between tumours of different

treatment resistance. Entire genomes can be sequenced with a

anatomical sites and tissues of origin were more pronounced than

high enough sample titre of ctDNA.35,37,39,40 Albeit in the early

between different tumours of the same anatomical site of

stages of research, this has exquisite potential to improve cancer

origin.

37,38

Trials testing the efficacy and feasibility of this concept – Page 54 | Volume 9: Number 1. 2016

treatment and research in terms of quality and patient tolerability if it proves effective and feasible.

RCSIsmjreview Summary

drugs (and drugs in general) target proteins altered by

In theory, the ultra-systematic and comprehensive variant

aberrations in the exome.43 Costs and time involved in WGS will

identification of WGS eliminates much of the time and money cost

continue to decrease as demand for the technology grows,

of running sequential single-gene tests. It is ideal for detecting the

although the initial investment in equipment and staff training is

maximum amount of genetic variants upon which to base

substantial. Individual institutions will only bear the costs to start

treatment consideration,

and has the advantage of rarely needing

the programme once evidence-based reviews, public pressure,

PCR or other techniques for amplification before sequencing –

and large-scale initiatives – like the 100,000 Genomes Project –

making it intrinsically more accurate than WES or targeted

provide a great enough stimulus.24

sequencing, which use enrichment techniques that could

In the short term, WGS will be almost exclusively used in clinical

potentially introduce amplification-related sequence errors.41

trials and research, but the knowledge it produces will filter down

However, at present WGS is used (nearly) solely in research

to inform and help interpret WES and other targeted clinical

settings. Too much data, with too little known about non-exomic

genetic tests. WGS identification of pathogenic variants will also

variants, is generated for clinical use. Outside of clinical trials,

continue to inform pharmaceutical development.21 Despite its

WES or other targeted sequencing strategies are used in order to

currently limited utility in the clinic, WGS is already informing

generate data relevant to clinical interpretation and use.42

research and will firmly establish a supportive role in medicine in

Realistically, targeted gene sequencing and/or WES will be

the near future, with real potential to become the gold standard

implemented before WGS in clinical contexts, as most anti-cancer

in personalised and genetic medicine in the long term.

References 1. Illumina. HiSeq X Ten System. [Internet] 2014. Available from: http://www.illumina.com/systems/hiseq-x-sequencing-system/sy stem.ilmn. 2. Herper M. The $1,000 Genome Arrives – For Real, This Time. Forbes

9. Xuan J, Yu Y, Qing T et al. Next-generation sequencing in the clinic: promises and challenges. Cancer Lett. 2013;340(2):284-95. 10. Hehir-Kwa JY, Pfundt R, Veltman JA et al. Pathogenic or not?

2014 January 2014 [Internet] [Accessed 2015 July 20] Available from:

Assessing the clinical relevance of copy number variants. Clin

http://www.forbes.com/sites/matthewherper/2014/01/14/the-1000-

Genet. 2013;84(5):415-21.

genome-arrives-for-real-this-time/. 3. Barbujani G, Ghirotto S, Tassi F. Nine things to remember about human genome diversity. Tissue Antigens. 2013;82(3):155-64. 4. Moorthie S, Hall A, Wright CF. Informatics and clinical genome sequencing: opening the black box. Genet Med. 2013;15(3):165-71. 5. Johnston JJ, Biesecker LG. Databases of genomic variation and phenotypes: existing resources and future needs. Hum Mol Genet. 2013;22(R1):R27-31. 6. Cooper GM, Shendure J. Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data. Nat Rev Genet. 2011;12(9):628-40. 7. Keogh MJ, Chinnery PF. Next generation sequencing for

11. Wolkenhauer O, Auffray C, Jaster R et al. The road from systems biology to systems medicine. Pediatr Res. 2013;73(4 Pt 2):502-7. 12. Koboldt DC, Steinberg KM, Larson DE et al. The next-generation sequencing revolution and its impact on genomics. Cell. 2013;155(1):27-38. 13. Haspel RL, Olsen RJ, Berry A et al. Progress and potential: training in genomic pathology. Arch Pathol Lab Med. 2014;138(4):498-504. 14. Bochud M. Genetics for clinicians: from candidate genes to whole genome scans (technological advances). Best Pract Res Clin Endocrinol Metab. 2012;26(2):119-32. 15. Li A, Meyre D. Jumping on the train of personalized medicine: a primer for non-geneticist clinicians: part 1. Fundamental

neurological diseases: new hope or new hype? Clin Neurol

concepts in molecular genetics. Curr Psychiatry Rev.

Neurosurg. 2013;115(7):948-53.

2014;10(2):91-100.

8. Kilpinen H, Barrett JC. How next-generation sequencing is

16. Li A, Meyre D. Jumping on the train of personalized medicine: a

transforming complex disease genetics. Trends Genet.

primer for non-geneticist clinicians: part 2. Fundamental concepts

2013;29(1):23-30.

in genetic epidemiology. Curr Psychiatry Rev. 2014;10(2):101-17.

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17. Stone K. Genomic testing update: whole genome sequencing may be worth the money. Ann Neurol. 2012;71(5):A7-9. 18. Manolio TA, Chisholm RL, Ozenberger B et al. Implementing genomic medicine in the clinic: the future is here. Genet Med. 2013;15(4):258-67. 19. Kullo IJ, Haddad R, Prows CA et al. Return of results in the

30. Pikor L, Thu K, Vucic E et al. The detection and implication of genome instability in cancer. Cancer Metastasis Rev. 2013;32(3-4):341-52. 31. Gao J, Ciriello G, Sander C et al. Collection, integration and analysis of cancer genomic profiles: from data to insight. Curr Opin Genet Dev. 2014;24:92-8. 32. Hansen AR, Bedard PL. Clinical application of high-throughput

genomic medicine projects of the eMERGE network. Front

genomic technologies for treatment selection in breast cancer.

Genet 2014;5:50.

Breast Cancer Res. 2013;15(5):R97.

20. Altman RB. Translational bioinformatics: linking the

33. Horswell S, Matthews N, Swanton C. Cancer heterogeneity and

molecular world to the clinical world. Clin Pharmacol Ther.

â&#x20AC;&#x153;the struggle for existenceâ&#x20AC;?: diagnostic and analytical challenges.

2012;91(6):994-1000.

Cancer Lett. 2013;340(2):220-6.

21. McEwen JE, Boyer JT, Sun KY et al. The Ethical, Legal, and

34. Peintinger F. Using molecular profiles to tailor treatment in breast

Social Implications Program of the National Human Genome

cancer: are they ready for prime time? Curr Opin Obstet

Research Institute: Reflections on an Ongoing Experiment.

Gynecol. 2014;26(1):21-6.

Ann Rev Genomics Hum Genet. 2014;15(1):481-505. 22. Dander A, Baldauf M, Sperk M et al. Personalized Oncology Suite: integrating next-generation sequencing data and whole-slide bioimages. BMC Bioinformatics. 2014;15(1):306. 23. McCarty CA, Chisholm RL, Chute CG et al. The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies. BMC Med Genomics. 2011;4:13. 24. Genomics England. The 100,000 Genomes Project. [Internet] 2015. Available from:

35. Schoenborn JR, Nelson P, Fang M. Genomic profiling defines subtypes of prostate cancer with the potential for therapeutic stratification. Clin Cancer Res. 2013;19(15):4058-66. 36. Chang F, Li MM. Clinical application of amplicon-based next-generation sequencing in cancer. Cancer Genet. 2013;206(12):413-19. 37. Wang L, Wheeler DA. Genomic sequencing for cancer diagnosis and therapy. Annu Rev Med 2014;65(1):33-48. 38. Heim D, Budczies J, Stenzinger A et al. Cancer beyond organ and tissue specificity: next-generation-sequencing gene mutation data

http://www.genomicsengland.co.uk/the-100000-genomes-p

reveal complex genetic similarities across major cancers. Int J

roject/.

Cancer. 2014;135(10):2362-9.

25. Burke W, Matheny Antommaria AH, Bennett R et al.

39. Ferte C, Trister AD, Huang E et al. Impact of bioinformatic

Recommendations for returning genomic incidental

procedures in the development and translation of

findings? We need to talk! Genet Med. 2013;15(11):854-9.

high-throughput molecular classifiers in oncology. Clin Cancer

26. Veenstra DL, Piper M, Haddow JE et al. Improving the efficiency and relevance of evidence-based

Res. 2013;19(16):4315-25. 40. Simon R, Roychowdhury S. Implementing personalized cancer

recommendations in the era of whole-genome sequencing:

genomics in clinical trials. Nat Rev Drug Discov.

an EGAPP methods update. Genet Med. 2013;15(1):14-24.

2013;12(5):358-69.

27. Wade CH, Tarini BA, Wilfond BS. Growing up in the

41. Sims D, Sudbery I, Ilott NE et al. Sequencing depth and

genomic era: implications of whole-genome sequencing for

coverage: key considerations in genomic analyses. Nat Rev

children, families, and pediatric practice. Annu Rev

Genet. 2014;15(2):121-32.

Genomics Hum Genet. 2013;14:535-55. 28. ENCODE. ENCODE: Encyclopedia of DNA [Internet] 2015. Available from: https://www.encodeproject.org/. 29. Pennisi E. Genomics. ENCODE project writes eulogy for junk DNA. Science. 2012;337(6099):1159.

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42. Thomas F, Desmedt C, Aftimos P et al. Impact of tumor sequencing on the use of anticancer drugs. Curr Opin Oncol 2014;26(3):347-56. 43. Mefford HC, Batshaw ML, Hoffman EP. Genomics, intellectual disability, and autism. New Engl J Med. 2012;366(8):733-43.

RCSIsmjstaff review Continuous glucose monitoring: a sweet deal for paediatric type 1 diabetics

Abstract Children diagnosed with type 1 diabetes mellitus (T1DM) are at particular risk for long-term complications, including diabetic retinopathy, neuropathy, and nephropathy. Over the last few decades, clinical advancements in glucose monitoring and methods of insulin delivery have improved quality of life in T1DM, making strict glycaemic control, which can reduce long-term complication risk, more achievable. The continuous glucose monitor (CGM) is a minimally invasive subcutaneous device, which assesses subcutaneous interstitial glucose levels at five-minute intervals. Used in conjunction with multiple daily insulin injections, or continuous subcutaneous insulin infusion via insulin pump, the CGM has been proven to enhance metabolic control, reducing HbA1c levels as well as time spent in hypoglycaemia. Furthermore, CGM allows for retrospective analysis of blood glucose trends by clinicians, leading to individualised and precise management strategies. However, limitations to its use include cost efficacy, sensor accuracy, and insertion site irritation. This review will discuss the Samar Atteih RCSI medical student

potential benefits and limitations of CGM use in a paediatric population, and the recommendation that CGM be made available to any paediatric diabetic who requests its use. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:57-61. Volume 9: Number 1. 2016 | Page 57

RCSIsmjstaff review Introduction

SMBG uses finger-prick testing with a glucometer to analyse capillary

Type one diabetes mellitus (T1DM) is a chronic autoimmune

blood glucose levels. This has long been the gold standard for

condition characterised by a total lack of insulin production by

diabetic self-testing because of its high accuracy rate. However,

pancreatic beta cells. In genetically susceptible individuals, an

glucometers only allow patients to assess glycaemic levels

interplay between genetic and environmental factors leads to the

periodically; therefore, their overall efficacy in contributing to

early development of islet cell autoantibodies, which target

enhanced glycaemic control is highly user dependent.9 A more

insulin-producing cells, thereby rendering individuals severely

recent technological advancement, the CGM, mitigates the

glucose intolerant.2

glucometer’s limitation of intermittent testing. This minimally

Prior to the discovery of insulin, doctors could do little for children

invasive device sits just beneath the skin and assesses subcutaneous

diagnosed with T1DM. Changes in diet, including carbohydrate

interstitial glucose levels at five-minute intervals, providing a

restriction, had little impact on disease progression, and death

systematic flow of data, which can be used for both real-time and

shortly followed diagnosis. When insulin was first derived from the

retrospective analyses.

pancreases of cattle and pigs in 1921, the prognosis of T1DM

The majority of people with T1DM are diagnosed in childhood and

improved drastically. In 1978, biosynthetic human insulin was first

early adolescence,5 when strict glycaemic control is more difficult to

developed, with the advent of various slow- versus fast-acting insulin

attain than in the adult population.10 Children and adolescents may

types shortly thereafter.

not understand the implications of the disease, and variations in

Nowadays, children diagnosed with T1DM are immediately

exercise and diet can make management difficult. In adolescents, this

commenced on lifelong insulin therapy to prevent severe long-term

is at least partly attributable to physiological changes and hormonal

complications, such as neuropathies, retinopathies, nephropathies,

fluctuations associated with puberty, which can affect insulin

early cardiovascular disease, and death.3,4 Strict glycaemic control –

absorption; additionally, psychological issues such as denial of the

defined as glycosylated haemoglobin (HbA1c) levels <7% – has been

illness in an attempt to fit in with peers can lead to poor adherence to insulin therapy.11

shown to significantly reduce the risk of these sequelae for the 6

estimated 500,000 children worldwide who currently live with T1DM.

While maintenance of normal blood glucose levels is crucial in

Over the last few decades, clinical advancements in glucose

diabetes management, intensive insulin therapy increases the risk of

monitoring and methods of insulin delivery have improved the

hypoglycaemia.12 Hyperglycaemia (capillary glucose levels >8mmol/l)

quality of life of people with type one diabetes, making strict

may lead to the abovementioned complications, but hypoglycaemia

glycaemic control more achievable. This article reviews the literature

(<4.0mmol/l) also poses a real threat, especially to the paediatric

available on one relatively new advancement, the continuous glucose

population. Many of these episodes of hypoglycaemia occur at night,

monitor (CGM), which, when combined with insulin therapy, has the

during sleep.9 Although it is possible that a hypoglycaemic event will

potential to aid the paediatric population with T1DM to achieve

awaken the patient, severe hypoglycaemia can rapidly lead to

target management goals.

convulsions, coma, and even death, if not treated promptly.13 Multiple episodes of hypoglycaemia may eventually result in a state

Management of paediatric diabetes mellitus

of ‘hypo-unawareness’, in which a diabetic patient does not realise

Management of T1DM can be broken down into two main

that their glucose levels are dangerously low. This is especially

components: insulin analogue therapy; and, self-monitoring of blood

common in the very young subset of patients, who may be unable

glucose (SMBG) levels.

to adequately express their symptoms, even if aware of them.13 In

Insulin analogue therapy consists of a basal dose of insulin to control

fact, the fear of hypoglycaemia has been shown to be a major

glycaemic levels throughout the day (‘background’ insulin), as well

contributing deterrent to adequate control for people with type one

as bolus doses of insulin taken for meals. Insulin is usually delivered

diabetes.12,14 The overall goal of intensive diabetes management is

via one of two methods: multiple daily injections (MDI); or,

therefore to reduce HbA1c levels without increasing the number of

continuous subcutaneous insulin infusion (CSII) via an insulin pump.

hypoglycaemic events.

While both methods have proven effective, multiple studies have shown CSII to be superior to MDI in the paediatric population7,8 –

The advantages of continuous glucose monitoring

perhaps because it involves one needlestick every three days rather

One undisputed advantage of CGM is improved metabolic control

than the four to eight daily injections required for MDI therapy.

and thus decreased risk of long-term complications. A meta-analysis

Page 58 | Volume 9: Number 1. 2016

RCSIsmjstaff review of randomised controlled trials comparing CGM to SMBG in

data is available on the paediatric subpopulation in particular.23

paediatric T1DM patients indicates the potential of CGM use, with

Due to variations in the literature, as well as the relatively recent

either MDI or CSII, to effectively reduce HbA1c levels when

evidence indicating its effectiveness, health insurance reimbursement

compared to SMBG;15 other independent studies show consistent

and government funding of the devices have been restricted to a

results.6,16,17 Studies also indicate significant decreases in

large extent, although this is slowly beginning to change in much of

post-prandial and nocturnal glycaemic deviations when using the

Europe.28 Unpublished analyses of cost-effectiveness in both Sweden

CGM in combination with an insulin pump (known as a

and the Netherlands found the cost-effectiveness to be

sensor-augmented pump or SAP).18 When compared to MDI, SAP

€36,000-52,000/QALY and €21,000/QALY, respectively, and the

use has also been shown to decrease HbA1c levels, with more

CGM system is now reimbursed by these governments for patients

paediatric participants achieving their age-specific HbA1c targets.19

meeting certain criteria.23 The HSE long-term illness scheme currently

This can be explained in part by the use of alarms triggered by

covers the cost of CGM sensors in the Republic of Ireland, and

hyperglycaemic excursions, which allow for improved daytime

reimbursement protocols vary throughout other European countries.29

dosing of insulin in response to hyperglycaemia.

If not reimbursed, maintenance of CGM is costly and may be a

In addition to this reduction in HbA1c levels, multiple studies have

deterrent to regular use, which as previously mentioned is vital to its

shown that CGM use leads to a decreased number of hypoglycaemic

efficacy. Furthermore, for a few months after transition to CGM,

episodes and overall total amount of time spent in hypoglycaemia,

multiple appointments with a multidisciplinary diabetes team and

both daily and nocturnally.

20,21

The use of alarms indicating

experts in CGM use are necessary. Although proven to be highly

hypoglycaemic episodes may be partially responsible, although one

beneficial, these appointments may also contribute to up-front (and

study found that over 50% of nighttime alarms fail to awaken

overall) costs.23

patients.22 Retrospective data analysis by clinicians leading to adjustments in insulin dosages likely has a more profound effect on these findings.

Sensor accuracy The first CGM system – Medtronic’s Minimed system – was approved

Another important advantage of CGM use is enhancing the

in 1999.30 Initially used only for retrospective analysis, subsequent

understanding of T1DM and disease management by both real-time

generations of CGM devices have improved in accuracy, as well as

and retrospective data analysis. Clinicians can make precise

percent functioning, as measured by mean difference between

adjustments to patient management after analysing trends in

glycaemic sensor and reference levels. While sensors are 80-91%

glycaemic levels in response to exercise, food intake and even

accurate for levels in the hyperglycaemic range, and 73-76% for

examination stress (in adolescents).23 Seeing the effects that these

those in the target range, the sensors are only 57-66% accurate at

activities have on their glycaemic levels may inspire confidence and

indicating hypoglycaemia and potentially overestimate the frequency

independence in managing the illness for patients, who are at

of nocturnal hypoglycaemia.23 SMBG using glucometers has been

increased risk of anxiety and depression, as well as for parents, who

shown to have at least 97% accuracy for all three glycaemic states.23

bear the brunt of the work of diabetes management and are also at

For this reason, there is an ongoing need to calibrate the sensors

increased risk.25,26 Psychological relief may also be conferred by

using glucometer testing at least every 12 hours.23 Due to the

improved metabolic control, decreases in hypoglycaemia, and

potential for inaccurate readings, patients and guardians are

real-time and retrospective data analysis allowing for better

routinely instructed on the importance of confirming

management of the disease. All of these factors may contribute to

hypo/hyperglycaemic episodes with finger stick testing before

future maintenance of glycaemic control and quality of life.

treating either, to avoid unnecessary risk.23,31

Potential limitations to continuous glucose monitoring

General irritation by sensor site and ‘alarm fatigue’

Cost efficacy

Despite low rates of sensor site infection and cellulitis,14 skin irritation

The benefits of CGM are largely undisputed. Meta-analysis of studies

from sensor adhesives, pain at insertion, retained subcutaneous

conducted in the United States has shown that CGM use is likely to

sensor tips, and annoyance at alarms have caused some concern

be the most cost-effective in a subset of patients with high baseline

among patients and their parents/guardians.32 However, despite

HbA1c levels (indicating poor control) and in patients who are able

these issues, overall satisfaction with CGM use is high among

to use the CGM frequently (at least six days per week),28 although no

patients and guardians.33 Volume 9: Number 1. 2016 | Page 59

RCSIsmjstaff review Latest advancements, ongoing clinical trials and the

One significant benefit of this device is effectively reducing

future of CGM

nocturnal hypoglycaemic events35 (and the fear of them) without

The journey to a closed loop system or ‘artificial pancreas’

the need of alarms to disturb the patient’s sleep. This encourages

The closed loop system or ‘artificial pancreas’, as regarded by some,

intensive management of T1DM in the paediatric population,12 in

has been undergoing clinical trials for multiple years. Essentially, the

which hypo-unawareness is especially common.13 While no data is

system is composed of CGM coupled with CSII via an insulin pump.

yet available on the long-term benefits or risks of this particular

The modified insulin pump uses specific algorithms to secrete

system, this is likely the most beneficial advancement to date in the

appropriate amounts of insulin in response to glucose level signals

management of paediatric T1DM, and towards the development of

from the CGM.

In theory, this should obliterate the need for

a fully automated, closed-loop system.

manual boluses at meal times; however, available literature indicates multiple limitations, the most prominent being lag time between

Conclusions

sensor signalling reaching the pump and actual changes in

Paediatric patients with T1DM face the challenge of maintaining

glycaemic levels.34 Due to these limitations, the system is not

glycaemic levels within target range throughout the day and night.

currently utilised clinically, and is unlikely to be for a number of

Findings that the paediatric population has overall higher HbA1c

years.

levels and decreased control when compared to the adult population10 make it vital to identify methods of increasing control

MINIMED 640G by Medtronic

and reducing risk of long-term complications. CGM is effective in

In 2014, Medtronic launched its Minimed 640G system, a

reducing paediatric HbA1c levels, number of hypoglycaemic events,

semi-closed loop system composed of an integrated insulin pump

and overall time spent in hypoglycaemia. Furthermore, CGM allows

and CGM sensor, modified to especially target nocturnal

for analysis of trends, which can be used by clinicians to alter patient

hypoglycaemia. The CGM sensors detect when glucose levels are

management for long-term benefit.14,21 Despite some limitations to its

falling below the normal range and send wireless signals to the

use, it has been recommended that CGM be supplied to any

insulin pump to suspend the release of the maintenance dose of

paediatric patient who desires it, and it is especially useful in those

insulin until glucose levels rise out of the danger zone, at which

with high baseline HbA1c levels, nocturnal hypoglycaemia, and those

point delivery is resumed.35

capable of maintaining regular CGM use.23

References 1. Nolan T. Global perspectives on diabetes. Diabetes Voice. 2011;56(2). 2. Maahs DM, West NA, Lawrence JM et al. Epidemiology of Type 1 diabetes. Endocrinol Metab Clin North Am. 2010;39(3):481-87. 3. Atkinson MA, Eisenbarth GS. Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 2001;358(9277):221-29. 4. Craig ME, Jefferies C, Dabelea D et al. Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 2014;15(S20):4-17.

7. Doyle EA, Weinzimer SA, Steffen AT et al. A randomized, prospective trial comparing the efficacy of continuous subcutaneous insulin infusion with multiple daily injections using 8. Pankowska E, Błazik M, Dziechciarz P. Continuous subcutaneous ´ insulin glargine. Diabetes Care. 2004;27(7):1554-8.

insulin infusion vs. multiple daily injections in children with type

1 diabetes: a systematic review and meta-analysis of randomized control. Pediatr Diabetes. 2009;10:52-58. 9. Boland E, Monsod T, Delucia M et al. Limitations of conventional methods of self-monitoring of blood glucose: lessons learned

5. Daneman D. Type 1 diabetes. Lancet. 2001;367(9513):847-58.

from 3 days of continuous glucose sensing in pediatric patients

6. Raccah D, Sulmont V, Reznik Y et al. Incremental value of

with type 1 diabetes. Diabetes care. 2001;24(11):1858-62.

continuous glucose monitoring when starting pump therapy in

10. Rewers M, Pihoker C, Donaghue K et al. Assessment and

patients with poorly controlled type 1 diabetes. The RealTrend

monitoring of glycemic control in children and adolescents with

study. Diabetes Care. 2009;32(12):2245-50.

diabetes. Pediatr Diabetes. 2009;10:71-81.

Page 60 | Volume 9: Number 1. 2016

RCSIsmjstaff review 11. Silverstein J, Klingensmith G, Copeland K. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care. 2005;28(1):186-212. 12. Irvine AA, Cox D, Gonder-Frederick L. Fear of hypoglycemia: Relationship to physical and psychological symptoms in patients with insulin-dependent diabetes mellitus. Health Psychol. 1992;11(2):135-38. 13. Clarke W, Jones T, Rewers A et al. Assessment and

century diabetes therapy. Diabetes Care. 2005;28(5):1231-9. 23. Phillip M, Danne T, Shalitin S et al. Use of continuous glucose monitoring in children and adolescents. Pediatr Diabetes 2012;13(3):215-28. 24. Dantzer C, Swendsen J, Maurice-Tison S et al. Anxiety and depression in juvenile diabetes: a critical review. Clin Psychol Rev. 2003;23(6):787-800. 25. Streisand R, Mackey ER, Elliot BM et al. Parental anxiety and depression associated with caring for a child newly diagnosed

management of hypoglycemia in children and adolescents

with type 1 diabetes: opportunities for education and

with diabetes. Pediatr Diabetes. 2008;9(2):165-74.

counseling. Patient Educ Couns. 2008;73(2):333-8.

14. Group JDRFCGMS. Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med. 2008;359(14):1464-76. 15. Foundation JDR. The effect of continuous glucose monitoring

26. Jaser SS, Linsky R, Grey M. Coping and psychological distress in mothers of adolescents with type 1 diabetes. Matern Child Health J. 2014;18(1):101-8. 27. Pickup JC, Ford Holloway M, Samsi K. Real-time continuous

in well-controlled type 1 diabetes. Diabetes Care.

glucose monitoring in type 1 diabetes: a qualitative

2009;32(8):1378-1383.

framework analysis of patient narratives. Diabetes Care.

16. Diabetes Research in Children Network Study G, Weinzimer S, Xing D et al. Prolonged use of continuous glucose monitors in

2015;38(4):544-50. 28. Huang ES, O’Grady M, Basu A et al. The cost-effectiveness of

children with type 1 diabetes on continuous subcutaneous

continuous glucose monitoring in type 1 diabetes. Diabetes

insulin infusion or intensive multiple-daily injection therapy.

Care. 2010;33(6):1269-74.

Pediatr Diabetes. 2009;10(2):91-6. 17. O’Connell MA, Donath S, O’Neal DN et al. Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial. Diabetologia 2009;52(7):1250-7. 18. Kordonouri O, Pankowska E, Rami B et al. Sensor-augmented

29. Heinemann L, Franc S, Phillip M et al. Reimbursement for continuous glucose monitoring: a European view. J Diabetes Sci Technol. 2012;6(6):1498-502. 30. Mastrototaro JJ. The MiniMed Continuous Glucose Monitoring System. Diabetes Technol Ther. 2000;2(1):13-18. 31. Messer L, Ruedy K, Xing D et al. Educating Families on Real

pump therapy from the diagnosis of childhood type 1

Time Continuous Glucose Monitoring: The DirecNet

diabetes: results of the Paediatric Onset Study (ONSET) after

Navigator Pilot Study Experience. Diabetes Educ.

12 months of treatment. Diabetologia. 2010;53(12):2487-95.

2009;35(1):124-35.

19. Bergenstal RM, Tamborlane WV, Ahmann A et al. Effectiveness

32. Tansey M, Laffel L, Cheng J et al. Satisfaction with continuous

of sensor-augmented insulin-pump therapy in type 1

glucose monitoring in adults and youths with type 1 diabetes.

diabetes. N Engl J Med. 2010;363(4):311-20.

Diabet Med. 2011;28(9):1118-22.

20. Chico A, Vidal-Ríos P, Subirà M et al. The continuous glucose

33. Ritholz M. Is continuous glucose monitoring for everyone?

monitoring system is useful for detecting unrecognized

Consideration of psychosocial factors. Diabetes Spectrum.

hypoglycemias in patients with type 1 and type 2 diabetes

2008;21:287-89.

but is not better than frequent capillary glucose

34. Hovorka R, Allen JM, Elleri D et al. Manual closed-loop insulin

measurements for improving metabolic control. Diabetes

delivery in children and adolescents with type 1 diabetes: a

care. 2003;26(4):1153-7.

phase 2 randomised crossover trial. Lancet.

21. Battelino T, Phillip M, Bratina N et al. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care. 2011;34(4):795-800. 22. Klonoff DC. Continuous glucose monitoring roadmap for 21st

2010;375(9716):743-51. 35. Bergenstal RM, Klonoff DC, Garg SK et al. Threshold-based insulin-pump interruption for reduction of hypoglycemia. N Engl J Med. 2013;369(3):224-32.

Volume 9: Number 1. 2016 | Page 61

RCSIsmjstaff review I eat, therefore I am: the gutâ&#x20AC;&#x201C;brain axis and appetite control

Abstract Traditionally, obesity has been viewed as a simple disease of excess calorific intake in the context of a sedentary lifestyle. However, while an increase in energy consumption without corresponding expenditure is a key force in the initial development of obesity, a number of homeostatic mechanisms conspire to maintain high adiposity in individuals who are already overweight. Both central neuronal mechanisms and peripheral endocrine signals drive increased appetite and reduced metabolic rate in the obese. This prevents weight loss from occurring as quickly as one would expect, and makes sustained weight loss of more than 15% almost impossible. Currently, the most effective therapy for obesity is bariatric surgery. While previously believed to effect weight loss through malabsorption, restriction of stomach capacity or both, it is now shown that these operations fundamentally change the internal milieu of obese individuals, favouring weight loss and a reduction in appetite via cumulative changes in neuroendocrine signalling. This has led to some exploration of Daniel Oâ&#x20AC;&#x2122;Reilly RCSI senior staff writer

methods to directly affect the final common pathways in the brain and more efficiently produce weight loss. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:62-6.

Page 62 | Volume 9: Number 1. 2016

RCSIsmjstaff review Introduction

of an extra 1kg a year or >50kg over the average adult lifespan.4

Obesity is fast becoming a global epidemic. For the first time in

It also means that once the set point has been driven upwards (as

human history, more people are dying as a result of relative

in obesity), the lipostat modifies energy expenditure and calorie

calorie excess than of calorie deficit. In developing nations,

intake to maintain our internally determined weight. Therefore,

obesity and malnutrition coexist to create a ‘double burden’ of

the traditional medical mantra of ‘eat less, move more’ may not

disease on already stretched health systems. The traditional

be sufficient for long-term, meaningful weight loss in those who

medical approach of prescribing increased exercise and reduced

are clinically overweight/obese.

calorie intake, although shown to produce modest, clinically significant weight loss (usually around 5-10%), is often difficult

Peripheral signals: signs of dietary intake

for patients to adhere to in the first instance3 and is prone to

Three separate organs act as peripheral nutrient sensors to the

recidivism. The interest this creates in pharmacological and

hypothalamic centres involved in appetite: the stomach/small

surgical means of treating obesity has resulted in greater

intestine, the pancreas and the adipose organ. Each contributes

understanding of how our appetite is regulated.

either to acute appetite regulation (satiety following a meal) or

Acquisition of calories and nutrients necessary for survival creates

the long-term control of eating. Signals may be endocrine, neural

a powerful selection pressure on an organism. Evolution has

or neuroendocrine in nature, and can be produced by direct

thereby resulted in a complex homeostatic network in individual

sensing of the relevant constituents of food (e.g., fatty acids) or

organisms to regulate appetite and prevent acute changes in

by mechanotransduction (stretch of the viscera leading to

adiposity.4 In humans, powerful neuroendocrine interplay exists

relevant hormone release or neural afferent firing).7 This gives the

between the digestive system, which initially receives and absorbs

central integrating regions of the brain a sense of the volume and

nutrients ingested by the organism, the adipose organ, a large

type of meal that has been ingested.

endocrine organ involved in both energy storage and anorexigenic signalling, and the brain, the centre of behaviour.

Signals from the periphery are almost all stimulated by dietary 5

intake. A variety of mechanisms highlight the complexity of

Greater understanding of the crosstalk between these three

appetite regulation; the major determinants of satiety from the

systems is required in order to facilitate the treatment of the

periphery, however, are anorexigenic (stimulate feelings of

obese patient, and ultimately to reduce the level of obesity and

fullness).8

its concomitant complications in the future.

Anorexigenic (appetite-suppressing) signals The lipostat hypothesis

Simple neuronal mechanisms act via the vagus nerve. Stretch of

Despite our general tendency to get bigger when calories are no

the stomach increases the rate of vagal afferent firing, which is

object, individually mammals tend to ‘guard’ their weight. A

processed initially in the nucleus tractus solitarius before

number of experiments illustrate this: animals were either overfed

projecting to the hypothalamus. As the stomach stretches and

or underfed for a relatively short time frame, then allowed an ad

mechanotransduction increases, the feeling of fullness increases

libitum diet. The animals exhibited compensatory behavioural and

proportionally.8

metabolic changes to restore their original weight, suggesting

Neuroendocrine mechanisms also increase the activity of the

that there is a sliding set point, which internally monitors weight

vagus nerve, either via receptors (e.g., CCK1 receptors

gain and loss and prevents drastic changes. This ‘lipostat’ is

responding to cholecystokinin and leading to increased vagal

situated – like many homeostatic regulatory centres – in the

afferent firing) or by increasing gastric stretch, such as the

hypothalamus.6

reduction of intestinal motility by peptide tyrosine tyrosine (PYY).

The lipostat purposefully integrates the peripheral signals of

The central role of the vagus nerve in communicating satiety

dietary intake and the central signals of satiety, and translates

signals from the gut is underlined by evidence that vagotomies in

them into appropriate behavioural, metabolic and appetite

animal models often result in a loss of anorexigenic hormone

changes, which maintain weight at its typical level. This is

signalling, resulting in overfeeding and weight gain.9

important from a homeostatic perspective: a 1% miscalculation

Hormones also act centrally to produce feelings of satiety.

of calorific intake or expenditure (around 20kcal a day, equivalent

Glucagon-like peptide 1 (GLP-1), perhaps better known as an

to a single serving of cabbage) would result in the accumulation

incretin since the addition of exenatide to the pharmacopoeia for Volume 9: Number 1. 2016 | Page 63

RCSIsmjstaff review diabetes, has an important role in generating central satiety.

regulating thyroid hormone signalling, and behaviour via

Delivery of GLP-1 antagonists centrally promoted overeating in

efferents to higher cortical centres.15,16 The cortex also plays a

experimental rodent models;

additionally, the SCALE study

role, with modifications in taste, smell and memory, all driven by

recently illustrated that the GLP-1 analogue ‘liraglutide’ produced

activity in the arcuate nucleus and circulating appetite-regulating

meaningful weight loss as an adjunct to diet and exercise.11

hormones.17

Pancreatic peptide (PP) also acts centrally via Y4 receptors and increases proportionally with the calorie content of ingested food

Alterations in signalling in the obese patient

boluses.7

So why, in spite of such overwhelmingly complex homeostatic

Two hormones increase proportionally with fat mass: insulin, a

machinery, do people become obese? As individuals gain fat

pancreatic hormone secreted in response to food ingestion, and

mass, levels of insulin and leptin secretion increase. As is seen in

leptin, an adipokine directly secreted from adipose tissue. These

type II diabetes mellitus (T2DM), high circulating levels of insulin

hormones act as acute and chronic negative feedback loops.

result in tissue becoming resistant to its effects, and failure of

Mice lacking leptin (ob/ob) are indistinguishable from their

peripheral tissues to uptake glucose.18 A similar process occurs in

heterozygote littermates at birth, but quickly gain weight

the central nervous system in regards to leptin: as higher levels

through massive overeating. Rarely, human obesity has been

accumulate in the blood, the brain ceases to respond

shown to be associated with a loss of leptin function; however, in

appropriately, negating leptin’s influence as a satiety signal.12

the vast majority of patients leptin is massively oversecreted.12

Subsequently, as patients increase their energy expenditure

This has important implications for how the hormone is sensed

(exercise) or reduce calorie intake (diet) in order to lose weight,

centrally and reduces the lipostat’s ability to appreciate total fat

GLP-1, PYY and other anorexigenic hormones are suppressed in

mass.

favour of ghrelin secretion.3 This acts via central mechanisms, resulting in changes in behaviour and metabolism that prevent

Orexigenic signals

effective weight loss, making it difficult for patients to attain

There is a single orexigenic signal secreted in the periphery:

sustained and clinically meaningful changes in fat mass.

ghrelin, a peptide secreted from the stomach, acts on its receptor (GHS-R) to stimulate appetite. Ghrelin levels are highest while

Bariatric surgery: anatomical or biochemical

fasting and are higher in individuals who are chronically fasted

intervention?

(such as those with anorexia nervosa and people on weight loss

An emerging therapy for obesity is bariatric surgery, particularly

diets). Ghrelin acts throughout the gut–brain axis to increase

the Roux-en-Y gastric bypass. This procedure was developed to

gastric motility, gastric acid secretion and calorific intake.

produce weight loss through restriction of total stomach volume (producing earlier vagal stimulation by stretch) and

Central signals: our hedonistic brain

malabsorption.3 However, it has since come to light that this

The brain is the integrative centre of the whole organism, allowing

mechanism alone is unlikely to result in the sustained weight loss

appropriate responses to both external and internal stimuli. Two

seen in patients postoperatively. Some 85% of patients with

important groups of neurons have been identified: an orexigenic

T2DM became normoglycaemic following the procedure,

group, Agouti-related peptide/neuropeptide Y neurons

independent of weight loss. This suggests that some change is

(AgRP/NPY); and, an anorexigenic group, pro-opiomelanocortin

elicited in hormonal signalling and, ultimately, the gut–brain

neurons (POMC). AgRP neurons are stimulated by ghrelin and

axis.19

inhibited by PYY, leptin and insulin. In POMC neurons the inverse

Weight loss following a Roux-en-Y gastric bypass is dissimilar

is true.

This bimodal system of antagonistic neurons integrates

physiologically from weight loss due to starvation, exercise or

peripheral signals, producing an appropriate feeling of hunger or

dieting. With the traditional ‘eat less, move more’ paradigm,

fullness. The result is a sensitive homeostatic sensor, which

ghrelin increases and GLP-1 and PYY decrease to create an

monitors input and modulates output by multiple efferent

appetite-stimulating hormonal milieu. Following Roux-en-Y the

pathways, such as the paraventricular hypothalamus, dorsomedial

inverse is true.20 The chance of a person having a significant

hypothalamic nucleus and the limbic system.14

response to Roux-en-Y bypass, or losing a clinically significant

This acts via a second order set of neurons to alter metabolism by

amount of weight following surgery, can be predicted with some

Page 64 | Volume 9: Number 1. 2016

RCSIsmjstaff review accuracy by measuring these hormones. Leptin is reduced to levels comparable to lean subjects, indicating a return to a non-obese hormone profile.17 Finally, non-specific inhibition of hormone signalling with somatostatin allows for an increase in appetite as tested by an ad libitum meal.21 Unfortunately, this surgery also carries the risk of developing malabsorption and dumping syndromes; thus, it is only reserved for individuals with very high BMIs (40kg/m2 without comorbidities or 35kg/m2 with comorbidities).22,23 Evidence is beginning to accumulate for a less drastic operation, the sleeve gastrectomy, which carries a lower risk of mortality and morbidity but also has a reduced chance of producing sustained weight loss and a change in obesity-related disease.24

Deep brain stimulation: neuromodulation of a final common pathway While the hormonal control elicited by gastric bypass is impressive, researchers are now considering how best to manipulate the final common pathway of satiety. Deep brain stimulation (DBS) is currently indicated for a number of diseases (notably Parkinson’s disease) with impressive reductions in symptoms.25 This intervention requires stereotactic placement of electrodes in the brain (around the lateral hypothalamus), but eliminates the risk of malabsorption.26 It is arguably more precise than the Roux-en-Y by consistently affecting the final common

(and calorie-) sparing devices for work and easy availability of

pathway.

calorie-dense foods, a veritable epidemic of ‘corpulence’ has

Although research is only beginning in this intriguing approach

emerged.29,30 While the best solution to this problem is

to a common illness, results are reasonably promising. A 2013

prevention, there will inevitably be individuals who gain enough

pilot study of bilateral implantation of DBS electrodes (developed

weight to endanger their health.

for Parkinson’s disease) into the lateral hypothalamic nuclei of

Medical treatment of obesity has historically been simplistic and

three patients with intractable obesity was performed safely and

has neglected the complexity of human biology and the powerful

had some evidence of efficacy. A major limiting factor of this

homeostatic mechanisms to prevent sudden changes in

study was that the electrodes that are produced for Parkinson’s

physiology. Prescription of diet and exercise will continue to be

neuromodulation are too large to target the specific areas of the

the mainstay of treatment in the overweight, but an awareness of

lateral hypothalamus associated with appetite;27 however, as the

the limitations of this strategy is an important consideration for

technology develops, more success may emerge from this

clinicians.

approach to the treatment of obesity. Additionally, a wide range

Understanding the gut–brain axis also allows for tailoring

of alternative targets is being explored – such as elements of the

treatment of the obese patient in novel ways, by using GLP-1

brain’s reward circuitry (nucleus accumbens) – suggesting new

agonists as an adjunct for weight loss or utilising surgery

directions for the future of bariatric surgery.28

(bariatric or neurological) to fundamentally alter the communication pathways between these organs, as discussed

Conclusions

above. Ultimately, this will produce a range of therapies that are:

Obesity has historically been associated with poor health.

a) effective; and, b) enduring in the fight against obesity,

Hippocrates reportedly stated: “Corpulence is not only a disease

reducing patient morbidity and mortality, and allowing

itself, but the harbinger of others”. In the modern era of energy-

individuals to lead healthier, happier and longer lives. Volume 9: Number 1. 2016 | Page 65

RCSIsmjstaff review References 1. Lozano R et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095-128. 2. Boutayeb A. The double burden of communicable and non-communicable diseases in developing countries. Trans R Soc Trop Med Hyg. 2006;100(3):191-9. 3. Tadross JA, le Roux CW. The mechanisms of weight loss after bariatric surgery. Int J Obes (Lond). 2009;33(Suppl 1):S28-S32. 4. Shin AC, Zheng H, Berthoud HR. An expanded view of energy homeostasis: neural integration of metabolic, cognitive and emotional drives to eat. Physiol Behav. 2009;97(5):572-80. 5. Berthoud HR, Morrison C. The brain, appetite, and obesity. Annu Rev Psychol. 2008;59:55-92. 6. Mitchel JS, Keesey RE. Defense of a lowered weight maintenance

16. Martin NM et al. Abnormalities of the hypothalamo-pituitary-thyroid axis in the pro-opiomelanocortin deficient mouse. Regul Pept. 2004;122:169-72. 17. Rolls ET. Processing in the brain and the control of appetite. Obes Prev. 2010:41-56. doi:10.1016/B978-0-12-374387-9.00004-0. 18. Ryan AS. Insulin resistance with aging. J Am Coll Nutr. 2010;6:551-63. 19. le Roux CW et al. Gut hormones as mediators of appetite and weight loss after Roux-en-Y gastric bypass. Ann Surg. 2007;246:780-5. 20. Beckman LM, Beckman TR, Earthman CP. Changes in gastrointestinal hormones and leptin after Roux en-Y gastric bypass procedure: a review. J Am Diet Assoc. 2010;4:571-84. 21. le Roux CW et al. Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and

level by lateral hypothamically lesioned rats: evidence from a

improve metabolic parameters. Ann Surg. 2006;243:108-14.

restriction-refeeding regimen. Physiol Behav. 1977;18:1121-5.

22. Vincent RP, Le Roux CW. Changes in gut hormones after bariatric

7. Sam AH, Troke RC, Tan TM, Bewick GA. The role of the gut/brain axis in modulating food intake. Neuropharmacology. 2012;63(1):46-56. 8. Ahima RS, Antwi DA. Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am. 2008;37(4):811-23. 9. Abbott CR et al. The inhibitory effects of peripheral administration of peptide YY(3-36) and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res. 2005;1044:127-31. 10. Meeran K et al. Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology. 1999;140:244-50. 11. Pi-Sunyer X et al. A randomized, controlled trial of 3.0mg of liraglutide in weight management. N Engl J Med. 2015;373:11-22. 12. Sader S, Nian M, Liu P. Leptin: a novel link between obesity, diabetes, cardiovascular risk, and ventricular hypertrophy. Circulation. 2003;108:644-6. 13. Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW. Central nervous system control of food intake and body weight. Nature. 2006;443:289-95. 14. Millington GW. The role of proopiomelanocortin (POMC) neurones in feeding behaviour. Nutr Metab (Lond). 2007;4:18. 15. Garfield AS et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat Neurosci. 2015;18(6):863-71. doi:10.1038/nn.4011.

Page 66 | Volume 9: Number 1. 2016

surgery. Clin Endocrinol (Oxf). 2008;69:173-9. 23. Fried M et al. Interdisciplinary European guidelines on metabolic and bariatric surgery. Obes Surg. 2014;24:42-55. 24. Caiazzo R, Pattou F. Adjustable gastric banding, sleeve gastrectomy or gastric bypass. Can evidence-based medicine help us to choose? J Visc Surg. 2013;150:85-95. 25. Universitaria C. Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinsonâ&#x20AC;&#x2122;s disease. N Engl J Med. 2001;345:956-63. 26. Halpern CH et al. Deep brain stimulation in the treatment of obesity. J Neurosurg. 2008;109:625-34. 27. Whiting DM et al. Lateral hypothalamic area deep brain stimulation for refractory obesity: a pilot study with preliminary data on safety, body weight, and energy metabolism. J Neurosurg. 2013;119:56-63. 28. Dupre DA, Tomycz N, Oh MY, Whiting D. Deep brain stimulation for obesity: past, present, and future targets. Neurosurg Focus. 2015;38:1-9. 29. Percik R, Stumvoll M. Obesity and cancer. Exp Clin Endocrinol Diabetes. 2009;117(10)563-6. doi:10.1007/978-1-4419-5515-9. 30. Ng M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384.

RCSIsmjstaff review The artificial womb: bridging the gap between embryo culture and the incubator

Abstract Advances in life support devices and ex vivo embryo culture in artificial endometria present a framework for the development of the artificial womb, a device capable of supporting long-term extrauterine gestation. We review the potential medical impact of such technology, proof-of-concept animal studies, related research, and emerging epigenetic, neurologic and heritability challenges in supporting extrauterine culture and gestation. Additional research is needed in a number of areas, particularly regarding poor outcomes in embryo culture. In addition, we examine ethico-legal, social and fiscal considerations, with a view towards preparing regulatory ethico-legal policies in anticipation of such technology. Finally, stakeholder engagement is called for to see the integration and implementation of existing technologies, and the development of the artificial womb as a clinical device of promising utility. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:67-72.

Opening

spend in utero. The prospective endpoint is

“[W]arm on their cushion of peritoneum and gorged

‘ectogenesis’, using an artificial womb as an

with blood-surrogate and hormones, the fetuses grew

achievable life support device capable of

and grew … ”

supporting in vitro gestation until viability, thus

Brave New World, Aldous Huxley, 1931

bridging the gap between IVF and conventional incubation in prematurity.1-11 In this article, we

Vincent Healy RCSI medical student

Advances in in vitro fertilisation (IVF), foetal

examine the conceivable impacts, latest research,

incubation and neonatology continue to reduce

and challenges of ectogenesis, and explore relevant

the essential time foetal gestation is required to

fiscal and ethico-legal considerations. Volume 9: Number 1. 2016 | Page 67

RCSIsmjstaff review

1700

Table 1: Timeline of assisted reproductive technologies.21,22

1700s

1800s

1923

1953

1978

1989

First reported artificial insemination

First reported sperm donation

‘Ectogenesis' coined to describe the artificial womb

Birth following gamete freezing

IVF baby born

Preimplantation genetic diagnosis utilised

pregnancy; roughly 15% of all pregnancies involve potentially life-threatening complications, resulting in 10 and 28 maternal deaths annually per 100,000 pregnancies in the UK/Ireland and the US, respectively.16,17 The artificial womb would obviate harmful environmental exposures, including in utero infection and teratogens (e.g., foetal alcohol syndrome). Eliminating just one common virus, cytomegalovirus, could lead to substantial reductions in mortality, morbidity and associated costs; 40,000 congenital cytomegalovirus infections in the US are responsible for approximately 400 deaths and 8,000 serious permanent neurodevelopmental and sensory disabilities annually.18 Total ectogenesis – denoting conception to delivery in the artificial womb – could circumvent infertility, particularly due to uterine Research into extended foetal extrauterine life support in the 1990s successfully incubated goat foetuses in artificial amniotic fluid.

absence or disease. Additionally, it could reduce international

Relevance and potential benefits

socioeconomically vulnerable women.19 Readily available ectogenesis

Due to the limitations of neonatal medicine and technology, at

could mitigate the considerable post-pregnancy morbidity for women,

present life is not viable outside the womb prior to approximately

including backache (45%), sexual dysfunction (20%), bowel problems

23-24 weeks’ gestation. Thus, neonatology reviews are increasingly

surrogacy arrangements, which disproportionately rely on

(17%) and urinary incontinence (11%) six months after delivery.20

calling for the development of an ‘artificial womb’ – a device capable of supporting long-term extra-uterine gestation – to minimise the morbidity and mortality of prematurity.

1,3-6

Expert opinion holds that

such a device is feasible to support gestation from as early as 14 weeks with modern knowledge and technology.

Research and challenges in ectogenesis technologies Proof-of-concept research First attempted in 2003, total ectogenesis involves support from embryo culture to full term. Liu et al. reported growing a mouse

Current challenges to foetal diagnostics and therapy in the uterine

embryo to term in a bioengineered uterus (albeit with deformities).

environment include accessibility, therapeutic failure and

However, in a follow-up experiment, the group transferred murine

procedure-associated adverse events, such as miscarriage, at rates of

embryos grown on engineered uterine tissues (EUIs) to the abdominal

0.81% in amniocentesis13 or 1.6% in foetal transfusion,14 in the

cavity – not the uterus – of adult mice at seven days, and left controls

developed world. In addition, owing to therapeutic limitations,

in vitro. Four days short of term, researchers removed all embryos for

multi-foetal pregnancies and maternal-foetal disease may currently be

comparison; those in vitro had developed hearts, but died. However,

indications for termination.15 The total accessibility of the foetal

the embryos transferred were anatomically normal and apparently

environment offered by ectogenesis creates significant potential for

healthy. In spite of such findings, Liu halted her experiments in

novel solutions in minimally invasive foetal monitoring, surgical access

response to pressure from interest groups and ethical concerns.23-25

and delivery of therapeutics, all of which (potentially) function to

Such proof-of-concept research highlights challenges to the successful

alleviate the morbidity and mortality associated with extreme

application of ectogenesis in bridging the gap between embryo

prematurity, structural anomalies and multi-foetal pregnancy. In

culture and the incubation of mature foetuses. At present, devices

addition, strategic transfer to, or conception in, the artificial womb

performing all the necessary functions of life support at later

could also significantly reduce the morbidity and mortality of

gestations – incubation, gas exchange, waste removal and nutrition –

Page 68 | Volume 9: Number 1. 2016

1992

1997

2014

2015

2016

Intracytoplasmic sperm injection

Birth following mitochondrial donation

Birth following uterus transplant

UK approves mitochondrial donation

Unsuccessful CRISPR/Cas9 gene editing of human embryos

UK licenses human embryo gene editing

exist. Cardiorespiratory, gut, and kidney replicators are present in the

2016

RCSIsmjstaff review

learning induced.29-31 Conversely, the harms of inappropriate or absent

form of extracorporeal membranous oxygenation (ECMO), total

stimuli are highlighted by a 2014 review finding that noisy,

parenteral nutrition, and dialysis, respectively, and can be used in

high-frequency environments disrupt functional organisation of

conjunction with the previously listed life support mechanisms. These

auditory cortical circuits, possibly increasing the risk for disorders of

devices have proven to be of immense clinical value; however,

hearing, language and attention.32

research to implement their long-term integrated use in earlier gestations has yet to progress beyond animal studies.7,25-27

Embryo quality and epigenetics

Proof-of-concept research for extended foetal extrauterine life support

In terms of maximising embryo quality, the immediate

in the 1990s successfully incubated goat foetuses in artificial amniotic

post-fertilisation culture environment is the most important

fluid, providing gas exchange using extracorporeal supplies of blood

determinant.33 However, existing gamete collection and embryo

via umbilical access. Physiologic stability was maintained in foetuses of

culture methods involve hormonal, physical, thermal and other

120-128 days (of total gestation – approximately 150 days) for periods

stresses, which alter epigenetic profiles, DNA methylation patterns,

in excess of 500 hours, with subsequently stable blood gas exchange

and gene expression.34-35 This is reported to exceed the adaptive

and survival upon removal. Results in similar animal studies clearly

capacity of embryos, lowering developmental capacity in animal

indicate the viability of such devices in the extended extrauterine

models36 and resulting in significantly increased anatomical birth

incubation of a premature foetus utilising umbilical arteriovenous

defects in children conceived by IVF and/or intracytoplasmic sperm

ECMO.

25-28

injection (ICSI) – with a meta-analysis pooled risk estimation of 1.37.37,38 One logical concern is epigenetic heritability of poor

Device challenges and neuroplasticity

outcomes. Murine models have demonstrated transgenerational

Assist devices currently undergoing development include the

inheritance of altered epigenetic reprogramming, resulting in

ECMO-type neonatal oxygenator NeonatOx, which has been

adulthood obesity, anxiety disorders and memory impairment.39 The

successfully implemented with preterm lamb models. Its continued

potential risks of unfavourable transgenerational inheritance in human

refinement includes miniaturisation to rectify inappropriate shunt

populations present potentially significant challenges to the continued

fractions associated with congestive heart failure.3 Additional

culture of embryos. Ultimately, embryo culture methods are

challenges to clinical application of such a device include the potential

suboptimal, and additional studies of altered gene expression are

inflammatory and infectious sequelae of blood-priming to initiate the

necessary to further interrogate aberrant imprinting, and to elucidate

circuit with non-foetal blood. Applicability to earlier generations or

how previously identified candidate genes and pathways are

total extrauterine gestation demands further research into the

disrupted.33,36

integration of other life support functions, in order to more fully

Currently, research involving engineered EUTs aims to recapitulate the

recapitulate placental function of the maternal uterus.

microenvironment of the maternal uterus with enhanced fidelity. EUTs

As incubator and life support technologies have progressed, key

already offer the ability not only to support murine embryo growth,

challenges in replicating the requisite stimuli for development have

but to also markedly improve development rate and quality compared

arisen. Mimicking the “tactile, kinaesthetic and vestibular

to standard IVF control culture media.40 These more closely simulate 29

concomitants of maternal speech, movement and physiology” is

utero-embryonic metabolic interactions, and provide the complex

critical to support neuroplasticity and prenatal sensory

mélange of chemosensory, nutritional and immunologic signalling

competence.29,30 This is fundamental, as prenatal plastic changes and

factors for optimum early gestation. In addition, they provide a

fine-tuning in neural assemblies that are required for speech

high-fidelity model for study of maternal-embryonic interactions

perception and understanding, among other functions, are stimulus or

towards maximising outcomes in ectogenesis.2,9,25 Volume 9: Number 1. 2016 | Page 69

RCSIsmjstaff review Ethics and attitudes

avoid the risks and burdens of pregnancy (59%). Men, single people,

Motherhood

secularists, and academic degree holders were found to have a more

A wealth of literature demonstrates complex debate on whether

positive attitude towards ectogenensis.43

mother-child relationships and female identity will be damaged by ectogenesis, or whether it will liberate women to escape gender

Fiscal considerations

constraints and procreate, similarly to men, without compromising

Private investment and commercial markets

health or socio-economic position. Significant division of opinion

Considerable return on developmental costs is conceivable in

surrounds ectogenesis and termination. Ultimately, all embryos are

commercial reproductive and infertility markets. Conventional IVF is

potential candidates for extra-uterine viability. This reframes the

high cost, with suboptimal pregnancy rates per embryo transfer, while

medicolegal understanding of abortion, dissociating termination of

surrogacy carries ethico-legal concerns. The perfected artificial womb

pregnancy from termination of offspring/motherhood, with opinion

could provide better health outcomes, at higher success rates, while

divided on how this might empower or disempower the parties

avoiding time lost through failed embryo transfers.44 The potential

involved.

market for ectogenesis is estimable from the high-growth sectors of

Genetic studies show that miscarriage often functions as a natural

surrogacy – over $2 billion USD in India alone19 – or the international

screening mechanism, involving termination of compromised or

IVF market, valued at $9.3 billion in 2012, and an anticipated $21.6

non-viable pregnancies, e.g., in aneuploidy. The ethico-legal

billion by 2020.45 In addition, commercially available ectogenesis could

considerations of replicating natural mechanisms in recognising and

be marketable as avoiding the morbidity, potential mortality,

terminating severely compromised offspring would fall under abortion

socioeconomic losses, career discrimination46,47 and direct medical costs

laws in many jurisdictions and may be complex in practice.

associated with vaginal and caesarean birth in the US – $32,093 and

How might this affect the legality of, or requirements for, termination?

$51,125, respectively.48

Should the decision-making capacity regarding bringing a conception to term be shared by both parents, having both contributed gametes

State interest – prematurity and environmental factor morbidity

equally, or revert to the state in certain jurisdictions? Might inalienable

The human and state-borne financial costs of prematurity and morbidity

legal rights be afforded from conception, and a legal responsibility on

due to environmental exposures are conceivably significant enough to

parent or state be proposed to bring all conceptions to term? How

support state-level interest in an alternative that is either financially

might viability, disease burden, quality of life, cost or legal capacity

competitive, or carries such medical advantage as to compensate

issues be assessed? In quality of life cases, how might medical, parental

cost–benefit ratios. On a ‘per child’ basis, there is wide scope for

or legal opinion be interpreted?

strategic early transfer to the artificial womb to undercut the relative

Societal demand

review finding mean preterm-associated costs as high as $326,953.49

In addition, it may be argued that there is an ethical imperative for

The annual societal economic burden of prematurity in the US alone

opportunity cost of US care at superior medical outcomes, with a 2013

state-funded pursuit of ectogenesis. Regarding healthcare in terms of

was $26.2 billion in 2005, including direct medical costs of between

distributive justice, it is argued that natural inequalities may generate a

$4.62 and $13.38 billion and special education costs of approximately

prima facie right to restitution (e.g., state-funded infertility treatment). In

$370 million.50

the Cambridge Quarterly of Healthcare Ethics, Smador argues that reproduction is a societal demand, which unequally imposes risk on

Conclusion

women.

We have examined the impacts of, latest research in, and challenges to

The health-related risks and social detriment of pregnancy may

partial and total ectogenesis, in addition to fiscal and ethico-legal

constitute a recognisable health-oriented need and natural injustice.

considerations. As discussed, additional research is needed in a number

Smador thus contends an imperative on the state to redress this prima

of areas, particularly regarding poor outcomes in embryo culture. There

facie right to restitutive justice by pursuing ectogenesis research and

is time in anticipation of such technologies to prepare regulatory

availability.

ethico-legal policies towards best practice. Finally, stakeholder

A pilot study in Israel, of mostly Jewish women, revealed majority

engagement is called for to see the integration and implementation of

support for: ectogenesis for wombless women (74.5%), foetus-saving

existing partial ectogenesis technologies and development of total

ectogenesis (65%) and women’s right to freely choose ectogenesis to

ectogenesis sooner rather than later.

Page 70 | Volume 9: Number 1. 2016

RCSIsmjstaff review References 1. Bulletti C, Palagiano A, Pace C, Cerni A, Borini A, de Ziegler D. The artificial womb. Ann N Y Acad Sci. 2011;1221:124-8. 2. Takagi S, Shimizu T, Kuramoto G, Ishitani K, Matsui H, Yamato M et al. Reconstruction of functional endometrium-like tissue in

Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2015;45(1):16-26. 14. Van Kamp IL, Klumper FJ, Oepkes D, Meerman RH, Scherjon SA,

vitro and in vivo using cell sheet engineering. Biochem Biophys

Vandenbussche FP et al. Complications of intrauterine

Res Commun. 2014;446(1):335-40.

intravascular transfusion for fetal anemia due to maternal

3. Schoberer M, Arens J, Erben A, Ophelders D, Jellema RK, Kramer BW et al. Miniaturization: the clue to clinical application of the artificial placenta. Artif Organs. 2014;38(3):208-14. 4. Davis RP, Bryner B, Mychaliska GB. A paradigm shift in the treatment of extreme prematurity: the artificial placenta. Curr Opin Pediatr. 2014;26(3):370-6. 5. Bryner BS, Mychaliska GB. ECLS for preemies: the artificial placenta. Semin Perinatol. 2014;38(2):122-9. 6. Rochow N, Chan EC, Wu WI, Selvaganapathy PR, Fusch G,

red-cell alloimmunization. Am J Obstet Gynecol. 2005;192(1):171-7. 15. Mahjoub S, Mahbouli S, Masmoudi A, Ben hmid R, Bra A, Karoui G et al. [Medical termination of pregnancy. indications, techniques and complications. Report of 55 cases]. Tunis Med. 2001;79(2):116-22. 16. Knight M, Kenyon S, Brocklehurst P, Neilson J, Shakespeare J, Kurinczuk JJ (eds.). on behalf of MBRRACE-UK. Saving Lives, Improving Mothers’ Care – Lessons learned to inform future maternity care from the UK and Ireland Confidential Enquiries

Berry L et al. Artificial placenta–lung assist devices for term

into Maternal Deaths and Morbidity 2009-2012. Oxford:

and preterm newborns with respiratory failure. Int J Artif

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Organs. 2013;36(6):377-91.

2014.

7. Schoberer M, Arens J, Lohr A, Seehase M, Jellema RK, Collins JJ et al. Fifty years of work on the artificial placenta: milestones in the history of extracorporeal support of the premature newborn. Artif Organs. 2012;36(6):512-6. 8. Vasavada R, Feng Q, Undar A. Current status of pediatric/neonatal extracorporeal life support: clinical outcomes, circuit evolution, and translational research. Perfusion. 2011;26(4):294-301. 9. Barmat LI, Liu HC, Spandorfer SD, Xu K, Veeck L, Damario MA et al. Human preembryo development on autologous endometrial coculture versus conventional medium. Fertil Steril. 1998;70(6):1109-13. 10. Giraud R, Siegenthaler N, Tassaux D, Richard JC, Reverdin S, Cikirikcioglu M et al. [When the heart and/or the lung fails: the ECMO]. Rev Med Suisse. 2011;7(321):2444-51. 11. Gelfand S, Shook JR. Ectogenesis: Artificial Womb Technology and the Future of Human Reproduction. Amsterdam: Rodopi, 2006. 12. Seaton SE, King S, Manktelow BN, Draper ES, Field DJ. Babies born at the threshold of viability: changes in survival and workload over 20 years. Arch Dis Child Fetal and Neonatal Ed. 2013;98(1):F15-20. 13. Akolekar R, Beta J, Picciarelli G, Ogilvie C, D’Antonio F.

17. WHO. Managing complications in pregnancy and childbirth. Geneva, Switzerland: World Health Organization, 2003. 18. Cannon MJ, Davis KF. Washing our hands of the congenital cytomegalovirus disease epidemic. BMC Public Health. 2005;5:70. 19. Singh V, Thakur P. Does surrogacy involve making families or selling babies. International Journal of Healthcare Sciences. 2014;2(1):129-30. 20. Thompson JF, Roberts CL, Currie M, Ellwood DA. Prevalence and persistence of health problems after childbirth: associations with parity and method of birth. Birth. 2002;29(2):83-94. 21. Jouannet P. [Evolution of assisted reproductive technologies]. Bull Acad Natl Med. 2009;193(3):573-82. 22. Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z et al. CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell. 2015;6(5):363-72. 23. Saletan W. The Organ Factory. Slate. 2005. 29 July 2005. 24. McKie R. Men redundant? Now we don’t need women either. The Guardian. 2002. 10 February 2002. 25. Chavatte-Palmer P, Levy R, Boileau P. [Reproduction without a uterus? State of the art of ectogenesis]. Gynecol Obstet Fertil. 2012;40(11):695-7.

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RCSIsmjstaff review 26. Sakata M, Hisano K, Okada M, Yasufuku M. A new artificial placenta with a centrifugal pump: long-term total extrauterine support of goat fetuses. J Thorac Cardiovasc Surg. 1998;115(5):1023-31. 27. Unno N, Kuwabara Y, Okai T, Kido K, Nakayama H, Kikuchi A et al. Development of an artificial placenta: survival of isolated goat fetuses for three weeks with umbilical arteriovenous extracorporeal membrane oxygenation. Artif Organs. 1993;17(12):996-1003. 28. Pak SC, Song CH, So GY, Jang CH, Lee KH, Kim JY. Extrauterine incubation of fetal goats applying the extracorporeal membrane oxygenation via umbilical artery and vein. J Korean Med Sci. 2002;17(5):663-8. 29. Ronca AE, Lamkin CA, Alberts JR. Maternal contributions to sensory experience in the fetal and newborn rat (Rattus norvegicus). J Comp Psychol. 1993;107(1):61-74. 30. Jamon M. The development of vestibular system and related

intracytoplasmic sperm injection: a meta-analysis. Fertil Steril. 2012;97(6):1331-7 e1-4. 39. Calle A, Fernandez-Gonzalez R, Ramos-Ibeas P, Laguna-Barraza R, Perez-Cerezales S, Bermejo-Alvarez P et al. Long-term and transgenerational effects of in vitro culture on mouse embryos. Theriogenology. 2012;77(4):785-93. 40. Lu SH, Wang HB, Liu H, Wang HP, Lin QX, Li DX et al. Reconstruction of engineered uterine tissues containing smooth muscle layer in collagen/matrigel scaffold in vitro. Tissue Eng Part A. 2009;15(7):1611-8. 41. Brown S. Miscarriage and its associations. Semin Reprod Med. 2008;26(5):391-400. 42. Smajdor A. The moral imperative for ectogenesis. Camb Q Healthc Ethics. 2007;16(3):336-45. 43. Simonstein F, Mashiach-Eizenberg M. The artificial womb: a pilot study considering peopleâ&#x20AC;&#x2122;s views on the artificial womb

functions in mammals: impact of gravity. Front Integr Neurosci.

and ectogenesis in Israel. Camb Q Healthc Ethics.

2014;8:11.

2009;18(1):87-94.

31. Partanen E, Kujala T, Naatanen R, Liitola A, Sambeth A,

44. Wang J, Sauer, MV. In vitro fertilization (IVF): a review of 3

Huotilainen M. Learning-induced neural plasticity of speech

decades of clinical innovation and technological advancement.

processing before birth. Proc Natl Acad Sci U S A.

Ther Clin Risk Manag. 2006;2(4):355-64.

2013;110(37):15145-50. 32. Lahav A, Skoe E. An acoustic gap between the NICU and womb:

45. Shields D, Patil R. Global In Vitro Fertilization (IVF) Market (Instruments, Reagents and Media, Technology, Geography) â&#x20AC;&#x201C;

a potential risk for compromised neuroplasticity of

Size, Share, Trends, Opportunities, Global Demand, Insights,

the auditory system in preterm infants. Front Neurosci.

Analysis, Research, Report, Company Profiles, Segmentation and

2014;8:381.

Forecast, 2013-2020. Allied Market Research, 2014. January 2014.

33. Duranthon V, Watson AJ, Lonergan P. Preimplantation embryo programming: transcription, epigenetics, and culture environment. Reproduction. 2008;135(2):141-50. 34. Urrego R, Rodriguez-Osorio N, Niemann H. Epigenetic disorders and altered gene expression after use of assisted reproductive technologies in domestic cattle. Epigenetics. 2014;9(6):803-15. 35. Uyar A, Seli E. The impact of assisted reproductive technologies on genomic imprinting and imprinting disorders. Curr Opin Obstet Gynecol. 2014;26(3):210-21. 36. Gad A, Schellander K, Hoelker M, Tesfaye D. Transcriptome profile of early mammalian embryos in response to culture environment. Anim Reprod Sci. 2012;134(1-2):76-83. 37. Grafodatskaya D, Cytrynbaum C, Weksberg R. The health risks of ART. EMBO Rep. 2013;14(2):129-35. 38. Wen J, Jiang J, Ding C, Dai J, Liu Y, Xia Y et al. Birth defects in children conceived by in vitro fertilization and

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46. Corse SJ. Pregnant managers and their subordinates: the effects of gender expectations on hierarchical relationships. J Appl Behav Sc. 1990;26:25-48. 47. Halpert JA, Wilson ML, Hickman JL. Pregnancy as a source of bias in performance appraisals. J Organ Behav. 1993;14(6):49-63. 48. THA. The Cost of having a Baby in the United States: Truven Health Analytics MarketScan(R) Study. Michigan: Truven Health Analytics, 2013. January 2013. 49. Huynh L, McCoy M, Law A, Tran KN, Knuth S, Lefebvre P et al. Systematic literature review of the costs of pregnancy in the US. Pharmacoeconomics. 2013;31(11):1005-30. 50. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes; Behrman RE, Butler AS (eds.). Preterm Births: Causes, Consequences, and Prevention. A Systematic Review of Costs Associated with Preterm Birth. Washington (DC): National Academies Press (US); 2007.

RCSIsmjstaff review Antibiotics in the 21st century: a fight against a familiar foe

Abstract Antibiotics form the cornerstone of treatment against infectious disease and have helped to drastically reduce mortality rates since the turn of the twentieth century. Through the years, antibiotic development has progressed through different phases of discovery techniques, but has now reached a dipping point in its productivity for a multitude of reasons, both scientific and financial. Furthermore, antimicrobial resistance (AMR) threatens to undo all the progress achieved by these miraculous drugs that were discovered, no less, from the culture of other soil microorganisms. Recent strides in technology and legislation hope to drive resurgence in the field. This is exemplified by teixobactin, a promising new antimicrobial compound, which has been hailed as one of the most exciting scientific discoveries of 2015. This article explores the historical journey of antibiotic discovery, the issues surrounding AMR, the challenges faced by antibiotic research and development (R&D), and the new and innovative strategies being employed to overcome these hurdles. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:73-9.

Stephanie Tung RCSI medical student

A brief history of antibiotic discovery

medicine, intensive care and oncology.

The discovery of antibiotics revolutionised

The development of the very first antibiotic

medicine by drastically improving the efficacy

began with Alexander Fleming’s discovery of

of treatment of infectious disease, which was

penicillin in 1928,2 catalysing an age of

the greatest contributor to mortality statistics in

antibiotic discovery – in particular the beta

the pre-1900s era. The Centers for Disease

lactams, one of the main classes of antibiotics

Control and Prevention (CDC) in the United

utilised in clinical practice to this day.3 The

States (US) reported a rapid decline in

golden era of antibiotic discovery, from the

infectious disease mortality from 1900 to 1999,

1940s to the 1960s, saw an explosion of new

crediting the development of antibiotics as a

antibiotics discovered through systematic

major contributor to this phenomenon.1

screening of soil microorganisms for

Antibiotics remain some of the most effective

antimicrobial activity.4 Roughly two-thirds of

agents in a physician’s arsenal against infectious

‘natural product’ antibiotics (natural substances

disease, and have helped to pave the way for

produced by microorganisms) were isolated

groundbreaking advances in other fields of

from soil Actinomycetes.5,6 However, this

medicine, such as surgery, transplantation

method of antibiotic discovery was restricted to Volume 9: Number 1. 2016 | Page 73

RCSIsmjstaff review

FIGURE 1: Representation of the 20-year discovery void in the antibiotic research and development timeline. The 1940s to the 1960s represents the period of greatest productivity in terms of antibiotic discovery, which was catalysed by the discovery of penicillin.29

cultivable soil microorganisms and dwindled during the 1970s as

Table 1: The ESKAPE pathogens.

a result. As new discoveries became scarce, scientists began utilising semi-synthetic methods to modify pre-existing antibiotic scaffolds, altering their activity and improving their pharmacokinetic properties.7,8 Synthetic approaches came to the forefront of antibiotic discovery in 1995, when the first complete bacterial genome

Enterococcus faecium

Staphylococcus aureus

Klebsiella pneumoniae

Acinetobacter baumannii

Pseudomonas aeruginosa

Enterobacter spp

(Haemophilus influenzae) was sequenced.9 The advent of genomics facilitated the exploration of a multitude of new genes

screening to identify novel antibiotics has been implicated as one

and, in turn, the foundation for a target-based approach to

of the reasons why many pharmaceutical companies have

screen for new classes of antibiotics.8 Major pharmaceutical

withdrawn from antibiotics research and development (R&D).

companies quickly adopted these high-throughput screening

Currently, only four large multinational pharmaceutical

techniques; however, roughly two decades later, they have seen

companies retain their antibiotic R&D divisions (GlaxoSmithKline,

limited success.8 To date, the only clinically-approved antibiotic

AstraZeneca, Merck and Pfizer) and as a result, the last two

discovered via high-throughput screening is bedaquiline, an

decades have seen a significant void in the discovery of novel

anti-tuberculosis agent.10 The collective failure of target-based

antibiotics.11

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RCSIsmjstaff review

FIGURE 2: Mechanisms of antimicrobial resistance (AMR). The acquisition and spread of AMR is driven by: (A) mutagenesis; or, (B) horizontal gene transfer in response to an external stress, such as the use of antibiotics in medicine or agriculture.18

Antibiotic resistance

fuelled by the uncontrolled use of methicillin in hospitals. The

Since the dawn of antibiotic discovery, experts have voiced

modifiable nature of acquired AMR suggests that the rate at

concerns regarding the threat of antimicrobial (antibiotic)

which resistance develops can be controlled via infection

resistance (AMR), most notably Fleming, who foretold the

prevention efforts, efficient infection diagnostics, and antibiotic

development of penicillin resistance in his Nobel Prize acceptance

stewardship during treatment.

speech.12,13 Today, AMR is a serious global health issue; the World

The rapid evolution of AMR is a result of bacterial genetic

Health Organisation (WHO) recently described it as the “single

plasticity, allowing for spontaneous and consistent acquisition of

greatest challenge in infectious diseases today”.14 The CDC

mutations through horizontal gene transfer (HGT) and

estimates that every year over two million people become

chromosomal mutations. These genetic changes manifest

infected with antibiotic-resistant bacteria and at least 23,000 die

through modification of target proteins, enzymatic inactivation of

as a result.15 In addition to the mortality and morbidity associated

drugs and prevention of target access. The frequency of

with AMR in the US, it also generates an economic burden of $20

mutations can be increased in response to loss of DNA repair or

billion USD in excess healthcare costs.16 In the past, AMR was

proofreading and the induction of pro-mutagenic pathways.19

confined to hospital-acquired infections and

HGT facilitates the rapid spread of resistance genes between

immunocompromised patients; however, it has now begun to

species via mobile genetic elements such as plasmids, leading to

spread into community-acquired infections.4

the emergence of multi-drug resistant (MDR) strains of bacteria

AMR can be classified into two different types: intrinsic and

dubbed ‘superbugs’. The ‘ESKAPE’ pathogens are responsible for

acquired. Intrinsic AMR refers to inherent characteristics of a

most MDR infections.20 The most worrisome pathogens exhibit

microorganism that render it resistant to antibiotics, which do

pan-drug resistance, resulting in minimal therapeutic options;

not change in response to antibiotic selective pressure. In

these include Acinetobacter baumannii, Pseudomonas aeruginosa,

contrast, acquired AMR is the product of microbial evolutionary change, conferring a survival advantage on resistant organisms

that has been accelerated by the selective pressure of antibiotic

carbapenem-resistant Enterobacteriaceae and the recently identified New Delhi metallo-β-lactamase-1-expressing Enterobacteriaceae.4,15

drugs used by humans. The main contributors to this selective pressure are the medical and agricultural sectors, which widely

Challenges in antibiotic development

misuse and overuse antibiotics.4,18 Acquired AMR is exemplified

In an effort to address the concerning lack of progress in

by the cautionary tale of the development of methicillin-resistant

developing novel antibiotics against MDR infections, the

Staphylococcus aureus (MRSA) around the 1960s, which was

Infectious Diseases Society of America launched the 10x’20 Volume 9: Number 1. 2016 | Page 75

RCSIsmjstaff review

FIGURE 3: A comparison of the two methods of culturing microorganisms from soil for antibiotic discovery. The traditional method involves directly culturing soil onto culture medium, which yields only 1% of organisms present in the soil. The new iChip-based technology involves seeding soil dilutions to approximate one bacterial cell in a single agar-filled chamber and placing it back in the soil, which greatly increases the yield.4

Initiative for the development and approval of 10 new antibiotics by 2020.

pathogens is particularly worrisome due to their intrinsic resistance to many antibiotics, making drug design problematic.7

A recent update reported that only two new

antibiotics (telavancin and ceftaroline fosamil) had been

Gram-negative organisms have an outer membrane that is

approved for marketing in the US, and these numbers were part

impermeable to amphipathic drugs. Additionally, their inner

of a downward trend.

Antibiotic R&D is a formidable task that

membranes and efflux pump systems also deter hydrophilic

requires substantial monetary investment to develop a new

molecules from entering the bacteria. One notable example is the

compound without any guarantee of success. Ironically, despite

enterococcus species, which is inherently resistant to beta-lactams

their life-saving capabilities, antibiotics are inherently less costly,

such as penicillins, cephalosporins and carbapenems. The ESKAPE

are administered for a shorter duration than many drugs used to

pathogens, most notable for causing life-threatening MDR

treat chronic medical conditions, are curative by nature, and tend

infections, are predominantly gram-negative pathogens, and

to be held in reserve in an effort to delay AMR development.

physicians are sorely in need of therapeutic agents to counteract

These factors mean that antibiotics generate less net return on

these life-threatening infections.

investment and are logically less appealing investments for pharmaceutical companies.7,22,23,24 The field of antibiotic

Strides in the right direction

development currently relies on the efforts of small

Economic incentives and new collaborative efforts are needed to

pharmaceutical and biotechnology companies, which often lack

address the commercial failure of antibiotics. Government

the resources to develop potential drugs in large-scale clinical

initiatives encouraging pharmaceutical companies to undertake

trials, therefore impeding much-needed progress.18

antibiotic R&D have been launched on both sides of the Atlantic.

Researchers face equally formidable obstacles in the search for

In 2011, the US Congress introduced the Generating Antibiotic

new antibiotics. Breakthroughs have become elusive due to

Incentives Now (GAIN) Act, which detailed new incentives to

over-mining of natural products and unsuccessful synthetic

advance antibiotic development.29 The European Commission

approaches. In the last decade, the focus of the field has been

founded a publicâ&#x20AC;&#x201C;private collaboration, the Innovative Medicines

limited to targeting resistant strains of gram-positive organisms

Initiative (IMI), with initial funding of â&#x201A;Ź223.7 million, to be used

such as MRSA and vancomycin-resistant Enterococci (VRE).

to tackle AMR and to speed the delivery of new antibiotics to

Recent data suggest that resistance rates in these gram-positive

patients.30 The IMI has also funded a multinational publicâ&#x20AC;&#x201C;private

pathogens have stabilised or decreased, but the incidence of

consortium, Driving Re-Investment in R&D and Responsible

drug-resistant tuberculosis and gram-negative strains has been

Antibiotic use (DRIVE-AB) to develop alternative economic

increasing.26,27,28 The emergence of new resistant gram-negative

strategies allowing for sustainable development of novel

Page 76 | Volume 9: Number 1. 2016

RCSIsmjstaff review

FIGURE 4: Postulated mechanism of action of teixobactin. Teixobactin (TEIX) is produced by a gram-negative bacterium and is exported across the outer membrane. In target gram-positive organisms, teixobactin’s targets – lipid II (precursors of peptidoglycan [PG]) and lipid III (precursor of wall teichoic acid [WTA]) – are readily accessible on the outside. Binding to multiple targets within the cell wall pathways interrupts the formation of a functional cell wall.44

antibiotics, while balancing appropriate usage of said resources.23 A

using the iChip technology is approximately 50% and significantly

recent review on AMR commissioned by the UK Government has

greater than the 1% yield from soil that will grow on a nutrient Petri

proposed the formulation of a global innovation fund to reward

dish using traditional culture methods.44

groups developing new antibiotics with lump sums.24

Teixobactin was isolated from a new species of β-proteobacteria

Innovative solutions are needed to address the scientific bottleneck

named Eleftheria terrae, which is related to Aquabacteria. It is a

facing antibiotic development. Scientists have taken to expanding

depsipeptide molecule that acts as a cell wall inhibitor by binding

their field of research on a macroscopic level by exploring other

two precursors of bacterial cell wall polymers: lipid II

ecological niches in search of antibiotic agents. Promising new

(peptidoglycan) and lipid III (teichoic acid).44 Structural analysis of

compounds have been sourced from deep sea sediment bacteria,

teixobactin demonstrated a unique chemical scaffold unlike existing

marine flora and fauna, and bacterial symbionts of insects, fungi

antibiotics, a highly desirable trait for new antibiotics. Teixobactin

and myxobacteria.31-37 Other novel research avenues to overcome

exhibits excellent activity against gram-positive pathogens

AMR include targeting molecular mechanisms of AMR, virulence

extending to drug-resistant strains, but has no activity against

factors, antimicrobial peptides, and bacteriophages, as well as

gram-negatives.

repurposing genomic-based antibacterial screening with new tools

There is an intriguing lack of development of resistance to

19,38-41

teixobactin during in vitro and in vivo testing;44 however, despite

such as combinatorial chemistry.

One untapped resource postulated to be a new avenue for

these promising results, teixobactin has yet to undergo clinical trials 42

antibiotic discovery is that of uncultivable soil microorganisms.

in humans, so its success remains to be proven despite the initial

Data suggests that the number of discovered antibiotics represents

enthusiasm about its potential. The authors have postulated that the

only 10% of the screened bacterial strains and only 1% of all

reason behind the lack of resistance development is due to

microorganisms.

teixobactin’s unique targets; lipids are essential to cell wall synthesis

A recent success story is teixobactin, the first new class of antibiotics

and are synthesised from organic precursors, whereas proteins are

with a novel mechanism, which was discovered using new

encoded by genes that can easily mutate in response to selective

technology for culturing soil microorganisms – iChip44 – a

pressure.44

multichannel device that allows the diffusion of nutrients and growth factors from the soil into separated chambers to allow for

Post-antibiotic era?

growth of previously uncultivable bacteria.45 A soil sample is diluted

The threat of AMR and the diminishing antibiotic pipeline has led

down to approximately one bacterial cell per given chamber and

many experts to ponder whether a post-antibiotic era is

placed back into its original environment. The growth recovery

imminent, in which common infections and minor injuries Volume 9: Number 1. 2016 | Page 77

RCSIsmjstaff review become lethal.46 In the past, antibiotic development just barely

prevention and antibiotic stewardship. Concerted efforts have

kept pace with the rate of bacterial evolution, and the lengthy

been made in legislation and funding towards revitalising the

lack of productivity in the pipeline certainly has left a sizeable

antibiotic discovery industry. The research community has also

gap between the two.

stepped forward with a variety of new approaches to tackling the

In order to close this gap, collaborative efforts are necessary, as

elusive issue of novel antibiotic discovery. Only time will tell

the problem has now become too large for one sector to handle

whether AMR can be held at bay long enough to allow for these

on its own.

efforts to come to fruition, and the hope is that human

Government and health organisations have begun taking action

innovation can indeed make up for lost time and allow us to

towards combating AMR development via public health

continue in this age-old battle against the microbes.

References 1. Centers for Disease Control and Prevention (CDC). Achievements in Public Health 1900-1999: Control of Infectious Diseases. [Internet]. [Accessed 2015 August 6]. Available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm. 2. Fleming A. On the antibacterial action of cultures of penicillium,

13. Barriere SL. Clinical, economic and societal impact of antibiotic resistance. Expert Opin Pharmacother. 2015;16(2):151-3. 14. World Health Organisation (WHO). WHO report finds systems to combat antibiotic resistance lacking. [Internet] [Accessed 2015 August 6]. Available from:

with special reference to their use in the isolation of B. influenzae.

http://www.who.int/mediacentre/news/releases/2015/antibiotic-resi

Br J Exp Pathol. 1929;10(3):226-36.

stance-lacking/en/.

3. Kardos N, Demain AL. Penicillin: the medicine with the greatest

15. Centers for Disease Control and Prevention (CDC). Antibiotic

impact on therapeutic outcomes. Appl Microbiol Biotechnol.

resistance threats in the United States, 2015. [Accessed 2015

2011;92(4):677-87.

August 6]. 13p. Available from:

4. Arias CA, Murray BE. A new antibiotic and the evolution of resistance. N Engl J Med. 2015;372(12):1168-70. 5. Weber T, Welzel K, Pelzer K, Vente A, Wohlleben W. Exploiting

http://www.cdc.gov/drugresistance/pdf/ar-threats-2013-508.pdf. 16. The Alliance for the Prudent Use of Antibiotics (APUA). The cost of antibiotic resistance to U.S. families and the health care

the genetic potential of polyketide producing streptomycetes. J

system. [Internet] [Accessed 2015 August 7]. Available from:

Biotechnol. 2003;106(2-3):221-32.

http://www.tufts.edu/med/apua/consumers/personal_home_5_1

6. Baltz RH. Genetic manipulation of antibiotic-producing Streptomyces. Trends Microbiol. 2009;12(5):520-7. 7. Fair RJ, Tor Y. Antibiotics and bacterial resistance in the 21st century. Perspect Medicin Chem. 2014;28(6):25-64. 8. Payne DJ, Gwynn MN, Holmes DJ, Pompliano DL. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov. 2007;6(1):29-40. 9. Fleischmann RD, Adams MD, White O, Clayton RA, Kirkness EF, Kerlavage AR et al. Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science. 1995;269(5223):496-512. 10. Lewis K. Platforms for antibiotic discovery. Nat Rev Drug Discov. 2013;12(5):371-87. 11. Boucher HW, Talbot GH, Benjamin DK Jr, Bradley J, Guidos RJ, Jones RN et al. 10x’20 progress – development of new drugs active against gram-negative bacilli: an update from the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(12):1685-94. 12. Fleming A. Penicillin. Nobel Lecture. December 11, 1945.

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451036133.pdf. 17. Hall BG, Barlow M. Structure-based phylogenies of the serine beta-lactamases. J Mol Evol. 2003;57(3):255-60. 18. Jabes D. The antibiotic R&D pipeline: an update. Curr Opin Microbiol. 2011;14(5):564-9. 19. Culyba MJ, Mo CY, Kohli RM. Targets for combating the evolution of acquired antibiotic resistance. Biochemistry. 2015;54(23):3573-82. 20. Boucher HW, Talbot GH, Bradley JS, Edwards JE, Gilbert D, Rice LB et al. Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(1):1-12. 21. Infectious Diseases Society of America. The 10x20’ Initiative: pursuing a global commitment to develop 10 new antibacterial drugs by 2020. Clin Infect Dis. 2010;50(8):1081-3. 22. Roca I, Akova M, Baquero F, Carlet J, Cavaleri M, Coenen S et al. The global threat of antimicrobial resistance: science for intervention. New Microbes New Infect. 2015;6:22-9.

RCSIsmjstaff review 23. Harbarth S, Theuretzbacher U, Hackett J. Antibiotic research and

32. Laport MS, Santos OC, Muricy G. Marine sponges: potential

development: business as usual? J Antimicrob Chemother.

source of new antimicrobial drugs. Curr Pharm Biotechnol.

2015;70(6):1604-7.

2009;10(1):86-105.

24. The Review on Antimicrobial Resistance. Securing new drugs for

33. Burgess JG, Jordan EM, Bregu M, Mearns-Spragg A, Boyd KG.

future generations: the pipeline of antibiotics. [Accessed 2015

Microbial antagonism: a neglected avenue of natural products

August 8]. Available from:

research. J Biotechnol. 1999;70(1-3):27-32.

http://amr-review.org/sites/default/files/SECURING%20NEW%20 DRUGS%20FOR%20FUTURE%20GENERATIONS%20FINAL%20W EB_0.pdf. 25. Loffler CA, MacDougall C. Update on prevalence and treatment of methicillin-resistant Staphylococcus aureus infections. Exp Rev Anti Infect Ther. 2007;5(6):961-81. 26. European Centre for Disease Prevention and Control. Communication from the Commission to the European Parliament

34. Donia MS, Ravel J, Schmidt EW. A global assembly line for cyanobactins. Nat Chem Biol. 2008;4(6):341-3. 35. Partida-Martinez LP, Hertweck C. Pathogenic fungus harbours endosymbiotic bacteria for toxin production. Nature. 2005;437(7060):884-8. 36. Piel J. Metabolites from symbiotic bacteria. Nat Prod Rep. 2009;26(3):338-62. 37. Wenzel SC, Muller R. The biosynthetic potential of myxobacteria

and the Council. Action plan against the rising threats from

and their impact on drug discovery. Curr Opin Drug Discov

Antimicrobial Resistance. [Accessed 2015 August 8]. Available from:

Devel. 2009;12(2):220-30.

http://ec.europa.eu/dgs/health_food-safety/docs/communication_a mr_2011_748_en.pdf. 27. Daxboeck F, Budic T, Assadian O, Reich M, Koller W. Economic

38. Waldor MK. Disarming pathogens – a new approach for antibiotic development. N Engl J Med. 2006;354(3):296-7. 39. Pastagia M, Schuch R, Fischetti VA, Huang DB. Lysins: the arrival

burden associated with multi-resistant gram-negative organisms

of pathogen-directed anti-infectives. J Med Microbiol. 2013;62(Pt

compared with that for methicillin-resistant Staphylococcus aureus

10):1506-16.

in a university teaching hospital. J Hosp Infect. 2006;62(2):214-18. 28. European Medicines Agency. The bacterial challenge: time to react. A call to narrow the gap between multidrug-resistant bacteria in the EU and the development of new antibacterial agents. [Accessed 2015 August 8]. Available from: http://ecdc.europa.eu/en/publications/Publications/0909_TER_Th e_Bacterial_Challenge_Time_to_React.pdf. 29. Infectious Diseases Society of America (IDSA), Spellberg B, Blaser M, Guidos RJ, Boucher HW, Bradley JS, et al. Combating

40. Bragg R, van der Westhuizen W, Lee JY, Coetsee E, Boucher C. Bateriophages as potential treatment option for antibiotic resistant bacteria. Adv Exp Med Biol. 2014;807:97-110. 41. Steckbeck JD, Deslouches B, Montelaro RC. Antimicrobial peptides: new drugs for bad bugs? Expert Opin Biol Ther. 2014;14(1):11-14. 42. Wilson MC, Mori T, Ruckert C, Uria AR, Helf MJ, Takada K et al. An environmental bacterial taxon with a large and distinct metabolic repertoire. Nature. 2014;506(7486):58-62. 43. Watve MG, Tickoo R, Jog MM, Bhole BD. How many antibiotics

antimicrobial resistance: policy recommendations to save lives.

are produced by the genus Streptomyces? Arch Microbiol.

Clin Infect Dis. 2011;52(Suppl. 5):S397-428.

2001;176(5):386-90.

30. European Commission. Combating antibiotic resistance:

44. Ling LL, Schneider T, Peoples AJ, Spoering AL, Engels I, Conlon BP

NewDrugs4-BadBugs (ND4BB). [Accessed 2015 August 8].

et al. A new antibiotic kills pathogens without detectable

Available from:

resistance. Nature. 2015;517(7535):455-9.

http://www.imi.europa.eu/sites/default/files/uploads/documents/ Press%20Releases/IMIpressRelease6thCallFINAL.pdf. 31. Blister B, Bischoff D, Strobele M, Riedlinger J, Reicke A, Wolter F et al. Abyssomicin C – a polycyclic antibiotic from a marine Verrucosispora strain as an inhibitor of the p-aminobenzoic

45. Nichols D, Cahoon N, Trakhtenberg EM, Pham L, Mehta A, Belanger A et al. Use of iChip for high-throughput in situ cultivation of “uncultivable” microbial species. Appl Environ Microbiol. 2010;76(8):2445-50. 46. Appelbaum PC. 2012 and beyond: potential for the start of a

acid/tetrahydrofolate synthesis pathway. Angew Chem Int Ed

second pre-antibiotic era? J Antimicrob Chemother.

Engl. 2004;43(19):2574-6.

2012;67(9):2062-8.

Volume 9: Number 1. 2016 | Page 79

RCSIsmjstaff review Watch this space: bringing medicine beyond Earth’s boundaries

Abstract Since the first manned flight by Yuri Gagarin in 1961, the human race has strived to push the boundaries of manned space travel. Originally driven by curiosity, in more recent years the new goal is to extend the range of human habitat beyond Earth’s limits. This will require extended duration space flights. However, humans evolved in the presence of gravity and Earth’s particular atmosphere. Leaving this protective environment poses a myriad of challenges to the human body, including microgravity, solar proton radiation, prolonged confinement and isolation, absence of natural light and circadian rhythm changes. Key effects identified include loss of bone density and muscle strength, adverse psychological changes and increased cancer risk. Future missions will routinely demand complex and physically demanding tasks, and astronauts will be unable to receive additional resources or communications from Earth in a timely manner. It is essential that effective countermeasures be developed to maintain or enhance human performance in microgravity. Increasing private sector investment in commercial space travel also means that future passengers will be a more diverse population that may be less tolerant to space travel than current astronauts. This increases the likelihood of life-threatening in-flight surgical or psychological emergencies. With current flights including only one crew member with limited medical training, changes Naomi O’Sullivan RCSI medical student

will need to be made to medical protocols to ensure mission success, such as prophylactic appendectomies and the inclusion of emergency physicians in future crews. Royal College of Surgeons in Ireland Student Medical Journal. 2016;1:80-4.

Page 80 | Volume 9: Number 1. 2016

RCSIsmjstaff review Introduction

Musculoskeletal adaptations

Driven by innate curiosity, fear of the unknown and potential

One of the best-understood consequences of space flight is the impact

commercial gain, humans have long strived to push the boundaries of

of microgravity on the musculoskeletal system. Bone and muscle are

manned space travel since that first flight by Yuri Gagarin in 1961.

active, dynamic organs that quickly respond to the physical forces

Recently, we have identified a new goal: to extend the range of

exerted upon them.1 Space flight neutralises the gravitational loading

human habitat beyond Earth through colonisation of other planets

required for skeletal remodelling and muscle growth,3,6,9 leading to

and prolonged space travel. However, leaving the protective cocoon

significant loss in bone density and widespread muscle atrophy.3

that we evolved in, no longer cushioned by the presence of gravity

Suboptimal nutrition, reduced vitamin D due to low levels of natural

and a precise balance of gases, poses a myriad of challenges to the

light, and higher ambient levels of CO2 lead to respiratory acidosis

human body – as demonstrated in the book (turned major motion

and increased bone resorption.10,11

picture) The Martian by Andy Weir.1 These include microgravity,

Postural muscles atrophy most due to their relatively unloaded state.6

radiation, prolonged confinement and isolation, and changes in

After two weeks of space flight, muscle mass decreases by 20%,

circadian rhythm. Key effects identified include loss of bone density,

extending to 30% by three to six months.12,13 The loss of bone density

decreased muscle strength and endurance, adverse psychological

is much more concerning, beginning immediately upon arrival in

changes, and increased cancer risk due to high-energy radiation.

space, with a 60-70% increase in urine and faecal calcium loss within

Unshaken by these dangers, we are rapidly making the advances in

the first few days.10 This continues with a 1-2% loss per month in

research and technology necessary to make extraterrestrial

weight-bearing bones;9,10 hence, osteopaenia could become a limiting

colonisation a reality. Missions will routinely require astronauts to

factor in mission duration.14 Future missions will inevitably involve

perform complex and physically demanding tasks, so it is essential to

strenuous physical work and extravehicular excursions, so increased

minimise adverse effects, particularly in light of the fact that astronauts

risk of fracture is a real concern.11

will be unable to receive additional resources or communications from

Countermeasures focus on the prevention of bone loss with exercise

earth in a timely manner. With increasing private sector investment in

and dietary measures, including low-salt and high-calcium diets, and

commercial space travel, the passengers of future flights will also be a

vitamin D and protein intake.12 Pharmacological agents are avoided

more diverse population, potentially less tolerant of space travel than

due to the potential for serious side effects that the crew may not be

the robust and rigorously trained athletes of today.

equipped to deal with.15 In-flight exercise programmes lack the impact forces associated with Earth’s gravity and are insufficient.7 Additionally,

Cardiovascular adaptations

the current two-hour daily exercise regimen consumes valuable

The cardiovascular system appears to adapt the most appropriately to

oxygen, food, water and crew time, and will only increase with longer

microgravity. The most frequently documented changes are related to

flights. One alternative proposal is to use intermittent artificial

shifts in body fluids and mild arrhythmias.2-4 During space flight, lack

gravity;16 recent studies indicate that human subjects may undergo

of gravity-induced hydrostatic forces lead to a cephalad shift and

daily exposure to artificial gravity without suffering debilitating motion

equilibration of fluid from lower extremities to the trunk and upper

sickness, and periodic exposure is effective in maintaining muscle

extremities.2 This manifests as nasal congestion and the classic “puffy

mass.17 However, this is a costly and difficult engineering task.

face/bird leg” appearance of astronauts.3 Fluids shifting towards the head distend the baroreceptors of the central vasculature, resulting in

Radiation exposure

suppression of the renin-angiotensin-aldosterone system (RAAS) and a

Perhaps the most sinister health concern is exposure to radiation

5,6

10% reduction in total blood volume.

These effects decrease over

time, but remain present for the duration of the flight.7 Increases in

beyond Earth’s orbit, which is vastly different to the ionising type to which humans are usually exposed,18 and is thought to produce

heart rate and premature atrial and ventricular contractions have also

distinct biological damage. Astronauts incur substantial but poorly

been reported in 30% of astronauts during extravehicular activity,

understood risks of carcinogenesis and degenerative disease. Solar

launch and orbit, thought to be due to catecholamine hyperactivity.8

flares are particularly concerning due to their unpredictable nature,

So far, crew members have tolerated these episodes well, but

while high energy (HZE) ions are the main contributor to the risk due

passengers on future flights will likely be much less conditioned. This

to their high ionisation power.18,19 During a three-year mission to

should be noted when developing future preflight medical

Mars, every cell nucleus in the body would be hit by a proton or

evaluations.

secondary electron every few days, and a HZE ion once a month. This Volume 9: Number 1. 2016 | Page 81

RCSIsmjstaff review would culminate in a whole-body dose of radiation equal to

well-documented form of displacement during space flight: the team

approximately 1 Sievert or more. The risk of cancer is significantly

transfers intra-group tension onto a remote individual.27,28 The most

increased by this exposure, and has prompted studies on how the risks

extreme case of frustration resulted in crew cutting contact with mission

– particularly of tumourigenesis – might be minimised.

control entirely for over 24 hours.24 Longer-duration flights are expected

Radiation exposure also has significant impacts on the human

to increase stress and the severity of the displacement response.

reproductive system, particularly in females. Flights to date have been

Proposed countermeasures include allowing more autonomy in

considerably shorter than the average menstrual cycle length, so no

planning work schedules, and greater involvement of mission control in

on-shuttle studies have been conducted to determine the impact on

pre-flight training exercises.24,29 This may also help to address the

the hypothalamic-pituitary-ovarian axis. The main concern is that

frequently reported feelings of sedentariness and monotony resulting

anovulation or hypothalamic amenorrhoea and reduced oestrogen

from hypostimulation and restricted social contacts.29

19-21

levels (which contribute to risk of osteoporosis) could occur.

The consensus is that more emphasis needs to be placed on

Radiation exposure, combined with the increased retrograde

personality and identification of behaviour predisposing to certain

menstruation during space flight, may predispose to the development

adaptations to prolonged confinement. Individuals’ insight into their

of endometriosis.

own capabilities, mental endurance, and response to stressors must be

The risks of these effects can be largely controlled by oral

taken into account.29 Biological markers such as polymorphisms

contraceptive or hormone replacement therapy. Due to radiation

involved in sleep-wake cycle, circadian rhythm and cognitive

levels associated with any space flight, and consensus that no embryo

regulation should also be used to identify those at increased risk of

could appropriately adapt to microgravity, pregnancy in space is

neurobehavioural vulnerability to sleep restriction.24,30

currently not feasible.23

Encouragingly, not all psychological changes experienced by

More research needs to be carried out on shielding options, including

astronauts are negative. Numerous astronauts report experiencing a

potential radioprotective drugs.

“transcendental, religious experience or sense of the unity of mankind” while in space.31 This positive phenomenon enabled

Psychological adaptations

astronauts to experience change as normal and beneficial, and to

NASA has predicted that psychological issues are all but inevitable,

believe that events would work out as well as could reasonably be

and pose a serious threat to mission success.21 Future crews must

expected.29 However, this salutogenic phenomenon is, in the majority

adhere to a strict and demanding schedule while confined in a

of cases, related to the perception of Earth from space.24 With the

spacecraft, removed from earthly conveniences and daily routines. To

longer duration flights to Mars, the inability to see Earth could have

date, no mission has been terminated prematurely due to behavioural

detrimental effects on psychological well-being.

disturbance, but this may be largely due to the current duration of flights, frequency of contact with ground control, and strict astronaut 24

Surgery in microgravity Life-threatening surgical conditions that may arise without warning in

selection criteria.

The longest prior simulated space mission lasted a mere 240 days;

healthy crew members include traumatic injuries, appendicitis,

the ambitious Mars 520 project confined a multinational crew of six

diverticulitis, cholecystitis and pancreatitis.32 As missions move further

healthy males to a 550m2 chamber on Earth for 520 days.26 While

from Earth, telemetric medical support and traditional

unable to mimic the effects of microgravity, radiation and real threat

communications travelling at the speed of light will be greatly

to life, the project isolated participants from Earth’s light-dark cycles,

delayed. For example, two-way contact on Mars would take a

limited their access to consumable resources, simulated

minimum of 44 minutes, which will pose great challenges to real-time

communication delays, and assigned daily maintenance work,

robotic surgery and support from mission control in medical

experiments and exercise identical to that predicted on a real mission

emergencies.33

to Mars.

While no surgeries have yet been performed on humans in space, the

Investigators noted disruptions to circadian rhythm and modest

first animal laparotomy was performed in 1967 and since then

increases in depressive symptoms and psychological distress, but

haemorrhage, large vessel repair and wound closure were not found

arguably the most interesting observation was an increase in

to be significantly more difficult than during terrestrial procedures.34,35

crew-perceived conflicts with ground control as the mission

However, restricted resources and limited crew medical training,

progressed.24 The development of an ‘Us vs Them’ attitude is a

including inability to provide basic perioperative and postoperative

Page 82 | Volume 9: Number 1. 2016

RCSIsmjstaff review care,36 still pose significant challenges. Immune dysregulation and the

some minor surgical skills (such as suturing).36 At the minimum, future

documented increased pathogenecity of bacteria in space could also

flights will need a physician astronaut with basic surgical skills and the

greatly increase the likelihood and severity of postoperative

ability to manage acute illness. Emergency physicians are likely the

infections. If significant operative complications occurred requiring

most suitable candidates for this position.

critical care support, there would almost certainly be loss of mission or of life. Support for prophylactic appendicectomies and

Conclusion

cholecystectomies is growing. Appendicitis and cholecystsitis are

This past year proved monumental for space exploration, imparting

common conditions and prophylactic appendicectomy has been

an even greater sense of urgency to efforts to extend our habitat

mandatory for the Australian Antarctic Programme for those spending

boundaries beyond Earthâ&#x20AC;&#x2122;s limits. The Mars Reconnaissance Orbiter

winter in Antarctica since 1950.38 No cases of cholecystitis or

identified hydrated salt minerals on Mars and SpaceX continued

appendicitis have been documented in space thus far, but this is

their success in developing fully and rapidly reusable launch vehicles

largely due to the relatively young age and lower BMIs of crew

that will drastically lower space flight costs.36,39 Perhaps most

members, combined with intensive medical screening; future

significantly, International Space Station astronauts consumed the

astronauts will likely be in less optimal condition and will undergo

first ever meal of space-grown lettuce, bringing the possibility of

more lenient screening. Arguably, prophylactic surgery could be

self-sustainable astronauts closer to reality.40 The uniquely

beneficial and necessary in preventing the catastrophic loss of mission

challenging medical setting that space flight presents will

or life; however, this is fraught with significant ethical issues. Having

undoubtedly further terrestrial medicine through spin-off

the surgery may become a significant advantage for candidates being

technologies, such as telemedicine, and greater understanding of

considered for a position on a flight, leading to peer, corporate and

human physiology. However, if future missions are to be successful,

public pressure to comply. Conversely, suffering operative

it is clear that current medical protocols must change. At a

complications may disqualify a candidate entirely from the flight.

minimum, emergency physicians must be included in all crews,

Regardless of whether this becomes mandatory, changes will need to

prophylactic surgeries must be seriously considered, and greater

be made to medical and surgical protocols to ensure mission success.

efforts need to be directed into truly effective and affordable

Currently, one crew member receives limited medical training and has

radiation countermeasures.

References 1. Weir A. The Martian. United States of America: Crown, 2014.

loss after long duration space flight. J Musculoskeletal Neuronal

2. Lowan HS, Trunky D, Rebagliati GS. Emergency medicine in

Interact. 2000;1:157-60.

space. J Emerg Med. 2006;32:45-54. 3. Aubert A, Beckers F, Verheyden B. Cardiovascular function and basics of physiology in microgravity. Acta Cardiol. 2005;60:129-51. 4. Leech CS, Johnson PC, Cintron NM. The endocrine system in space flight. Acta Astronaut. 1988;12:161-6. 5. Williams D, Kuipers A, Mukai C. Acclimation during space flight: effects on human physiology. CMAJ. 2009;180:1317-23. 6. Guell A. Countermeasures: extending manned space flight. Acta Astronaut. 1995;35:271-80. 7. Leach CS, Inners LD, Charles JB. Changes in total body water during space flight. J Clin Pharmacol. 1991;31:1001-6. 8. Mills PJ, Meck JV, Waters WW. Peripheral leukocyte sub-populations and catecholamine levels in astronauts as a function of mission duration. Psychosom Med. 2001;63:886-90. 9. LeBlanc A, Schneider V, Shackelford L. Bone mineral and lean tissue

10. Oganov VS, Shneider VS. Skeletal system. In: Nicogossian AE, Gazenko OG (eds.). Space Biology and Medicine: joint US/Russian publication in five volumes. 1996;3:246-66. 11. Buckley JC. Bone loss: managing calcium and bone loss in space. In: Barratt MR, Pool SL (eds.). Space Physiology. Oxford University Press; 2006:5-21. 12. Clement G. Musculoskeletal system in space. In: Fundamentals of Space Medicine. Dordrecht, Netherlands: Kluwer Academic Publishers; 2003:173-204. 13. Shackelford LC. Musculo-skeletal response to space flight. In: Barrat MR, Pool SL (eds.). Principles of Clinical Medicine for Space Flight. New York: Springer Science and Business Media; 2008:293-306. 14. Holick M. Microgravity-induced bone loss â&#x20AC;&#x201C; will it limit human space exploration? Lancet. 2000;355:1569-70. 15. Cavanagh P, Licata A, Rice A. Exercise and pharmacological

Volume 9: Number 1. 2016 | Page 83

RCSIsmjstaff review countermeasures for bone loss during long duration space flight.

[Updated 1971; accessed 2015 July 4]. Available from:

Gravit Space Biol Bull. 2005;18(2):39-58.

http://ntrs.nasa.gov/search.jsp?R=19720008366.

16. LeBlanc AD, Spector ER, Evans HJ, Sibonga JD. Skeletal responses to space flight and the bed rest analog: a review. J Musculoskelet Neuronal Interact. 2007;7:33-47. 17. Caiozzo VJ, Haddad D, Lee S. Artificial gravity as a countermeasure to microgravity: a pilot study examining the effects on knee

29. Kobasa SC, Hilker RR, Maddi SR. Who stays healthy under stress? J Occup Med. 1979;21:595-8. 30. Franken P, Chollet D. The homeostatic regulation of sleep need is under genetic control. J Neurosci. 2001;21:2610-21. 31. Antonovosky A. Health, Stress and Coping: New Perspectives

extensor and plantar flexor muscle groups. J Appl Physiol.

on Mental and Physical Well-being. Jossey-Bass: San

2009;107:39-46.

Francisco, California, 1979.

18. Cucinotta FA, Kim MY, Chappell L. How safe is safe enough?

32. Ball GC, Kirkpatrick AW. Prophylactic surgery prior to

Radiation risk for a human mission to Mars. PLoS ONE.

extended duration space flight: is the benefit worth the

2013;8:e74988.

risk? Can J Surg. 2012;55:125-31.

19. Drinkwater BL, Nilson K, Chestnut H III. Bone mineral content of amenorrheic and eumenorrheic athletes. N Engl J Med. 1984;311:277-81. 20. Marcus R, Cann C. Menstrual function and bone mass in elite women distance runners: endocrine and metabolic features. Ann Intern Med. 1985;102:158-63. 21. Slack KJ, Shea C, Leveton LB. Risk of behavioural and psychiatric conditions: NASA evidence-based review. [Updated 2009; accessed

33. Stewart LH, Trunkey D, Rebagliati GS. Emergency medicine in space. J Emerg Med. 2007;32:45-54. 34. Yaroshenko GL, Dawson DL, Melton S. Characteristics of surgical intervention in conditions of weightlessness. Voen Med Zh. 1967;10:69. 35. Campbell MR, Bilica RD, Johnston SL III. Animal surgery in microgravity. Aviat Space Environ Med. 1992;63:524-8. 36. Brown D, Webster G. NASA Confirms Evidence That Liquid

2015 July 4]. Available from:

Water Flows on Todayâ&#x20AC;&#x2122;s Mars [Internet]. Washington: NASA;

http://humanresearchroadmap.nasa.gov/evidence/reports/BMED.p

2015 [updated 2015 September 28; cited 2016 February

df.

16]. Available from:

22. Wood DH, Yochmowitz MG, Salmon YL. Proton irradiation and endometriosis. Aviat Space Environ Med. 1983;54:718-24. 23. Harm DL, Jennings RT, Meck JV. Invited review: gender issues related to spaceflight: a NASA perspective. J Appl Physiol. 2001;91:2374-83. 24. Van dongen HPA, Bynard MD. Systematic interindividual differences in neurobehavioural impairment from sleep loss: evidence of trait-like differential vulnerability. Sleep. 2004;27:423-33. 25. Lapierrea J, Bouchard S, Martin T. Transcultural group performance in extreme environment: issues, concepts and emerging theory. Acta Astronaut. 2009;64:1304-13. 26. Basner M. Psychological and behavioural changes during

http://www.nasa.gov/press-release/nasa-confirms-evidence-t hat-liquid-water-flows-on-today-s-mars. 37. Wilson JW, Ott CM, Honer zu Bentrup K. Spaceflight alters bacterial gene expression and virulence and reveals a role for global regulator Hfq. Proc Natl Acad Sci U S A. 2007;104:16299-304. 38. Lugg DJ. Antarctic epidemiology: a survey of ANARE stations 1947-1972. In: Polar Human Biology. Chicago, IL: Year Book Medical Publishers, 1974:93-105. 39. Graham W. SpaceX returns to flight with OG2, nails historic core return. America: NASASpaceFlight.com. [Updated 2015 December 21; cited 2016 February 16]. Available from:

confinement in a 520-day simulated interplanetary mission to

http://www.nasaspaceflight.com/2015/12/spacex-rtf-core-re

Mars. [Updated 2014; accessed 2015 July 4]. Available from:

turn-attempt-og2/.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0 093298 - pone.0093298-Slack1. 27. Tajfel H, Billing MG, Bundy RP. Social categorization and inter-group behavior. Eur J Soc Psychol. 1971;1:149-78. 28. Kanas NA, Fedderson WE. Behavioral, psychiatric and sociological problems of long-duration space missions. NASA technical report.

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40. Herridge L. Meals Ready to Eat: Expedition 44 Crew Members Sample Leafy Greens Grown on Space Station. Florida: NASA ; 2015 [updated 2015 August 13; cited 2016 February 16]. Available from: http://www.nasa.gov/mission_pages/station/research/news/ meals_ready_to_eat.

RCSIsmjperspective MICHAEL BRAVO looks at the heated debates between the open access movement and more traditional bodies, and what they mean for modern medicine.

SHARING AND CARING?

Open access vs closed doors Introduction Amidst the furore surrounding â&#x20AC;&#x2DC;anti-vaxxerâ&#x20AC;&#x2122; campaigns, and the issues surrounding public funding of healthcare, the overworking of junior doctors, and the use of medical marijuana, a 15-year war has been fought behind the scenes in the world of science and medicine. The issue of access to and sharing of scientific research has become divisive. The open access (OA) movement advocates for freely accessible and reusable research, while traditional publishers claim copyright on the material they publish, since they absorb the costs of maintaining online repositories and expert review boards. Now, as more and more government grants require free and open access to the information provided by these articles, the issue is receiving more public focus. The OA movement has extended to medicine, focusing notably on science research and pharmacology, but also on the education of trainee doctors, with a surprising Irish influence.

For the scientist: open access research The key battle that is being fought focuses on whether the sale of scientific knowledge in the form of journal subscriptions is valid despite reduced costs due to digitisation and the fact that much of this research has direct benefits to the public. One answer to this problem has been the advent of the OA philosophy, which

espouses unrestricted access to research articles along with the rights to re-use these articles.1,2 Publishers assert that their subscription fees are legitimate because they provide the resources to publish these articles widely, they ensure high-quality research via a free-market approach, and they provide a long-standing reputation, conferring legitimacy to any papers published in their journals.3 However, OA journals argue that restricting access to academic research that is already being funded from public grants is not only disingenuous, but also impedes progress and discovery. By putting information behind a paywall, only those individuals or institutions that can afford a subscription can use that article for their own research, creating a social hierarchy of access to information.3

The OA movement has extended to medicine, focusing notably on science research and pharmacology, but also on the education of trainee doctors, with a surprising Irish influence. Volume 9: Number 1. 2016 | Page 85

RCSIsmjperspective Further complicating the situation, journal subscription fees have risen by more than three times the inflation rate over the last 30 years, despite a reduction in operating costs due to digitisation.4 In fact, the average annual price for a health sciences journal subscription is $1,694 USD, which is still far below the average for a chemistry journal subscription, which will cost an individual on average $4,942.5 It seems that the current journal publishing elite – only five companies, which publish 50% of all research6 – are taking advantage of their privileged status. Thus, in an effort to provide freely-accessible quality research to everyone, OA journals like PLoS and BioMed Central (as well as thousands of others) have sprung up and not only offer this information for free, but allow anyone to use the research, figures or data freely under Creative Commons licenses. This movement has also encouraged the development of OA-friendly research tools and platforms like Mendeley, ResearchGate, Overleaf, Figshare and others, which allow not only the free sharing of this information, but an OA approach to collaboration, leading to thousands of articles that would not otherwise have been produced.

In 2008, the US National Library of Medicine in the National Institutes of Health developed ClinicalTrials.gov, a repository of the results for every trial performed on every drug that is approved by the Food and Drug Administration in the US. Of course, someone must cover the costs of OA publishing, so most OA journals charge publishing fees to the authors, thus putting the onus on the producer of the research (known as “Gold OA”).7 While this has the benefit of ensuring that OA journals are not inundated with requests to publish, it can at times be predatory, leading to exploitation of authors.8 For example, a number of vanity presses have popped onto the scientific landscape, leading to largely unreviewed papers and articles being published under the name of OA, but in fact lacking the necessary scrutiny that is required of quality scientific research.9 It also means that even if the OA journal is legitimate, well-reviewed and well produced, the Gold OA approach can limit what an early-career scientist or student can realistically publish because of a lack of funding. For example, Elsevier, the third largest OA publisher, has fees ranging from $500 to $5,000 for its Gold OA journals.10 Further complicating the issue is that many OA journals accept manuscripts from a broad range of disciplines, leading to questions about the quality of the editorial process and how likely the ‘peers’ are to be from the same specialty.9 The saving grace is that those OA journals which are well-established and have instituted legitimate peer-review systems are considered to have the same scientific quality and impact as Page 86 | Volume 9: Number 1. 2016

subscription journals, especially in the field of biomedicine.11 In short, while OA is far from perfect, it provides a tenable and credible alternative to traditional subscription journals.

For the physician: open access pharmaceuticals This push for open access is not isolated to the publishing of scientific research, but has also spread to the world of drug development. The information garnered from drug trials has always been the property of the development company, giving them the prerogative to disclose that information as they see fit. Of course, pharmaceutical companies will suppress or minimise the trials they perform that do not support the adoption of their drug, as this makes financial sense. However, the problem that arises is that these unpublished trials may have direct benefit to the general public and the scientific community. In 2008, the US National Library of Medicine in the National Institutes of Health developed ClinicalTrials.gov, a repository of the results for every trial performed on every drug that is approved by the Food and Drug Administration in the US.12 Even then, only 13.4% of all drug trials in the US were reported to ClinicalTrials.gov in a span from January 2008 to September 2012.13 The purpose was to provide OA for all trials, with complete reporting of side effects and complications, not just those that were most common, as decided by drug companies. The need for this repository is clear – despite OA in the repository, the negative side effects of drugs are reported in published articles only 45% of the time.14 Although compliance with laws to submit data to ClinicalTrials.gov has improved, it is still far from ideal, especially considering that only summaries of the trials (not actual patient-level data) are submitted to the repository.13 Pharmaceutical companies have a responsibility to provide any and all information to those to whom they advertise and sell, especially those physicians who will prescribe and recommend their drugs. In fact, there are additional benefits to providing the information in an open fashion. Jay Bradner of the Bradner Lab at the Dana-Farber Cancer Institute at Harvard Medical School developed JQ1, an anti-BRD4 chemical, which targets large solid tumours.15 However, rather than keep the molecule to himself and seek financial gain, he sent it out to his colleagues – up to 70 labs throughout the world. Their contributions were small at first: one group performed crystallography to reveal the chemical’s structure;16 another recorded the chemical converting tumour cells back to normal cells.17 At this time, over 450 labs have used JQ1 in their own research and the amount of literature published about JQ1 has doubled every year for the seven years since they began sharing the molecule, leading to eight human clinical trials and more knowledge about their own chemical than could have been achieved by their own lab in that time. Of course, the downside has been that in openly sharing both information and the chemical probes themselves, the venture has been an expensive lesson in sharing (since Dr Bradner’s lab covered the costs of distribution), despite the benefits that have been received from that sharing.

RCSIsmjperspective For the student: free open access medicine Finally, the movement towards OA has even invaded the world of education, with a unique Irish influence. Free OA medical education (or meducation), also known as FOAM, was first conceived in Dublin in 2012 (over a pint of Guinness) with the purpose of providing both an online curriculum and medical education that is freely available to all. It hearkens back to the Hippocratic Oath, which advocates for freely teaching medicine to all interested parties.18 It has been bolstered by the unique progress afforded by social media, with blogs, YouTube videos, Twitter feeds and Facebook pages dedicated to giving students the opportunity to access sophisticated resources providing asynchronous learning without having to spend anything (except a monthly internet bill). In fact, FOAM resources have become some of the most frequently visited medical websites on the internet, with KevinMD, Medscape and iTeachEM ranking among the top medical education websites, and blogs like Burnt Orange Scrubs, Life in the Fast Lane, and The Presenting Complaint among some of the most visited websites for medical students in the world.18,19 Conferences focused on FOAM have even begun to

thrive, with the Social Media and Critical Care Conference (SMACC) now in its fourth year and being hosted in Dublin this year. In short, the OA approach has now made positive impacts in the world of medical education, providing quality resources to facilitate student learning and further entrenching the OA movement in a younger generation of physicians.

Conclusion There are still some significant hurdles to completely adopting a free and open approach to research and medicine, especially when it comes to funding the publication of research. However, the benefits far outweigh the detriments; most notably, the increased rates of discovery, the provision of medical information to the public, and the delivery of high-quality education resources to any student hoping to improve their learning. As medical students, we have a duty to consider and ultimately adopt an OA approach, where we consider sharing our own research and investigation. It is only with this perspective that we can advance our professional development and improve the quality of care of our patients.

References 1. Marchant S. Ready, set, open access. Ready, set, open access! 2015. [Internet] BioMed Central blog. Available from: http://blogs.biomedcentral.com/bmcblog/2015/10/19/ready-se t-open-access/. 2. The Case for Open Access. [Internet] PLOS One. Available from: https://www.plos.org/open-access/. 3. Marincola E. Elizabeth Marincola: Advance science with open-access publishing [Internet]. TEDMED. 2013. Available from: https://www.youtube.com/watch?v=9ztwFtF-lgA. 4. Kyrillidou M, Morris S (eds.). Monograph and Serial Costs in ARL Libraries 1986-2011. Washington, DC, 2011. 5. Henderson K, Bosch S. Whole lotta shakin’ goin’ on | Periodicals Price Survey 2015. [Cited 2015 Apr 23]. Available from: http://lj.libraryjournal.com/2015/04/publishing/whole-lotta-sha kin-goin-on-periodicals-price-survey-2015/#_. 6. Larivière V, Haustein S, Mongeon P. The oligopoly of academic publishers in the digital era. PLoS ONE. 2015;10(6):e0127502. 7. Price D. Gold or green: which is the best shade of open access? [Internet]. Times Higher Education. Available from: https://www.timeshighereducation.com/news/gold-or-green-wh ich-is-the-best-shade-of-open-access/420454.article. 8. Butler D. Investigating journals: The dark side of publishing. Nature. 2013;495(7442):433-5. 9. Haug C. The downside of open-access publishing. N Engl J Med. 2013;368(9):791-3. [Internet] Available from: http://www.nejm.org/doi/full/10.1056/NEJMp1214750. 10. Elsevier. Elsevier Policies – Pricing. Article publishing charges (APC). [Internet]. Available from: https://www.elsevier.com/about/company-information/policies/ pricing.

11. Björk BC, Solomon D. Open access versus subscription journals: a comparison of scientific impact. BMC Med. 2012;10(1):73. 12. Jones N. Half of US clinical trials go unpublished. Nature. 2013 Dec 3. Available at: http://www.nature.com/news/half-of-us-clinical-trials-go-unpubl ished-1.14286. 13. Anderson ML, Peterson ED. Compliance with results reporting at ClinicalTrials.gov. N Engl J Med. 2015;372(24):2370-1. 14. Riveros C, Dechartres A, Perrodeau E, Haneef R, Boutron I, Ravaud P. Timing and completeness of trial results posted at ClinicalTrials.gov and published in journals. Dickersin K (ed.). PLoS Med 2013;10(12):e1001566; discussion e1001566. 15. Open-source cancer research. TEDxBoston; 2011 May. Available from: https://www.ted.com/talks/jay_bradner_open_source_cancer_re search?language=en#t-346388. 16. Matzuk MM, McKeown MR, Filippakopoulos P, Li Q, Agno JE et al. Small-molecule inhibition of BRDT for male contraception. Cell. 2012;150(4):673-84. 17. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Bradner JE et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904-17. 18. Nickson CP, Cadogan MD. Free Open Access Medical education (FOAM) for the emergency physician. Emerg Med Australas. 2014;26(1):76-83. 19. Scott KR, Hsu CH, Johnson NJ, Mamtani M, Conlon LW, DeRoos FJ. Integration of social media in emergency medicine residency curriculum. Ann Emerg Med. 2014;64(4):396-404.

Volume 9: Number 1. 2016 | Page 87

RCSIsmjperspective

Empathy is the new black

AMELIA REID examines changing attitudes to the art of communication in medicine. In medical practice today, increasing attention is being given to the art of communication, to expressing (and better still, feeling) empathy, and viewing a person as more than their physical or psychological presenting complaint; that is, moving from a dehumanising approach – as exemplified by describing a patient as ‘the appendicectomy in bed 4’ – to an understanding and acknowledgement of the person and his or her experience, values, feelings and personal situation. There has been a trend away from the paternalistic approach of the doctor, to a more collaborative, ‘patient-centred’ approach to consultation. A more egalitarian approach encourages the physician to see patients as having agency and a legitimate role in decisions about their treatment, to follow their lead, and to appreciate experiences and problems from the patient’s point of view – including understanding their expectations and life circumstances more broadly.1,2 Page 88 | Volume 9: Number 1. 2016

Communication is especially sensitive and difficult in the context of palliative and end-of-life care for the physician, the patient and the patient’s family. For this reason, discussions about dying, and the patient and family’s wishes, occur infrequently. Malpractice in medicine With medicine becoming increasingly litigious, malpractice claims provide one window into the impact of poor communication. Levinson et al. have found that physicians who have not had legal claims made against them are more likely during their consultations to use humour, ask patients for their opinions, spend more time

RCSIsmjperspective with patients (than their sued colleagues), educate patients about what to expect with a given diagnosis and treatment plan, and encourage them to ask questions.3 Similarly, the emotional states of patients are just as important as their physical states, with individuals citing a lack of clear explanations, sympathy or honesty, or a reluctance to apologise, as further reasons for pursuing legal action against a doctor.4 There has been a shift, at least in principle, in many major hospitals from defensive denial and legal protection to admission of fault, apology, and compensation.

Similarly, levels of depression have been shown to decrease when the doctor communicates clearly and sympathetically the severity of a diagnosis, the life expectancy, and the impact a diagnosis is likely to have on someone’s life. This is partly because a protracted legal battle is not only traumatic for the patient or family, but also very expensive and distracting for the hospital.4,5 Taking a non-punitive approach also creates an environment in which a doctor is more likely to disclose an error, rather than trying to conceal or deny it. The majority of patients and physicians favour knowing what has gone wrong and why. Additionally, many hospital policies advocate full disclosure, investigation, explanation, apology, and some form of compensation. Unfortunately, however, these approaches are still uncommon.5 Assessing patient satisfaction by way of malpractice claims is, however, focused on reputational and financial risk. It is one means of retrospectively assessing a person’s psychological state, and level of comfort and satisfaction with consultation and treatment, but is by no means ideal. It is the result of a failed procedure or medical error and/or poor handling of a case, and does not necessarily speak to the ethical dimensions of honesty and the physician’s care for the patient. A more appropriate measure is to examine the person’s emotional state and responses during or immediately following a consultation.6 Evaluation of this approach suggests that patients experience lower levels of anxiety when they are prepared for a diagnosis, have the people they want with them when they are told the diagnosis, receive written information as well as clear verbal communication on the day of the consultation, have time to ask questions and discuss how they are feeling, and to be reassured. In one study, even one minute of compassion shown by the physician in a consultation was shown to decrease the levels of anxiety participants felt.7 Similarly, levels of depression have been shown to decrease when the doctor communicates clearly and sympathetically the severity of a diagnosis, the life expectancy, and the impact a diagnosis is likely to have on someone’s life.6

Communication at the end of life Communication is especially sensitive and difficult in the context of palliative and end-of-life care for the physician, the patient, and the patient’s family. For this reason, discussions about dying, and the patient and family’s wishes, occur infrequently. When they do, there are serious shortcomings. Multiple studies have identified key themes of importance to dying patients by interviewing the patients themselves, their family members and physicians.8-10 These focused on what was important to patients and whether the same concerns applied equally to their doctors and other caregivers. These themes included being straightforward with all the information imparted, using clear and understandable language, having a willingness to discuss dying and to use the words ‘death’ and ‘dying’ as opposed to using euphemisms, delivering news sensitively, choosing an appropriate time and place to break bad news, listening to patients, and encouraging questions.8-10 This requires the physician to balance the need to give honest and distressing advice without broaching a discussion of death when the patient is not ready, and potentially causing greater distress or hopelessness.10 Apart from the emotional and psychological effects, poor communication has ramifications regarding the choice a patient makes about their treatment. When a patient has an accurate understanding of their diagnosis and prognosis, they are more likely to choose a therapy that focuses on comfort and palliative measures rather than life-extending interventions.11 The latter patients often accept aggressive and distressing interventions, which, when controlled for known prognostic factors, do not increase their survival rate.11

A programme of purposefully driven cultural change, involving everyone from the consultants to the cleaners, drove expectations of professional behaviour using evidence, videos, workshops and other strategies. Teaching communication and empathy Most medical schools now supplement the academic record and the standardised aptitude tests with some form of interviewing in an effort to identify those candidates who have, or at least exhibit, qualities such as motivation, ethical values, resilience, maturity, and social and communication skills. Variations such as the ‘multiple mini interview’ (MMI), which use multiple stations to better assess a candidate’s ‘soft skills’, are becoming more common. A typical MMI might use a series of trained interviewees or actors from diverse backgrounds, and videos, which candidates are asked to interpret. All of these measures are designed to select for high-demand courses those students who it is hoped will be well-rounded, empathetic and collaborative practitioners. Volume 9: Number 1. 2016 | Page 89

RCSIsmjperspective However, notwithstanding these efforts to filter out unsuitable applicants and select those with the most promising interpersonal as well as academic skills, effective and empathetic communication is not guaranteed. In fact, it has been shown that levels of empathy decline as medical students progress through medical school, jeopardising the quality of care they are likely to be able to offer as practising doctors.12 Reaching a consensus on the definition of empathy has been difficult. However, most agree that to be empathetic one must possess interpersonal sensitivity and be able to put oneself ‘in the patient’s shoes’.13 There is, however, no consensus on whether empathy should be defined as an emotional or a cognitive quality, and whether it is a skill that one can acquire or is an attitude one possesses. Some view empathy as an innate quality, an aspect of personality, and therefore difficult to teach or to predict.14 A well-known effort to increase ‘patient satisfaction’ is that of the Cleveland Clinic in the USA. Of the range of patient satisfaction scores, communication was particularly poor: 14% for doctor communication skills and 16% for nurse communication skills. In the author’s words:15 “Patients did not want to be in the hospital. They were afraid, sometimes terrified, often confused, and always anxious. They wanted reassurance that the people taking care of them really

understood what it was like to be a patient. Their families felt the same way. Patients also wanted better communication: they wanted information about what was going on in their environment and about the plan of care; they wanted to be kept up to date even on minute activities. And they wanted better co-ordination of their care. When nurses and doctors did not communicate with one another, patients were left feeling that no one was taking responsibility for them”. (p 3) A programme of purposefully driven cultural change, involving everyone from the consultants to the cleaners, drove expectations of professional behaviour using evidence, videos, workshops and other strategies. The intention was to ‘make everyone a caregiver’ and to redesign the operations around patient needs rather than organisational efficiency or clinicians’ convenience. From 2008 to 2012, the hospital’s ranking on a US government patient survey of 4,600 hospitals rose from the 55th to the 92nd percentile.15 A caution, however, is needed. The risk in teaching communication strategies and skills is that the health professional simply learns some new phrases and uses them without feeling, either because the feeling is lacking – that is, they are not able to show empathy (which, in itself, raises some serious questions about their suitability to practise) – or because time, exhaustion and practical demands override their inclination to communicate well.

References 1. Ong LM, De Haes JC, Hoos AM, Lammes FB. Doctor-patient communication: a review of the literature. Soc Sci Med. 1995;40(7):903-18. 2. Weston WW, Brown JB, Stewart MA. Patient-centred interviewing Part I: understanding patients’ experiences. Can Fam Physician. 1989;35:147-51. 3. Levinson W, Roter D, Mullooly J, Dull V, Frankel R. Physician-patient communication: the relationship with malpractice claims among primary care physicians and surgeons. JAMA. 1997;277(7):553-9. 4. Vincent C, Young M, Phillips A. Why do people sue doctors? A study of patients and relatives taking legal action. Lancet. 1994;343(8913):1609-13. 5. Mazor K, Simon S, Yood R, Martinson B, Gunter M, Reed G et al. Health plan members’ views about disclosure of medical errors. Ann Intern Med. 2004;140(6):409-18. 6. Schofield P, Butow P, Thompson J, Tattersal M, Beeney L, Dunn SM. Psychological responses of patients receiving a diagnosis of cancer. Ann Oncol. 2003;14(1):48-56. 7. Fogarty LA, Curbow BA, Wingard JR, McDonnell K, Somerfield MR. Can 40 seconds of compassion reduce patient anxiety? J Clin Oncol. 1999;17(1):371-9. 8. Hanson LC, Danis M, Garrett J. What is wrong with end-of-life care? Opinions of bereaved family members. J Am Geriatr Soc. 1997;45(11):1339-44.

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9. Tulsky JA, Fischer GS, Rose MR, Arnold RM. Opening the black box: how do physicians communicate about advance directives? Ann Intern Med. 1998;129(6):441-3. 10. Wenrich M, Curtis J, Shannon S, Carline J, Ambrozy D, Ramsey P. Communicating with dying patients within the spectrum of medical care from terminal diagnosis to death. Arch Intern Med. 2001;161(6):868-74. 11. Weeks JC, Cook EF, O’Day SJ, Petersen LM, Wenger N, Redding D et al. Relationship between cancer patients’ predictions of prognosis and their treatment preferences. JAMA. 1998;279(21):1709-14. 12. Hojat M, Vergare M, Maxwell, K, Brainard, G, Herrine S, Isenberg G et al. The devil is in the third year: a longitudinal study of erosion of empathy in medical school. Acad Med. 2009;84(9):1182-91. 13. Shapiro J. How do physicians teach empathy in the primary care setting? Acad Med. 2002;77(4):323-8. 14. Batt-Rawden S, Chisolm M, Anton B, Flickinger T. Teaching empathy to medical students: an updated, systematic review. Acad Med. 2013;88:1171-7. 15. Merlino J, Raman A. Health care’s service fanatics. Harvard Business Review, 2013 [Internet] [Accessed 2015 October 10] Available from: https://hbr.org/2013/05/health-cares-service-fanatics.

RCSIsmjperspective

A global responsibility JESSICA SUDDABY examines the challenges and opportunities involved in refugee and migrant healthcare in Europe.

The current migration to Western Europe is unparalleled. In the summer of 2015, Europe experienced the highest influx of refugees since World War II.1 In 2015, an estimated 60 million people were displaced globally, with approximately 50% of these people under 18 years of age. The main reason for this large influx is that Syria has become the world’s top source of refugees as a consequence of the Syrian Civil War.2 In addition to the Syrian refugees, large waves of migrants and refugees from other countries in Asia, Africa and the Balkans are migrating to Europe in the hopes of escaping conflict, bad governance and poverty.3

countries like the Czech Republic, Slovakia, Romania and Hungary have rejected the plan (Figure 1).7 Ireland has taken a more moderate approach, reflecting its size and means. The Irish Government has established an Irish Refugee Protection Programme, in which Ireland has agreed to accept up to 4,000 displaced persons in response to the current migration crisis.8 However, Ireland estimates the cost of hosting migrants to be €12 million per 1,000 migrants.9 Therefore, taking in large numbers of migrants and refugees could potentially put enormous strain on economic resources.

Response in the European Union 45000 40000 35000 30000 25000 20000 15000 10000 5000 0

Germany France Spain Poland Netherlands Romania Belgium Sweden Austria Portugal Czech Rep. Ireland Finland Slovakia Bulgaria Croatia Lithuania Slovenia Estonia Latvia Luxembourg Cyprus Malta

EU Resettlement Plan

Number of refugees

In response to this large wave of refugees, many European countries have agreed to accept migrants and refugees. The number of asylum applications received in 2015 by European Union (EU) nations more than doubled compared to 2014. In 2015, there was an estimated total of 1,117,890 asylum applications from stateless people across the EU.4 The majority of applications are from people originating from Syria and Afghanistan.5 Germany is currently the recipient of the largest number of asylum applications – with 476,620 applications received in 2015 – followed by France, Sweden, Italy and the United Kingdom.6 This influx of migrants and refugees to Europe has, however, created tension within the EU. Many countries do not agree to what extent Europe as a whole should respond to the refugee crisis due to the political and economic implications of taking in large numbers of migrants and refugees. While many nations support the EU quota plan to relocate refugees currently in Italy and Greece, other

FIGURE 1: EU Resettlement Plan. NB: The UK and Denmark are not taking part. Source: Dept. of Foreign Affairs, European Commission. Volume 9: Number 1. 2016 | Page 91

RCSIsmjperspective In addition to the Syrian refugees, large waves of migrants and refugees from other countries in Asia, Africa and the Balkans are migrating to Europe in the hopes of escaping conflict, bad governance and poverty. Migrant and refugee healthcare In addition to political and economic concerns, migrant and refugee health has become a growing issue. Its importance on the global health radar has become evident: the “right to health of refugees and other displaced people” was declared one of five key areas of global health on which the M8 Alliance, a collaborative network of academic institutions with 23 members from 16 different countries, called for action at the 2015 World Health Summit (WHS) in Berlin.10 In the statement, the M8 Alliance determined that the immediate health problems of refugees, and the long-term mental health and well-being of these millions of men, women, and children, were neglected areas of global health that must be addressed in co-operation with refugee agencies and the humanitarian sector.10 The following discussion is based on major topics discussed at the Migrant and Refugee Health workshop at the WHS 2015.

Infection and disease in refugee camps One major concern associated with the overall health of migrants and refugees is disease in refugee camps. The United Nations High Commissioner for Refugees (UNHCR) was not prepared for a refugee crisis of this scale. Thus, many refugee camps are crowded and undersupplied, providing conditions for the onset of chronic malnutrition and the spread of infection. Measles, hepatitis A, leishmaniasis, poliomyelitis, meningitis and scabies, diseases that have been virtually eradicated in developed countries, have spread through vulnerable populations in Syria and refugee camps in neighbouring countries.11 In addition, migration itself contributes to higher infection rates as vectors move further, faster, and in greater numbers than ever before. One route often used by migrants is from East Africa, through Sudan and Libya, to North Africa and eventually to Europe.12 This has led to the introduction of microbes rarely seen in developed countries such as Borrelia recurrentis, Rickettsia prowazekii, and Bartonella quintana, which cause infectious diseases such as louse-borne relapsing fever (LBRF), epidemic typhus, and trench fever, respectively.12 Thus, it is important to address the issues of crowding and poor hygiene in these camps to reduce the spread of infectious diseases.

Migrant and refugee access to healthcare Even if migrants and refugees make it to their host country, there are many challenges, both formal and informal, to gaining access to healthcare. One formal challenge is legal access. While in some European countries, migrants and refugees are fully entitled to healthcare, other European countries provide minimal rights to Page 92 | Volume 9: Number 1. 2016

healthcare, which usually means that migrants and refugees may only access emergency services.13,14 In Ireland, asylum seekers are given medical cards for the period during which their application for refugee status is being considered, which gives them access to medical care free of charge.15 Individuals granted refugee status are regarded as ordinary residents and fall under the usual rules for entitlement to health services.16 In Germany, however, the law restricts healthcare for asylum seekers to instances of “acute diseases or pain”, meaning that only absolutely unavoidable medical care is provided.16,17 In 2005, legal restrictions to access to healthcare for migrants and refugees at the time of their arrival were found to exist in 43% of European nations, compared to healthcare available to citizens in the host country.18 These countries included Austria, Denmark, Estonia, Finland, Germany, Hungary, Luxembourg, Malta, Spain, and Sweden.18 In all of these countries, except for Austria, the restrictions were entitlements to emergency healthcare only.18 As migrant and refugee health continues to be a growing topic of interest in global health affairs, governments and politicians will need to reopen the discussion about the legal extent to which migrants and refugees will be ensured access to healthcare.

The United Nations High Commissioner for Refugees (UNHCR) was not prepared for a refugee crisis of this scale. Thus, many refugee camps are crowded and undersupplied, providing conditions for the onset of chronic malnutrition and the spread of infection. Cultural barriers to healthcare for migrants and refugees Informal barriers to health for migrants and refugees are largely cultural and include inadequate language services and cultural training. For instance, in Ireland there is a translation service called Rotext; however, many healthcare professionals are not even aware of it.19 A great deal can be done on a healthcare professional level to improve language services for refugees and migrants by having translators who can aid in the communication between the physician and the patient. It is important that the translator does not merely translate literally, but attempts to communicate some of the feelings and nuances that would otherwise be lost in translation, so that the physician can better serve the patient. It is also critical to provide cultural training for healthcare professionals working directly with migrants and refugees. The awareness of the cultural determinants of health – including shared conventions, understandings, practice, ideas, symbols and artefacts of a given culture – has impacts on clinical care and informs clinical practice.20 In addition, by providing language services and cultural training for migrants and refugees, informal barriers to healthcare can be reduced. In Germany, the government spent €2 billion on

RCSIsmjperspective language training for migrants and refugees, a significant step in reducing cultural barriers.21 Although the current refugee crisis presents many challenges for European health systems, in many ways it can be viewed as an opportunity for European nations to test the strengths and weaknesses of their own health systems. At the WHS 2015, the M8 Alliance took clear stances on the issues of migrant and refugee healthcare in Europe. The M8 Alliance asserted that refugees should have access to healthcare services equivalent to that of the host population.10 Refugee policies should

prioritise the integration of new refugees into the new country’s health and social systems.10 In addition to the immediate health concerns discussed, they also declared it critically important to be aware of the long-term mental health and well-being of the millions of men, women and children that have been displaced. This will require action from a healthcare perspective as well. Ultimately, the M8 Alliance feels that the migrant and refugee crisis in Europe is a global health issue that requires the co-operation of the international community and humanitarian sector at large to respond in a co-ordinated manner.

References 1. Boehler P, Pecanha S. The Global Refugee Crisis, Region by Region. [Internet] New York Times. 2015 Jun 8 [cited 2015 Oct 31]. Available from: http://www.nytimes.com/interactive/2015/06/09/world/migra nts-global-refugee-crisis-mediterranean-ukraine-syria-rohingyamalaysia-iraq.html. 2. UNHCR: The UN Refugee Agency. Facts and Figures about Refugees. [Internet] [cited 2016 Feb 7]. Available from: http://www.unhcr.org.uk/about-us/key-facts-and-figures.html. 3. Council on Foreign Relations. CFR backgrounders: Europe’s Migration Crisis [Internet] [cited 2016 Feb 7]. Available from: http://www.cfr.org/migration/europes-migration-crisis/p32874. 4. Eurostat. Asylum and new asylum applicants – annual aggregated data. [Internet] [cited 2016 Mar 3]. Available from: http://ec.europa.eu/eurostat/tgm/table.do?tab=table&init=1&l anguage=en&pcode=tps00191&plugin=1. 5. UNHCR: The UN Refugee Agency. Worldwide displacement hits all-time high as war and persecution increase. [Internet] [cited 2016 Mar 3]. Available from: http://www.unhcr.org/558193896.html. 6. UNHCR: The UN Refugee Agency. 2015 UNHCR subregional operations profile – Northern, Western, Central and Southern Europe: Germany [Internet] [cited 2015 Nov 8]. Available from: http://www.unhcr.org/pages/49e48e5f6.html. 7. Holehouse M. EU quota plan forced through against eastern European states’ wishes [Internet]. The Telegraph, 2015 [Internet] [cited 2016 Mar 1]. Available from: http://www.telegraph.co.uk/news/worldnews/europe/1188302 4/Europe-ministers-agree-relocation-of-120000-refugees-by-larg e-majority.html. 8. Department of Justice and Equality. Update on Ireland’s Response to EU Migration and Refugee Crisis. [Internet] [cited 2015 Oct 31]. Available from: http://www.justice.ie/en/JELR/Pages/PR15000457. 9. European Commission. The EU and Migration. [Internet] [cited 2016 Feb 8]. Available from: http://www.ec.europa.eu/ireland/key-eu-policy-areas/eu-and-m igration/index_en.htm. 10. M8 Alliance. M8 Alliance Statement. World Health Summit 2015 –

We Must Act on Global Health. 2015. Available from: http://www.worldhealthsummit.org/fileadmin/downloads/2015/W HS/Documents/M8_Alliance_Statement_WHS_Berlin_2015.pdf. 11. Sharara SL, Kanj SS. War and Infectious Diseases: Challenges of the Syrian civil war. PLoS Pathog. 2014;10(11):e1004438. 12. Cutler SJ. Refugee crisis and re-emergence of forgotten infections in Europe. Clin Microbiol Infect. 2016;22(1):8-9. 13. Asgary R, Segar N. Barriers to healthcare access among refugee asylum seekers. J Health Care Poor Underserved. 2011;22(2):506-22. 14. UNHCR: The UN Refugee Agency. Ensuring Access to Health Care: Operational Guidance on Refugee Protection and Solutions in Urban Areas [Internet] [cited 2015 Nov 8]. Available from: http://www.unhcr.org/4e26c9c69.html. 15. Citizens Information Board. Medical services and entitlements for asylum seekers [Internet] [cited 2016 Mar 11]. Available from: http://www.citizensinformation.ie/en/moving_country/asylum_seek ers_and_refugees/services_for_asylum_seekers_in_ireland/medical_s ervices_and_entitlements_for_asylum_seekers.html. 16. Citizens Information Board. Health services for visitors to Ireland. [Internet] [cited 2016 Mar 1]. Available from: http://www.citizensinformation.ie/en/health/entitlement_to_health _services/health_services_and_visitors_to_ireland.html. 17. Asylum Information Database. Health care – Germany [Internet] [cited 2016 Mar 1]. Available from: http://www.asylumineurope.org/reports/country/germany/receptio n-conditions/health-care. 18. Norredam M, Mygind A, Krasnik A. Access to health care for asylum seekers in the European Union – a comparative study of country policies. Eur J Public Health. 2006;16(3):286-90. 19. Refugee health [Internet] [cited 2016 Mar 1]. Available from: http://www.irishhealth.com/article.html?id=2384. 20. Helman C. Culture, Health and Illness: An Introduction for Health Professionals. Butterworth-Heinemann, 2013. 21. Alderman L. Germany Works to Get Migrants Jobs. The New York Times. 2015 Sep 17 [Internet] [cited 2016 Mar 1] Available from: http://www.nytimes.com/2015/09/18/business/international/migr ants-refugees-jobs-germany.html.

Volume 9: Number 1. 2016 | Page 93

RCSIsmjperspective THE FUTURE OF SURGERY OR

a robotic waste of money? SAMY BESHAY wonders if robotic surgery is here to stay, or just an expensive surgical white elephant.

Introduction The past few decades have seen extensive advances in surgical techniques as technology adapts to the ever-demanding needs and expectations of patients.1 One such medical advance is the use of robotic arms and devices to assist in surgery, including one of the most common surgical robots used in gynaecological surgeries, the da Vinci® Surgical System (Intuitive Surgical, Inc.; Sunnyvale, CA, USA).1 The Mayo Clinic defines robotic surgery as the “use of advanced surgical tools to perform minimally invasive surgery for complex procedures with increased precision, flexibility and control compared to traditional surgical methods”.2 Initially, robotic surgery Page 94 | Volume 9: Number 1. 2016

was introduced to compensate for limitations in human dexterity and to reduce surgical complications.3 However, a majority of the potential benefits of robotic surgery are not being realised to the fullest extent in Ireland as a result of the lack of acclimatisation into surgical theatres.4,5 The high cost of operating and maintaining a robot, as well as the extensive training involved, have often outweighed the potential benefits for its utilisation in the wider context of surgery.5 Therefore, the question arises as to whether the use of robots in surgery is here to stay for the long term or is a waste of money.

RCSIsmjperspective Cost-effectiveness analysis The Health Service Executive (HSE), which runs the public healthcare system in Ireland, has determined that the clinical benefits of robotic surgery compared to traditional methods are negligible and not cost-effective. Performing surgery using the da Vinci® Surgical System has been found to consistently cost more than traditional laparoscopic procedures,6 operating at an approximate cost of €1.45 million with hundreds of thousands more in annual maintenance fees and licensing agreements.6,7 In addition to these high fixed costs, robotic procedures are marred by increased operating times, which increase the overhead costs of a hospital.8

The high cost of operating and maintaining a robot, as well as the extensive training involved, have often outweighed the potential benefits for its utilisation in the wider context of surgery. Therefore, the question arises as to whether the use of robots in surgery is here to stay for the long term or is a waste of money. In the United States, the surgical system is used for a wide range of operations in both urology and gynaecology.5,9-10 However, for nearly all operations, robotic surgery consistently costs several thousand dollars more when compared with local best practice.11 A recent study published in the Journal of the American Medical Association (JAMA) found that robotically assisted hysterectomy was not more efficient compared to the traditional laparoscopic methods, and the only notable variation between the two was the substantially increased cost associated with the robotic technology.12 In a prospective cohort study by Desille-Gbaguidi et al.,11 robotic surgery was shown to cost 2.6 and 2.7 times as much as laparoscopy for endometrial and cervical cancers, respectively. The significant increases in cost associated with robotic surgery were attributed to the time and labour of preparation, anaesthesia, incubation and equipment set-up, which increased overhead costs and reduced the availability of the operating room,11 with a non-significant reduction in average hospital stay. However, upon performing further analyses, it was shown that reducing hospital stay duration by one day in a given patient, and performing two daily operations using the robot, may allow robotic surgery to be the most cost-effective treatment option.11 The increased cost of robotic surgery is echoed in a case-control study by Sarlos et al.13 in the context of hysterectomy. Another study found that robotic surgery increased operating time, leading to an increase of approximately €2,000 when compared to laparoscopy.14 While Desille-Gbaguidi et al. reported set-up time to

be a major contributor to the cost of the da Vinci® Surgical System, Sarlos et al. determined that preparation time at their practice had decreased with each successive surgery.12,13 With improved training, costs associated with set-up may be minimised.14 The robotic system reportedly offered surgeons better ergonomic control and a wider range of motion when compared to current gold standards, and greater perceptual awareness, but it was disadvantaged by preventing access to the patient during the procedure.14

Surgical training involved with robotic technology While experienced surgeons cannot readily use a robotic system, training curricula that integrate didactic and experiential sessions exist for all surgical disciplines, particularly within gynaecology and urology.15 Expertise-based trials have shown that the learning curve for experienced open and laparoscopic surgeons is approximately eight to 12 cases, assuming a completion of 100 previous surgeries.16 For a naïve surgeon, it is estimated that 80-100 cases are needed before sufficient expertise is achieved with the robotic system.15 Hanly et al. had also demonstrated that with more experience, set-up time decreased by 30% and operative time lowered by 20% at their practice, minimising the elevated overhead costs associated with a robotic surgical system.17 Moreover, specifically training an Irish surgeon on the robotic technologies is arduous and tedious, often requiring a visit overseas to the United States for training in multiple facilities.18 The surgeon will also require mentor supervision during his or her first 15 to 20 procedures with the robot to gain the essential knowledge and expertise, after he or she returns to Ireland, a process that can take several months or even years.18 This not only decreases the amount of surgeries that an Irish surgeon will perform, but also increases waiting times and limits the amount of surgeons available at a given hospital.18

Context of Irish healthcare – integration into Irish hospitals The implementation of robotic surgery has been severely limited in Ireland where there are only three systems in the entire country: one actively used in the public healthcare system at the Cork University Maternity Hospital8 and two in the private sector.7,18 These surgical robots are primarily used in gynaecological care in hysterectomy procedures. Regardless of whether or not the use of a surgical robot has improved patient outcomes in gynaecological surgeries, it is undoubtedly a heavy burden on the publicly funded healthcare system in Ireland. A study by Teljeur et al. found that in Ireland, the cost of a robot-assisted hysterectomy is nearly €3,300 more than the existing mix of both open and traditional laparoscopic surgery.7 In countries such as the United States, where the da Vinci® Surgical System is thriving with over 2,000 robots in use, it is simple to maximise a robot’s use.19 A high volume of patients ensures that the substantial investment cost of the robot and its lifespan are capitalised upon and that the costs of licence agreements are compensated for. However, in smaller countries such as Ireland, where the demand is much lower and there are significant constraints Volume 9: Number 1. 2016 | Page 95

RCSIsmjperspective on the public healthcare system, it is much more difficult to capitalise on the investment in a surgical robot. The single surgical robot in the Irish public healthcare system is used primarily for hysterectomies and averages around 100 cases per year, a quarter of the number of cases a typical robot in the United States would see.12

Robotic surgery in Ireland has not fully developed and there is very little infrastructure to support its development. Possible suggestions to increase this number would include allowing the robot to perform non-gynaecological procedures, or putting a referral system in place that allows tertiary facilities to access the robot. In either sense, robotic surgery in Ireland has not fully developed and there is very little infrastructure to support its development.7

Conclusion Although robotic surgery may improve the functional design and visualisation for surgeons, in the patient-centred world of medicine, if it does not equate to more efficient outcomes, it is not practical to use in the wider context of surgery. Moreover, in times of scarce resources, healthcare investments should be directed towards interventions that demonstrate both positive patient outcomes and cost-effectiveness. As Prof. Lord Darzi, an RCSI graduate and world-renowned surgeon and inventor of surgical methods, once stated regarding the efficiency of robotic surgical techniques: “Healthcare systems all over the world are facing completely different pressures compared with 20 years ago … the whole way in which we provide healthcare has got to change. The world is crying out for low-cost, high-impact technologies that can be employed widely across the globe”.20 For the time being, it is evident that more research is required before robotic surgery is fully integrated into the Irish healthcare system. As it stands, robotic surgery is, indeed, a waste of money.

References 1. Lee N. Robotic surgery: where are we now? Lancet. 2014;384(9952):1417. 2. Mayo Clinic. Robotic Surgery Definition [Internet] [updated 2011 November 23; cited 2014 December 23]. Available from: http://www.mayoclinic.org/tests-procedures/robotic-surgery/basi cs/definition/prc-20013988. 3. Liao G, Zhao Z, Lin S, Li R, Yuan Y, Du S et al. Robotic-assisted versus laparoscopic colorectal surgery: a meta-analysis of four randomized controlled trials. World J Surg Oncol. 2014;12:122. 4. Jones A, Sethia K. Robotic surgery. Ann R Coll Surg Engl. 2010;92(1):5-8. 5. Barbash GI, Glied SA. New technology and health care costs – the case of robot-assisted surgery. N Engl J Med. 2010;363(8):701-4. 6. Singer E. The Slow Rise of the Robot Surgeon. MIT Technology Review. March 24, 2010. 7. Teljeur C, O’Neill M, Moran PS, Harrington P, Flattery M et al. Economic evaluation of robot-assisted hysterectomy: a cost-minimisation analysis. BJOG. 2014;121(12):1546-53. 8. Cadiere GB, Himpens J, Germay O et al. Feasibility of robotic laparoscopic surgery: 146 cases. World J Surg. 2011;25(11):1467-77. 9. Hashizume M, Sugimachi K. Robot-assisted gastric surgery. Surg Clin North Am. 2003;83(6):1429-44. 10. Park J, Choi GS, Lim K, Jang Y, Jun S. S052: a comparison of robot-assisted, laparoscopic, and open surgery in the treatment of rectal cancer. Surg Endosc. 2011;25(1):240-8. 11. Desille-Gbaguidi H, Hebert T, Paternotte-Villemagne J, Gaborit C, Rush E, Body G. Overall care cost comparison between robotic and laparoscopic surgery for endometrial and cervical cancer. Eur J Obstet Gynecol Reprod Biol. 2013;171(2):348-52.

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12. Wright JD, Ananth CV, Lewin SN et al. Robotically assisted vs laparoscopic hysterectomy among women with benign gynaecologic disease. JAMA. 2013;309:689-98. 13. Sarlos D, Kots L, Stevanovic N, Schaer G. Robotic hysterectomy versus conventional laparoscopic hysterectomy: Outcome and cost analyses of a matched case-control study. Eur J Obstet Gynecol Reprod Biol. 2010;150(1):92-6. 14. Patel HR, Linares A, Joseph JV. Robotic and laparoscopic surgery: cost and training. Surg Oncol. 2009;18(3):242-6. 15. Ahlering TE, Skarecky D, Lee D, Clayman RV. Successful transfer of open surgical skills to a laparoscopic environment using a robotic interface: initial experience with laparoscopic radical prostatectomy. J Urol. 2003;170(5):1738-41. 16. Hanly EJ, Marohn MR, Bachman SL, Talamini MA, Hacker SO, Howard RS et al. Multiservice laparoscopic surgical training using the da Vinci surgical system. Am J Surg. 2004;187(2):309-15. 17. Browne B. Public patients deserve the benefit of robotic surgery. [updated 2013 November 21; cited 2014 December 23]. The Medical Independent. Available from: http://www.medicalindependent.ie/38760/public_patients_deser ve_the_benefit _of_robotic_surgery. 18. da Vinci Products FAQ. Intuitive Surgical. [Internet] [updated 2012 November 23; cited 2014 December 23]. Available from: http://www.intuitivesurgical.com/products/products_faq.html. 19. O’Sullivan OE, O’Carroll M, Hewitt M, O’Reilly BA. Gynaecological robotic surgery in an Irish setting: cost analysis. Gynecol Surg. 2013;10(2):1-7. 20. Lord Darzi of Denham. Imperial College London News Release. [updated 2010 October 4; cited 2014 December 23]. Available from: http://www3.imperial.ac.uk/newsandeventspggrp/imperialcollege/n ewssummary/news_4-10-2010-11-57-6.

RCSIsmjperspective A FUTURE FOR

anaesthesia? DAVID LORIGAN asks whether the emerging role of perioperative physician represents a new career path for anaesthetists.

Introduction

An ageing population

In an ever-evolving healthcare environment, industrialised countries are constantly faced with new and difficult challenges. Foremost among these is the changing age profile of western populations. Against this backdrop, there is a strong argument for a single specialty assuming the role of perioperative physicians, a concept much discussed in anaesthetic conferences. There are pros and cons to anaesthetists filling the role â&#x20AC;&#x201C; from a healthcare perspective and from the perspective of the specialty of anaesthesia. However, their unique skillset makes them ideal candidates, if certain practical barriers can be overcome.

In most industrialised countries life expectancy is increasing, while the number of live births is decreasing, with the result that in these countries the population is ageing.1 The most recent census showed that Ireland is no exception, with an increase in the number of over-85s and a relative decrease in the under-14 category.2 The United States faces a similar situation.3 Because people are living longer with existing chronic conditions, the ageing patient tends to have more comorbidities, making their management more complex. Patients who are higher risk due to their age or comorbid diseases have the highest mortality rates.4 Volume 9: Number 1. 2016 | Page 97

RCSIsmjperspective This results in a rise in the number of high-risk patients presenting for surgery. To complicate matters further, there is increasing pressure to reduce the number of surgical inpatients and to perform more surgical procedures as day cases.5,6 Postoperative complications have been shown to negatively impact long-term survival more than either comorbid disease or intraoperative adverse events;7 therefore, it is imperative that perioperative care also extends for a period beyond discharge. In this context, it is clear that patients need optimal preoperative management in order to maximise their chances of a positive outcome. On this background, there is a strong argument for a single physician taking the lead in the care of the patient, from the decision to undergo surgery until a specified time postoperatively. Mantz et al. (2010) observed that “perioperative care may have a major impact on long-term postoperative mortality and major complications in surgical patients by decreasing the rate of individual decisions”.8 This is the proposed realm of the perioperative physician.

An example of this process in practice is the American Society of Anesthesiologists’ Surgical Home model, in which a single physician co-ordinates a patient-centred, multidisciplinary team to guide the patient throughout the entire surgical experience.10 Reviews of this model of care are heartening in that they report positive outcomes in many areas, including patient satisfaction and cost reduction.11 Longer hospital stays increase the healthcare burden in a number of ways. The longer a patient remains in hospital, the higher their chances of developing a hospital-acquired infection, which in turn increases mortality.12 Increased length of stay for an individual patient reduces the amount of bed space available for new patients, as well as increasing the financial burden on the healthcare system. Limiting the amount of time patients spend in hospital by proactively avoiding preventable complications reduces the financial burden on healthcare systems, as patients require fewer re-admissions and, ultimately, fewer hospital days.7,8 Various specialties have already offered their services privately as perioperative physicians.13 Here we will discuss the merits of the anaesthetist performing the role.

Streamlining of medical practice in the perioperative period is reported to improve “co-ordination and management of surgical patients and has been shown to increase quality, reduce complications, ... and improve the patient’s perception of the surgical experience”.

The anaesthetist as a perioperative physician

The perioperative physician The perioperative physician takes charge of the patient from the time of the decision to have surgery, managing the patient through the preoperative phase, in which the health of the patient is optimised and comorbidities are controlled as best as possible, and then through the surgery. The same physician follows up after discharge to monitor recovery, ensuring that day cases do not become re-admissions and that postoperative complications are kept to a minimum. This specialist is not a lone doctor, but the co-ordinator of a multidisciplinary team, membership of which will vary based on individual patient needs. There is evidence that a single co-ordinator for the perioperative period improves the co-ordination and management of surgical patients, and has multiple benefits to the patient and hospital in terms of cost reduction, positive outcome and patient satisfaction.9,10 In addition, a single specialty performing the role leads to standardised practice, which results in fewer mistakes.11 This streamlining of medical practice in the perioperative period is reported to improve “co-ordination and management of surgical patients and has been shown to increase quality, reduce complications, increase the efficiency and cost-effectiveness of perioperative care, and improve the patient’s perception of the surgical experience”.10,11 Page 98 | Volume 9: Number 1. 2016

The anaesthetist already takes part in perioperative medicine.14 While the surgeon’s primary concern is dealing with the disease process, the anaesthetist’s concern is keeping the patient alive for the duration of surgery and managing the patient’s physiological response to the insult, both intra- and postoperatively. The anaesthetist already needs to be intimately familiar with the patient’s medical history in order to provide optimal analgesia and to predict possible complications during surgery; becoming involved in the care of the patient from an earlier stage and taking responsibility for their management heightens pre-operative knowledge of the patient and their medical history. This in turn aids the anaesthetist in avoiding complications intra- and postoperatively, while making them the most suitable physicians to undertake post-surgical follow up. Anaesthetists’ roles as intensivists make them ideal candidates. On a daily basis they manage very ill patients with multiple comorbidities, with the result that they have a wealth of experience managing complex cases and optimising physiological function in patients who require intricate medical management. As part of this role they liaise with members of virtually every specialty in the hospital, managing patients as part of multidisciplinary teams. The perioperative physician is merely an extension of this role. In addition, some feel that the unique training, skills and experience of anaesthetists mean that they are natural candidates for the role, more so than any other specialist.13 They already have crucial experience in risk assessment and quality improvement,15 areas vital to the field of perioperative care; the importance of risk assessment in particular cannot be overestimated, and has been highlighted as a means of minimising surgical risk through anticipation of patient-specific complications and optimisation of organ function prior to surgery.16 Advocates for the concept of anaesthetists expanding to the role of perioperative care feel that they should embrace the role,17 and that not to do so would be to limit the scope of practice and sphere of

RCSIsmjperspective influence of the anaesthetist in the medical environment.13 On the other hand, if anaesthetists were to take on the role of perioperative physician, it could mean a loss of focus in their current role as anaesthetists, intensivists and pain managers, potentially detracting from care in those areas. Compounding this, a recent report by the College of Anaesthetists of Ireland revealed significant shortages of manpower at all levels, from specialist anaesthetist trainees to consultant, and an over-reliance on non-training NCHDs to run services.18 Expanding the role of an already stretched service to include broader perioperative care may place too much strain on an already overloaded specialty. Anaesthetists would add significant value to the healthcare service as perioperative physicians, but only if sufficient resources were made available to make further positions available at all levels.

Practical issues There are a number of practical issues that could come into play in expanding perioperative care. Clear definitions of where the role begins and ends would need to be agreed upon in order to optimise patient care. Follow-up of patients postoperatively by the perioperative physician is also a difficult question, particularly in the ambulatory setting, as the speed of recovery is bound to be quite

variable. This could create an unsustainable care burden if a large number of patients required extended postoperative management. The importance of developing objective criteria and the need to develop evidence-based guidelines in order to receive certification, are crucial to developing the role.10 Currently, there is no training scheme or college that covers the full scope of the perioperative physician.13 It is necessary to define what core knowledge, skills, and experience are expected of the perioperative physician, and at what stage of the training, from basic to advanced, the competencies should be achieved.13

Conclusion In the context of an industrialised country with an ageing population and pressure to increase the number of surgical procedures as day cases, there can be little doubt as to the value a perioperative physician would provide to all parties involved. There are compelling arguments for anaethetists to take on this role, not least as it would be an expansion of their current role in surgical care. There are a number of practical issues that would need to be resolved in order to facilitate incorporation of the role into the perioperative process, but it is certainly an idea that merits further exploration.

References 1. Anderson GF, Hussey PS. Population aging: a comparison among industrialized countries. Health Aff (Millwood). 2000;19:191-203. 2. Census 2011 Ireland and Northern Ireland [press release]. Available from: http://www.cso.ie/en/census/:CSO2011reports. 3. Pearson WS, Bhat-Schelbert K, Probst JC. Multiple chronic conditions and the ageing of America: challenge for primary care physicians. J Prim Care and Community Health. 2012;3(1):51-6. 4. Pearse RM, Holt PJ, Grocott MP. Managing perioperative risk in patients undergoing elective non-cardiac surgery. BMJ. 2011;343:d5759. 5. Group PC. Acute Hospital Bed Capacity Review: A Preferred Health System in Ireland to 2020. HSE website: HSE, 2007. Available from: http://www.lenus.ie/hse/handle/10147/45900. 6. U.S. outpatient surgeries on the rise [press release]. CDC Newsroom, 2009. Available from: http://www.cdc.gov/nchs/pressroom/09newsreleases/outpatients urgeries.htm. 7. Khuri SF, Henderson WG, DePalma RG, Mosca C, Healey NA, Kumbhani DJ et al. Determinants of long-term survival after major surgery and the adverse effect of postoperative complications. Ann Surg. 2005;242:326-41; discussion 41-3. 8. Mantz J, Dahmani S, Paugam-Burtz C. Outcomes in perioperative care. Curr Opin Anaesthesiol. 2010;23:201-8. 9. Kash BA, Zhang Y, Cline KM, Menser T, Miller TR. The perioperative surgical home (PSH): a comprehensive review of US and non-US studies shows predominantly positive quality and cost outcomes. Milbank Q. 2014;92:796-821.

10. Schweitzer MF, Fahy B, Leib M, Rosenquist R et al. The Perioperative Surgical Home Model. ASA Newsletter. 2013(77):58-9. 11. Vetter TR, Goeddel LA, Boudreaux AM, Hunt TR, Jones KA, Pittet JF. The Perioperative Surgical Home: how can it make the case so everyone wins? BMC Anesthesiol. 2013;13:6. 12. Barnett AG, Page K, Campbell M, Martin E, Rashleigh-Rolls R, Halton K et al. The increased risks of death and extra lengths of hospital and ICU stay from hospital-acquired bloodstream infections: a case-control study. BMJ Open. 2013;3(10):e003587. 13. Grocott MP, Pearse RM. Perioperative medicine: the future of anaesthesia? Br J Anaesth. 2012;108:723-6. 14. Eichhorn JH, Grider JS. Scope of Practice. In: Barash PG (ed.). Clinical Anaesthesia. Philadelphia: Lippincott Williams & Wilkins, 2013. 15. Holt NF. Trends in healthcare and the role of the anesthesiologist in the perioperative surgical home – the US perspective. Curr Opin Anaesthesiol. 2014;27:371-6. 16. Kehlet H, Mythen M. Why is the surgical high-risk patient still at risk? Br J Anaesth. 2011;106(3):289-91. 17. Bartels K, Barbeito A, Mackensen GB. The anesthesia team of the future. Curr Opin Anaesthesiol. 2011;24:687-92. 18. Mannion D, O’Sullivan E, Foy F, Golden M, Golden B, Smith J et al. Providing Quality, Safe and Comprehensive Anaesthesia Services in Ireland – A review of Manpower Challenges. Ireland: College of Anaesthetists of Ireland, 2014.

Volume 9: Number 1. 2016 | Page 99

RCSIsmjperspective THE BLUNT TRUTH:

can marijuana fund better healthcare? HUGH McGOWAN looks at the financial and ethical implications of legalisation of marijuana. Introduction

clinically.8 In Ireland, MS advocacy groups successfully campaigned for a

Marijuana, also known as cannabis, consists of dried leaves, stalks,

change in the Misuse of Drugs Act 1977 to allow cannabis-based drugs

∆9-Tetrahydrocannabinol (THC) and cannabidiol are the primary active

to be made available by prescription.9,10 Using cannabinoids as

flowers and seeds of the Cannabis sativa plant.

neuroprotective agents has shown potential in vivo and in vitro for

components in cannabis and are thought to act on cannabinoid

epilepsy, and may be effective in treating neurodegenerative diseases,

receptor sites CB1 and CB2 to produce psychoactive effects on mood,

including Huntington’s, Parkinson’s, and Alzheimer’s diseases.4,11,12 Use of

perception and psychomotor performance. Cannabis plants contain

cannabidiol and other cannabinoids that act as CB2 receptor agonists

over 60 cannabinoids, which act additively, synergistically, or

could inhibit the inflammatory processes involved in neurodegenerative

antagonistically with THC and cannabidiol, modifying the drug’s

diseases.13 In Alzheimer’s disease, there is evidence that cannabidiol

effects.1,2 To determine whether legalising marijuana could provide

prevents degenerative pathways that lead to neuronal death; however,

adequate funding for addiction services, this paper discusses available

these patients may be concerned by the prospect of cognitive decline as

literature pertaining to the financial benefits, health implications and

seen in MS trials.6,7,14

societal impact that legalisation has, paying particular attention to

The use of cannabinoids as anti-proliferative and apoptogenic agents

Colorado, USA, where the effects of legalisation can be observed and

has shown promise against a variety of tumour types. There is some

used to estimate the effect it would have in Ireland.

evidence that cannabinoids can specifically target tumour cells, making them exceptionally desirable for use as anti-cancer agents.

Medical uses

Palliative uses of cannabinoids in cancer and other life-altering

Claims exist that cannabis can effectively treat numerous diseases; some

conditions increases the profile of cannabis-based drugs as potential

of the potential uses include treatment of muscle spasticity in multiple

therapeutic agents.15 Studies investigating the use of marijuana to

sclerosis (MS), as a neuroprotective agent against neurodegenerative

treat pain are subject to intense scrutiny.16,17 Some conclude that there

diseases, in the treatment of chronic pain, in the treatment of cancer,

is little or no benefit in using cannabis over conventional pain

3-12

and in a palliative setting.

The illicit uses of marijuana are thus not the

medication and that the psychological side effects are unacceptable;18

only considerations when looking at the issue of legalisation.

however, cannabinoids have the potential to act synergistically with

Reducing spasticity in MS sufferers with cannabis has had positive results

opiates and benzodiazepines to allow for a reduction in doses, limiting

in placebo-controlled trials, but is accompanied by acute cognitive

the associated side effects of these drugs.4

effects as well as dizziness, nausea, headache and fatigue.3-5 Studies of

Although not a comprehensive list of the possible medical indications

patients with MS using cannabis also showed a decrease in cognitive

of marijuana-based medicines, the above examples illustrate the

6,7

performance compared to non-users.

In an attempt to circumvent side

effects and enhance therapeutic effects, oromucosal and oral

potential benefits that may exist. Further research is needed to isolate and fully develop selective molecules targeting the endogenous

preparations of THC and cannabidiol have been developed to treat

cannabinoid system to balance therapeutic effects with side

muscle spasticity in patients with MS, and have shown positive results

effects.4,11,12,18

Page 100 | Volume 9: Number 1. 2016

RCSIsmjperspective Impact of substance use

ascertain the far-reaching effects that some of these impairments

In Ireland, arguably the most important public health concerns are

could impose, it is certain that there would be direct demand on

associated with the use of alcohol and tobacco, both legally

the healthcare system as a result of increased prevalence of

available to the adult population. The cost of alcohol to Irish

psychosis in the population.

society is in excess of €3.5 billion per year, including €1.2 billion across a range of healthcare services. Alcohol is the most common substance for which addiction treatment is sought in Ireland.

Just

Current addiction treatment In Ireland, the three substances for which addiction treatment is

as with alcohol, driving under the influence of cannabis is

sought most are alcohol, marijuana and heroin. In 2011 cannabis

associated with a riskier driving style and increased reckless

overtook heroin as the second most sought addiction treatment.19

behaviour;20 therefore, legalisation of cannabis could easily result in

Treatment for alcohol addiction consists of multi-tiered

an increase in dangerous driving and road traffic accidents, with

intervention strategies, ranging from identification of the problem

an associated increase in hospital admissions. The use of tobacco

and providing advice to reduce harm, to provision of specialist

and marijuana are strongly linked in young people, with use of one

healthcare from multidisciplinary teams. Due to the complex

increasing the likelihood of use of the other.

21,22

nature of alcohol addiction, and high levels of comorbidity that

Smoking is a

major cause of morbidity, costing those who smoke an average of 10 quality years of life, and is responsible for one in 10 deaths.

accompany it, treatment costs escalate as severity increases. However, there is evidence that alcohol addiction treatment results

The average treatment cost in Ireland for a smoking-related illness

in savings to the healthcare system of five times the amount that is

is €7,700, with an estimated health expenditure on

initially invested.31 Quitting marijuana without formal treatment is

smoking-related illness of €500 million in 2009.24 Studies show

associated with increased use of alcohol and tobacco, but not with

that young adults perceive quitting smoking tobacco preferable to

uptake of new substance use.32 Simple interventions such as

quitting marijuana, and that the desire to quit one does not

motivating users to quit by highlighting usage-related problems

correlate to the desire to quit the other.

21,22

The likelihood of

has been shown to significantly increase the chances of a

smoking tobacco is increased if one’s mother smoked while

permanent change in behaviour in a study of young women aged

pregnant, and there have been suggestions of increased

18 to 24, particularly where there have been previous attempts to

probability of marijuana use due to enhanced receptor expression in the foetus, which contributes to addiction in later life.

The

quit.33 It is reasonable to assume that such interventions would produce similar effects in males. The potential for this form of

propensity for users to continue using cannabis, and for this use to

intervention to have low associated costs, and for it to be available

increase the likelihood of future generations using cannabis, is a

from frontline services such as GPs and addiction helplines, has

cause for concern, as it could potentiate a rise in consumption

considerable appeal.

levels over time. Studies show that of those who experiment with marijuana, 9% become addicted, increasing to almost 17% if

Potential revenue

marijuana use begins in the teen years, and up to 50% if it is

Financially, there is the potential benefit of tax revenue from the

smoked daily.

legalisation of marijuana. In 2012, cannabis herb, plants, and resin

Quitting is made more difficult due to the low cost and high

received by the forensic science laboratory in Ireland for testing

availability of the drug, even though withdrawal is less severe than

was valued at €71.8 million, accounting for over 60% of the value

with other drugs.

26-28

A survey of young people aged 15 to 24 in

of controlled drugs reported by the laboratory.34 Annual costs for

Europe discovered that 42% of Irish participants had used

tackling drug crime in Ireland are approximately €30 million, only

cannabis, with an EU average of 31%. Some 72% of Irish

a fraction of this being spent on marijuana.35 In the 2014 tax year,

participants considered it easy to obtain cannabis, and 25%

the state of Colorado generated $34.8 million USD through

believed that regular cannabis use posed no health risks.29

application of sales taxes and licensing fees for medical and retail

Marijuana use has been shown to influence the academic

marijuana.36 In 2011 Ireland had a population of 4.5 million

achievement of users and is linked to impaired cognition, memory,

people; similarly, in 2010 Colorado had an estimated population of

and problem solving, lower levels of life satisfaction, lower IQ (with

five million. The comparable demographics in terms of population,

frequent adolescent use), and increased risk of chronic psychosis

age and gender profiles mean that it could be possible to generate

where predisposition exists.6,26,27,30 Although it is difficult to

similar revenue in Ireland.37-39 Volume 9: Number 1. 2016 | Page 101

RCSIsmjperspective Results of legalisation

Conclusion

Direct observation of the effects of legalising marijuana is an invaluable

Legalising marijuana to pay for addiction treatment is a stopgap

tool in determining whether it is advisable to legalise marijuana in other

measure. Development of cannabis-based drugs that minimise

areas. Since the legalisation of marijuana in Colorado, the perception of

psychological impairment and psychoactive properties has considerable

risk associated with the use of marijuana has decreased compared to

appeal, and creating avenues for research and regulation is preferable

states where medical marijuana is not available. The changing

to legalisation permitting herbal preparations of unknown

attitudes towards risk are seen in the increase in levels of risky use,

concentration. Legalising marijuana for recreational use introduces an

particularly among males. Availability of the drug legally has increased

addictive and intoxicating product, which impairs cognitive function,

the odds of use to 1.92 times the usage seen in prohibition states.

to the general public. Significant costs are already incurred by society

Before legalisation of marijuana in Colorado, the number of fatal car

due to the use of alcohol and tobacco, and as such the introduction of

crashes where the driver tested positive for marijuana was decreasing,

a new addictive agent makes little sense. Factoring in the rising

but it began to increase after legalisation. No equivalent increase was

requests for cannabis addiction treatment, which is already the second

seen in prohibition states.41-43 In Colorado the use of marijuana increased

most requested addiction treatment in Ireland, arguments for

after commercial legalisation; however, introduction of medical

legalisation are significantly undermined, with the prospect of

marijuana resulted in no significantly increased use due to limited

commercial availability threatening to further exacerbate the problem.

patient numbers qualifying for prescriptions. The usage by adolescents

Although the revenue that would be generated is potentially

was also seen to decrease where medical marijuana was available,

significant, a fine balance would be required to prevent the associated

possibly due to an association with the chronically and terminally ill.42,44

health and safety concerns, rendering any income generated obsolete.

References 1. Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry. 2001;178:101-6. 2. Broyd SJ, Greenwood L, Croft RJ, Dalecki A, Todd J, Michie PT et al.

9. Department of Health. Minister White signs New Regulations to provide for cannabis-based medicinal products. [Internet] [Accessed 2015 January 12]. Available from:

Chronic effects of cannabis on sensory gating. Int J Psychophysiol.

http://health.gov.ie/blog/press-release/minister-white-signs-new-r

2013;89(3):381-9.

egulations-to-provide-for-cannabis-based-medicinal-products/

3. Wingerchuk D. Cannabis for medical purposes: cultivating science, weeding out the fiction. Lancet. 2004;364(9431):315-6. 4. Baker D, Pryce G, Giovannoni G, Thompson AJ. The therapeutic potential of cannabis. Lancet Neurol. 2003;2(5):291-8. 5. Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TM, Bentley H et al. Smoked cannabis for spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ. 2012;184(10):1143-50. 6. Brook JS, Stimmel MA, Zhang C, Brook DW. The association between

10. Dáil Éireann. Misuse of Drugs Act 1977. Dáil Éireann. Report number: No. 12 of 1977, 1977. 11. Sirven JI. Editorial: Medical marijuana for epilepsy: Winds of change. Epilepsy Behav. 2013;29(3):435-6. 12. Hofmann ME, Frazier CJ. Marijuana, endocannabinoids, and epilepsy: Potential and challenges for improved therapeutic intervention. Exp Neurol. 2013;244:43-50. 13. Rom S, Persidsky Y. Cannabinoid receptor 2: potential role in

earlier marijuana use and subsequent academic achievement and health

immunomodulation and neuroinflammation. J Neuroimmune

problems: a longitudinal study. Am J Addict. 2008;17(2):155-60.

Pharmacol. 2013;8(3):608-20.

7. Honarmand K, Tierney MC, O’Connor P, Feinstein A. Effects of

14. Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo

cannabis on cognitive function in patients with multiple sclerosis.

AA. Neuroprotective effect of cannabidiol, a non-psychoactive

Neurology. 2011;76(13):1153-60.

component from Cannabis sativa, on b-amyloid-induced toxicity

8. Notcutt W, Langford R, Davies P, Ratcliffe S, Potts R. A placebo-controlled, parallel-group, randomized withdrawal study of subjects with symptoms of spasticity due to multiple sclerosis who are receiving long-term Sativex® (nabiximols). Mult Scler. 2012;18(2):219-28.

Page 102 | Volume 9: Number 1. 2016

in PC12 cells. J Neurochem. 2004;89(1):134-41. 15. Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther. 2015;97(6):575-86. 16. Bostwick JM, Reisfield GM, DuPont RL. Clinical decisions: medicinal use of marijuana. N Engl J Med. 2013;368(9):866-8.

RCSIsmjperspective 17. Stacey BR, Moller JL. Letters to the Editor: Marijuana for pain relief: don’t jump to conclusions. J Pain. 2013;14(10):1250-1. 18. Campbell FA, Tramer MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ. 2001;323(7303):13-6. 19. Condron I. Substance misuse in the eastern counties of HSE South. Drugnet. 2012;(45):13. 20. Bergeron J, Paquette M. Relationships between frequency of driving under the influence of cannabis, self-reported reckless driving and risk-taking behavior observed in a driving simulator. J Safety Res. 2014;49:19-24. 21. Ramo DE, Liu H, Prochaska JJ. Tobacco and marijuana use among adolescents and young adults: a systematic review of their co-use. Clin Psychol Rev. 2012;32(2):105-21. 22. Ramo DE, Delucchi KL, Liu H, Hall SM, Prochaska JJ. Young adults who smoke cigarettes and marijuana: analysis of thoughts and behaviors. Addict Behav. 2014;39(1):77-84.

32. Copersino ML, Boyd SJ, Tashkin DP, Heustis MA, Heishman SJ, Dermand JC et al. Quitting among non-treatment-seeking marijuana users: reasons and changes in other substance use. Am J Addict. 2006;15(4):297-302. 33. Caviness CM, Hagerty CE, Anderson BJ, de Dios MA, Hayaki J, Herman D et al. Self-efficacy and motivation to quit marijuana use among young women. Am J Addict. 2013;22(4):373-80. 34. An Garda Síochána. Annual Report 2012. An Garda Síochána. Report number: 1, 2012. 35. Ahern D. Dáil Eireann Debate. [Internet] [Accessed 2015 January 12] Available from: http://debates.oireachtas.ie/dail/2009/02/10/00204.asp. 36. Brohl BJ et al. Annual Report. Colorado department of revenue. 2014. 37. U.S. Census Bureau. Colorado. [Internet] [Accessed 2015 January 12] Available from: http://quickfacts.census.gov/qfd/states/08000.html. 38. Schuermeyer J, Salomonsen-Sautel S, Price RK, Balan S,

23. Brugha R, Tully N, Dicker P, Shelley E, Ward M, McGee H. SLÁN

Thurstone C, Min SJ et al. Temporal trends in marijuana

2007: Survey of Lifestyle, Attitudes and Nutrition in Ireland.

attitudes, availability and use in Colorado compared to

Smoking Patterns in Ireland: Implications for policy and

non-medical marijuana states: 2003-11. Drug Alcohol Depend.

services. Department of Health and Children, 2009. 24. Holohan T, Devlin J, Keegan J, McEvoy S, O’Brien D, Howell F et al. Tobacco Free Ireland: Report of the Tobacco Policy Review Group. Department of Health, 2013. 25. Porath AJ, Fried PA. Effects of prenatal cigarette and marijuana exposure on drug use among offspring. Neurotoxicol Teratol. 2005;27(2):267-77. 26. Budney AJ, Roffman R, Stephens RS, Walker D. Marijuana

2014;140:145-55. 39. Central Statistics Office. This is Ireland: Highlights from Census 2011, Part 1. Central Statistics Office, 2012. 40. Richmond MK, Page K, Rivera LS, Reimann B, Fischer L. Trends in detection rates of risky marijuana use in Colorado health care settings. Subst Abuse. 2013;34(3):248-55. 41. Cerdá M, Wall M, Keyes KM, Galea S, Hasin D. Medical marijuana laws in 50 states: investigating the relationship

dependence and its treatment. Addict Sci Clin Pract.

between state legalisation of medical marijuana and marijuana

2007;4(1):4-16.

use, abuse and dependence. Drug Alcohol Depend.

27. Volkow ND, Baler RD, Compton WM, Weiss SRB. Adverse health effects of marijuana use. N Engl J Med. 2014;370(23):2219-27. 28. Farrell M, Buchbinder R, Hall W. Should doctors prescribe cannabinoids? BMJ. 2014;348:g2737. 29. The European Commission. Young People and Drugs. The European Commission. Report number: 401, 2014. 30. Brook JS, Stimmel MA, Zhang C, Brook DW. Antisocial behavior at age 37: developmental trajectories of marijuana use extending from adolescence to adulthood. American J Addict. 2011;20(6):509-15. 31. Heather N, Raistrick D, Godfrey C. Review of the effectiveness

2012;120(1-3):22-7. 42. Salomonsen-Sautel S, Min SJ, Sakai JT, Thurnstone C, Hopfer C. Trends in fatal motor vehicle crashes before and after marijuana commercialisation in Colorado. Drug Alcohol Depend. 2014;140:137-44. 43. Gorman DM, Charles Huber J Jr. Do medical cannabis laws encourage cannabis use? Int J Drug Policy. 2007;18(3):160-7. 44. Choo EK, Benz M, Zaller N, Warren O, Rising KL, McConnell KJ. The impact of state medical marijuana legislation on adolescent marijuana use. J Adolesc Health. 2014;55(2):160-6.

of treatment for alcohol problems. National Treatment Agency & Department of Health: UK, 2006.

Volume 9: Number 1. 2016 | Page 103

RCSIsmjinterview

Committed to sport DANIEL O’REILLY interviews Dr Michael Webb, Medical Director of Ulster Rugby. Dedicated to the team

Dr Michael Webb is the Medical Director of Ulster Rugby and an assistant team doctor to the Ireland senior rugby team. He is the current Chairman of the Pro12 Doctors Group and has worked extensively as a team doctor within rugby for both the Ulster and Ireland teams at all levels since 2000. He is also a part-time general practitioner in Newtownards, Co. Down. How did you get involved in sports medicine in the first place?

picture, such as exercise in people with chronic conditions such as diabetes, asthma, or cardiovascular disease, is essential.

I suppose sport has always been a passionate interest; it’s something I have always wanted to work in. I studied in Trinity and at the time our anatomy professor, Moira O’Brien, was one of the pioneers of sports medicine in Ireland. At that stage there was no real run-through sports medicine training so her advice to me was to choose something else – be that orthopaedics, emergency medicine or general practice – and to do sports medicine on top of that. So that’s what I did: general practice training, and then parallel to that I did my sports medicine training in Bath University. After I stopped playing rugby I started helping my local club, then the Ulster U21s, then the Ireland U18s. Things have kind of just snowballed as the years have gone on. I suppose I now have what would be called a portfolio career; I still do some general practice, but sports medicine has become an ever-increasing part of my job.

Yes, health promotion, but also for someone who has a chronic medical condition: what are they able to do? How do they fulfill their potential? Similarly then, in terms of exercise for the nation: how do we advise on that? Just simple things like the fact that girls reach peak bone mass by age 13/14 and that is done through skeletal loading, so should we have primary school children bouncing up and down on their feet for five minutes every morning? Simple little interventions like that. ... It essentially covers all of medicine. Then you have team medicine, which covers everything as well, so even within sports medicine there are loads of specialist areas, which is an attraction.

So you played rugby until you were finished with your GP training?

What do you think about the issues surrounding concussion?

Yeah, I trained in England and then came back to Northern Ireland and was doing locum GP work for a couple of years, and at that stage, well, the rugby packed me in as much as I did it. It became too difficult managing the demands of the job, training and most of all the pain post games!

It’s changed unbelievably quickly. I would have had a keen interest dating back to 2007/2008 but a lot of that was watching what was happening in the States – they are probably three or four years ahead of us in what they’ve experienced with regard to concussion. In many ways the explosion in interest has been a really good thing because the media interest has driven the public interest in it. We have been able to do a huge amount of work trying to educate people and I think it’s now on people’s radar and they are willing and interested to learn more about it. When we started our education initiatives back in 2009, really very few people came along to anything we tried to do while now, regularly, we’ll have one hundred plus people at our workshops, so that’s been great! The evidence would say that we’ve become very much better at ‘recognise and remove’, and our threshold for diagnosis has dropped significantly. Players are now reporting symptoms earlier because they realise how important it is that they report any symptoms they are experiencing – even seemingly trivial or short-lasting ones. Also, coaches, parents and teachers are becoming more vigilant, looking out for signs of concussion and picking these up, so we’re becoming good at that. And I think we

What makes sports medicine different from other fields you might also have an interest in, such as general practice? It’s a relatively new discipline. I think we are still finding our feet a bit on how we position ourselves. What’s happened in the UK is that a lot of what developed as sports medicine is now repositioning itself as ‘exercise medicine’, because I think that’s where we will have the population benefit. The benefits of exercise are so well documented, and similarly, lack of physical fitness is associated with so much morbidity, that that is where the big ‘wins’ are to be had. The difficulty is influencing those in decision-making positions because it probably seems less pressing than a lot of other health priorities. I think that to have a cohort of well-qualified doctors there to advise not just on sports injuries and musculoskeletal medicine, but also on the wider Page 104 | Volume 9: Number 1. 2016

So you think it’s moving in a health promotion kind of direction?

RCSIsmjinterview have also gotten really good at keeping people out for the requisite period of time. Actually, one of the issues we’ve come across now is the medical clearance to go back to sport, and as a medical community we are lagging behind a little bit. One big concern is that concussion doesn’t become such a divisive topic that children or their parents get put off participation in sport. Because the benefits of contact sport so far outweigh any potential risks. It would be very sad if people were turned away from sport because of a perceived risk of long-term problems that in real terms is relatively low. And certainly the risk now would seem to be lower than it was five years ago because the condition is likely to be managed so much better now than it was even then.

Do you think it will change how contact sports are played? We are already seeing a change in how these sports are played. It’s interesting – Brian McLaughlin (Ulster Head coach 2009-2012) took a session in my local club this year with U12s/U14s and he was talking about how guys came to the ruck, and he was talking about injury prevention. He was saying: “You lead with your shoulder and your hip and keep your head well out of the way”, so that was really fascinating for me to see. Coaches are already taking it on board. That is one big positive thing. I also think there is an onus on the lawmakers of sports to remain aware of trends and keep on top of that, and implement good evidence-based rule changes. I am sure that all sport will continue to evolve with regard to safety. In fairness, sports realise that for the PR side of each individual sport, player welfare is key. ... I know certainly within world rugby, every meeting they have, player welfare is the first thing on their agenda. And that is being driven not only by concussion but also by the desire to make the overall game as safe as possible.

Do you think rugby is at risk of diminishing popularity? Rugby is still a contact sport, and that’s why a lot of people like watching it. It’s also why a lot of people like playing it as well. I don’t think you need to disbar contact completely but there is no point in having any needless risk. I think how you prepare for games is important, certainly how you train. I don’t think there is any point doing hours and hours of pointless contact training – straight away you can drop your exposure to risk of injury way down there. There are lots of interventions you can introduce that, when put together, can make a big difference.

Do you think strength and conditioning has changed the nature of injuries? Statistics would actually show that serious injuries in rugby haven’t gone up, which almost belies the public perception. I think over the past 10-15 years we have become better at managing injuries, and perhaps if we hadn’t done that then maybe the injuries incidence would have risen a bit. There’s no doubt that players have become bigger and faster, but that’s probably maxed out now. The World Cup has taught us a lesson

– if you look at New Zealand, they have taken the view that they are looking to be a little bit more mobile and lose a bit of the excess weight. For me, that’s really exciting and that’s the way rugby should go.

With the doping scandal in the IAAF, do you think that’s changing the way you do your job as someone who is involved in sports medicine? Do you think it is going to be more of an issue? It’s a big part of our job. My biggest fear with our professional players isn’t deliberate doping, it’s guys making an inadvertent mistake over something or another – taking a supplement, or taking a cough or cold remedy with pseudoephedrine in it. That’s a bigger concern. I think within rugby in Ireland there is no evidence of any sort of systemic doping. However, you’d need to be naïve to say there’s no risk. We know that within the general population there is quite a prevalent use of anabolic agents for aesthetic purposes. These are not professional athletes. Clearly if there is a lot of this in local gyms, the fear would be that 16-, 17- or 18-year-old kids, who want to be bigger to be a bit better at rugby, could make poor life choices and be tempted to take anabolic or other banned agents. It’s so important that this cohort are well educated about all the potential risks of getting involved in this, so that they understand why it would be a huge mistake to do so.

What do you think is coming down the line as far as sports medicine as a career is concerned? I think a lot of it is probably hampered by health economics and the problem is that, for example here in Northern Ireland, the health budget is going up every year but it’s not keeping pace with inflation and currently the NHS is really struggling. It’s hard to position yourself against cancer services or children’s heart services, and there is an endless list of very deserving medical causes, who are all fighting for the same piece of the pie. There is a problem there for sports medicine to develop in any big way. I think hopefully it can continue to steadily evolve. We need policy makers who have the vision to see the benefits of prevention that will come with a fitter population.

And are you involved in any research yourself at the moment? We have a schools injury audit running up here where we are following all our senior rugby-playing schools. This is the second year of the study. The research group encompasses some orthopaedic surgeons and sports medicine doctors in Belfast and researchers from the University of Ulster. Ulster Rugby and the IRFU are part funding it along with support from the MITRE charity. It’s an injury audit of schoolboy rugby players – and again, we talked about it earlier – and the aim is to establish the injury patterns within the game so that we can use good, objective evidence to inform lawmakers who want to make the game as safe as possible. It’s one of the biggest studies of its kind that’s ever been done in the world and already we’ve gleaned some really interesting information, which is very exciting. Volume 9: Number 1. 2016 | Page 105

RCSIsmjtravel brief

Nepal: a country shaken LUKE GIN volunteered in Nepal in the aftermath of 2015â&#x20AC;&#x2122;s devastating earthquake.

In April of 2015 an earthquake struck the small mountainous country of Nepal, killing over 9,000 people. The government was going through a political upheaval and the $4.1 billion USD earthquake reconstruction fund sat in the bank, while thousands of families faced the winter with nothing more than a sheet of plastic for shelter.1 Although the Nepali people are resilient and resourceful, the situation was bleak for many. Nepal was my home for 12 years while my dad worked as a missionary doctor in a rural hospital. In May, I had the opportunity to go back for two weeks with my dad and brother to lend a hand in the rebuilding process.

a truck and head off, arriving after several hours on dirt roads. The destruction was widespread and devastating, and although the newer brick and cement houses had survived, almost all of the mud and stone houses had collapsed. Distributing the supplies took all day, but everyone in need got enough to build a temporary house. The next morning a man asked for help to build a home that would survive the monsoon and the winter. Until then, his wife and 12-year-old daughter had been sleeping under a tarp. It took us two days to put up his bamboo house, which will last several years until they can rebuild their own house.

Rebuilding When we arrived in Kathmandu, we met with friends who work for an NGO, Human Development Community Services (HDCS), which my dad used to work with. HDCS had been working on earthquake relief for several weeks, so they were able to offer insight into the current situation. Later that morning, we headed off toward Besi Sahar, a town eight hours from Kathmandu, close to the epicentre of the quake. When we got there we met with the HDCS hospital administrator and the mayor of the district. They advised us to go to a village close to the epicentre, where 30 houses had been completely destroyed. Two weeks after the earthquake, there was not a large need for medical aid or food; the main issue was shelter. The earthquake destroyed over half a million homes.2 Families slept under tarps, in chicken coops or anywhere that provided shelter from the elements and fast-approaching monsoons. My former high school track and field team had raised some money for earthquake relief, with which we bought roofing tin and building supplies for all 30 houses in the village. This all took several days, but soon we were able to load up

Reflection

Page 106 | Volume 9: Number 1. 2016

Being able to give back in a small way to the place that helped to shape who I am today was an amazing opportunity. It reminded me why I want to be a doctor, and of the great needs of many around the world.

Reference 1. No relief for Nepal quake victims as relief fund in limbo. [Internet] [Updated 2015 September 25; cited 2015 October]. Available from: http://www.channelnewsasia.com/news/asiapacific/no-relief-fornepal-quake/2149890.html. 2. Bruton B. Nepal Earthquakes: Survivors Face Years of Anxiety, Depression. [Internet] [Updated 2015 May 14; cited 2015 October 30]. Available from: http://www.nbcnews.com/storyline/nepal-earthquake/nepal-men tal-health-n357866.

RCSIsmjtravel brief

Fostering hope AMENAH DHANOON travelled to Turkey to volunteer with Syrian refugees. Turkey is one of the biggest hosts for Syrian refugees, with 1.9 million people seeking refuge there in 2015.1 This became very apparent to me in August 2015 when I was on holiday there. I contacted a humanitarian NGO that is very active in aiding Syrian refugees, the International Blue Crescent (IBC) Relief and Development Foundation. I was assigned to a city called Gaziantep, where many child-friendly spaces (CFS), and primary and secondary schools, have been opened for Syrian refugees. Together with its German partner Malteser International, IBC is running a temporary field hospital (TFH) in Kilis, a town 3km away from the warzone in Syria. Growing up in Gaziantep I accompanied a Syrian psychologist to a CFS in Gaziantep. This particular programme ran a morning and afternoon shift five days a week, with approximately 40 children in each, divided based on age. Learning exercises with a focus on psychosocial support were organised to educate these children, whose education had been interrupted by the devastating civil war. Group activities and games focused on expressing emotions, making new friends, building self-confidence, and showing artistic skills and other talents. The teachers attempted to convert the fear and anxiety these children were experiencing into hope for the future. Although interacting with children was a tremendous experience, it was also an emotionally challenging one.

relatives. The determination and faith of patients, particularly in the physiotherapy room, was truly admirable and eye opening. Patients were surprisingly open to sharing their stories. One woman had been injured by barrel bombs dropped by air forces. She lost one of her three daughters when her house collapsed, but was miraculously able to deliver her fourth baby at the TFH despite injuries to both her legs. The TFH provided her with much-needed medical and psychosocial support in the form of daily consultations and stress-relieving exercises. Another story that was particularly touching was that of a 10-year-old boy who had lost his arm in the war. This extremely smart and sociable young boy was attending school to learn to write with his left hand in order to fulfil his dream of becoming a doctor, but expressed a desire for a prosthetic arm to be able to play with his siblings again. Reflection Apart from getting a closer view of the hardship associated with such crises, and an opportunity to help where possible, this was also a valuable learning experience, as I had the chance to practise in my mother tongue of Arabic, improve my communication skills, and be supervised in performing some basic medical procedures. This experience also opened my mind to Turkish culture and the generosity of Turkish people and, importantly, emphasised the role medical professionals play in such trying conditions.

Reference Crisis in Kilis Initially, I took a public minibus from Gaziantep to Kilis, but due to the proximity to the Syrian border the IBC arranged for a car to drive me to the hospital. The TFH, with a capacity to accommodate 48 inpatients, receives conflict-affected patients for postoperative care. Intensive physiotherapeutic care of war-injured patients is provided, in addition to psychosocial support for patients and

1. Amnesty International. Syriaâ&#x20AC;&#x2122;s refugee crisis in numbers [Internet] [updated 2015 September 4; cited 2015 December 28]. Available from: https://www.amnesty.org/en/latest/news/2015/09/syrias-refugee -crisis-in-numbers/.

Volume 9: Number 1. 2016 | Page 107

RCSIsmjtravel brief

The mass approach DANIELLE WUEBBOLT spent some time in Shanghai seeing how medical teams there managed breast cancer care. When I first considered travelling to Shanghai, with its population of 14.35 million people,1 I wondered how the medical system coped with the massive population. Given that breast cancer is one of the world’s top ten causes of death for women and, together with cardiovascular and cerebrovascular disease, contributed to 70% of all female Chinese fatalities in 2010, I decided to observe breast cancer patient care.2,3 I was placed in the Comprehensive Breast Health Center at the Ruijin Hospital in Shanghai, where I had the opportunity to shadow the chief resident of breast cancer surgery team one.

Multidisciplinary team meetings Each morning began with patient rounds, followed by multidisciplinary team meetings, where – to maximise efficiency and deal with time constraints – each physician used a tablet to cast a vote for the next treatment for the specific patient case. Treatments receiving the highest number of votes were employed.

Operating theatre The Ruijin Hospital has an entire floor of operating theatres dedicated to breast-related surgery, ranging from mastectomies to central line insertions and breast reconstructions using silicone implants. Surgeons performed up to five to six procedures per day and discharged patients back to the ward, where medical students (including myself) performed dressing changes and monitored for postoperative infections or drainage tube complications. Typically, patients remained for up to three days before being discharged home.

Outpatient clinic The chief resident and I worked in a small room with connections to other rooms, facilitating communication with other physicians. Patients returning for bandage changes saw a nurse or medical Page 108 | Volume 9: Number 1. 2016

student, then had a consultation with the physician. As the patients came into the room, they handed the physician their medical and payment card before quickly explaining their medical concern. Breast examinations were completed while the patient was standing and lifting their shirt, not lying down. The entire hospital visit often lasted less than five minutes.

Reflection Seeing how the Shanghai physicians efficiently handled an overwhelming number of patients (and their families) was an incredible experience. During a consult, other patients or family members often waited just outside, or even entered the room and bombarded the physician with questions and concerns. I was not accustomed to this sort of interaction, but the chief resident was extremely patient with the women and often handled multiple appointments at the same time. Additionally, the physicians and students all spoke English and were eager to teach and answer any questions, demonstrating an abundance of grace, patience and understanding, which I wish to emulate in the future.

Reference 1. UN Data. Statistics. [Internet] [Accessed 2015 October] Available from: http://data.un.org/Data.aspx?d=POP&f=tableCode%3A240. 2. Women’s Health fact sheet N334 [Internet]. World Health Organization: Media Center; 2013 Sept [cited 2015 Oct 22]. Available from: http://www.who.int/mediacentre/factsheets/fs334/en/. 3. Li Y, Wang L, Jiang Y, Zhang M, Wang L. Risk factors for noncommunicable chronic diseases in women in China: surveillance efforts. Bull World Health Organ. 2013;91:650-60.

RCSIsmj book reviews A tale of two theatres DANIEL O’REILLY looks at two very different takes on a neurosurgical career.

Do No Harm: Stories of Life, Death and Brain Surgery Henry Marsh Paperback: 304 pages Publisher: Weidenfeld & Nicolson Published: 2014 ISBN-13 978-1780 225920 Neurosurgery is often seen as an impossibly technical and emotionally distant specialty. Two surgical memoirs produced on either side of the Atlantic give an insight into the challenges and rewards of a neurosurgical career. Do No Harm: Stories of Life, Death and Brain Surgery by British neurosurgeon Henry Marsh describes his meandering career in hindsight as he prepares to retire. When the Air Hits Your Brain: Tales from Neurosurgery by Frank Vertosick Jr is an autobiographical take on becoming an American neurosurgeon, from his time as a medical student through to the end of his residency. While both books address the same central theme, their tone and approach could not be more different. Matter-of-fact In Do No Harm the style is matter-of-fact and anecdotal. Each chapter is named after a different neurosurgical condition, wherein Marsh outlines his own experience with managing the disease and weaves elements of his personal and professional life into his factual accounts of each case. These can be harrowing, hilarious or, more often, a mixture of both, as Marsh recounts struggles against disease, discusses bureaucracy in the NHS, and muses on a surgical life. As a narrator Marsh is painfully honest, sharing both his triumphs and his failures. In a notable exception to the condition-oriented titles of his chapters, ‘Hubris’ recounts an early experience with the consequences that can arise from major neurological surgery and shows how profoundly affected a doctor can be by a case gone wrong. Marsh’s journey into neurosurgery is certainly not typical, with a prior degree in politics, philosophy and economics, a short stint as a porter, and an early diversion into anaesthetics all featuring in his portfolio. This contributes to his likeability as a narrator, as he displays the myriad of experiences and how they brought him to the profession he finally entered. The trainee’s perspective When the Air Hits Your Brain is from the beginning more jovial in tone. Written from the perspective of Vertosick as a trainee, it betrays the naivety and immaturity of his early coping mechanisms with difficult

When the Air Hits Your Brain: Tales from Neurosurgery Frank Vertosick Jr Paperback: 272 pages Publisher: W. W. Norton & Company Published: 2008 ISBN-13 978-0393 330496 cases. Vertosick writes with a distinctly American voice, outgoing and with an ascerbic wit, describing his younger self as confident to the point of arrogance. His description of medical students as falling into three categories – “Slackers, Keeners and Wild Cards” – may strike close to home for many a student in our own College, while his rules of neurosurgery may compete with the famous rules of Samuel Shem’s ‘House of God’ as the finest medical guidelines committed to print. His own pursuit of what he views as perfection, “the surgical psychopath”, is described in detail, and his description of his reaction to an unsuccessful aneurysm surgery performed by one of his senior colleagues may make even the most hardened, cynical student cringe. However, as the book develops, his professional goals are altered by a number of cases. When one finally emerges from the book it is with a sense of how Vertosick developed as both a surgeon and a person through his training. Something to offer all readers So why compare these two memoirs? Beyond the profession of the men writing them, do these books have anything in common? I have already underlined the differences in tone and perspective that make both books intriguing reads in very different ways. Ultimately, both books stress the importance of compassion in the pursuit of a medical career. Both describe the self-doubt that can emerge from managing difficult cases, the consequences of one’s actions as a medical professional, and working in a high-stress environment. In spite of both narrators’ chosen niche, there are lessons in these books for readers in both medical and non-medical careers, and both are engaging from front to back. When the Air Hits Your Brain is rightly regarded as a medical classic, while Do No Harm has featured on scores of non-fiction writing awards lists. As a final note, one other reasonably famous neurosurgeon, Harvey Cushing, remarked: “I would like to see the day when somebody would be appointed surgeon somewhere who had no hands, for the operative part is the least of the work”.1 Upon finishing both these books, the reader comes away with the impression that there is a great deal more to surgery than performing procedures, and that almost eight decades on from Cushing’s death, his thoughts are as true as ever.

References 1. Bliss M. Harvey Cushing: A Life in Surgery. Oxford University Press, 2007.

Volume 9: Number 1. 2016 | Page 109

RCSIsmjabstract Oestrogen receptor gene mutations in endocrine-resistant breast cancer Benjamin Lau RCSI medical student

Introduction

Results

Breast cancer is the most common form of cancer in females. The

All exons were amplified by PCR with the exception of exon 1,

majority of breast cancers express the oestrogen receptor; oestrogen

which did not yield a specific PCR product even after redesigning

exposure drives cell growth and division in the breast, and is therefore a

primers. Sequencing was successful except exon 4, which was not

major risk factor for tumour development. Tamoxifen, a selective

sequenced accurately. A heterozygous point mutation at

oestrogen receptor modulator (SERM), is effective in treating oestrogen

nucleotide 336 resulting in an alanine to guanine substitution at

receptor positive breast cancer due to its anti-oestrogen actions in

amino acid 112 was detected in exon 8, changing the codon

mammary tissue. However, metastatic disease may recur after the

from ACA to ACG. However, both codons encode the amino acid

tumour develops drug resistance.3 Mutations in the ligand binding

threonine, and therefore the mutation was non-functional.

domain of ESR1, the gene coding for the oestrogen receptor, have previously been found in metastatic breast tumours.4 This experiment

Conclusion

explored the possibly of resistance due to mutations in ESR1.

There was no functional mutation found in the ESR1 gene of the LY2 cells. Experimentation with alternate methods is needed to

Methods

produce a suitable PCR product for exon 1. Further investigation

Genomic DNA was extracted from tamoxifen-resistant LY2 cells and

into alternate mechanisms, such as cross-talk between the

cells of their parent cell line MCF7, which are tamoxifen sensitive, using

oestrogen receptor and other growth factor receptors or ligands, is

a DNeasy Blood & Tissue Kit (Qiagen; Manchester, UK). Specifically

needed to determine the cause of endocrine resistance in breast

designed primers were used to target each of the eight exons in the

cancer cells.3

ESR1 gene, which were amplified by polymerase chain reaction (PCR). Agarose gel electrophoresis was used to confirm that the PCR products

Acknowledgements

were the correct size. The PCR products were then purified using a

Many thanks to Prof. Leonie Young, Jean McBryan and everyone

MinElute PCR Purification Kit (Qiagen), quantified by a Nanodrop 2000

in the RCSI Endocrine Oncology Research Group at York House

Spectrophotometer (Thermo Fisher Scientific; Wilmington, USA) and

for their help and support in this experiment.

sent to GATC Biotech for sequencing. The results of sequencing were compared using the bioinformatics tool BLAST.5

FIGURE 1: Images of the MCF7 PCR products on electrophoresis gels. Columns on the left show a reference ladder with increments of 100 base pairs.

FIGURE 2: Images of the LY2 PCR products on electrophoresis gels. Columns on the left show a reference ladder with increments of 100 base pairs.

FIGURE 3: Comparison of MCF7 and LY2 sequences in exon 8 with the point mutation highlighted.

References 1. Anderson KN, Schwab RB, Martinez ME. Reproductive risk factors and breast cancer subtypes: a review of the literature. Breast Cancer Res Treat. 2014;144(1):1-10. 2. Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med. 1998;339(22):1609-18. 3. Wong C, Chen S. The development, application and limitations of breast cancer cell lines to study tamoxifen and aromatase

Page 110 | Volume 9: Number 1. 2016

inhibitor resistance. J Steroid Biochem Mol Biol. 2012;131:83-92. 4. Toy W, Shen Y, Won H, Green B, Sakr RA, Will M et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439-45. 5. Basic Local Alignment Search Tool. [Internet] [Accessed 2015 March 2] Available from: http://blast.ncbi.nlm.nih.gov/Blast.cgi.

Image by Catherine Tennant.

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